For decades, medical cancer treatment has generally meant chemotherapy, radiation, or surgery, alone or in combination. But things are changing rapidly. Today, new approaches such as immunotherapies and targeted therapies are becoming available, with many more in research and development. In many cases, the new treatments are more effective, with fewer side effects.

Its an exciting time to be in cancer research and cancer discovery, said Colin Duckett, PhD, professor of pathology, interim chair of the Department of Pharmacology and Cancer Biology, and vice dean for basic science."

Were moving into this era where we have a new set of tools we can use to treat cancer.-Colin Duckett, PhD

Researchers in the Duke Cancer Institute (DCI) and across the School of Medicine are helping to create these new tools, fueled by the knowledge and experience of experts from a wide range of disciplines.

Indeed, cancer research has always been a team-based endeavor at DCI.

DCI was specifically created a decade ago to break down barriers between disciplines to stimulate collaborative research and multidisciplinary interaction, said DCI Executive Director Michael Kastan, MD, PhD, the William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology.

Adding fuel to the fire is the Duke Science and Technology (DST) initiative, which aims to catalyze and support collaborative research in service of solving some of the worlds most pressing problems, including cancer.

The new tools, though varied, all represent advances in personalized cancer medicine. Targeted treatments are chosen based on the genetic signature of a patients tumor. Some immunotherapies take personalization even further, by manipulating a patients own immune cells to create a treatment for that individual alone.

To match treatments to patients, the multidisciplinary Duke Molecular Tumor Board, led by John Strickler, MD, HS11, and Matthew McKinney, MD06, HS06-09, HS10-13, helps providers identify best practices, newly approved treatments, or clinical trials for advanced cancer patients based on genetic sequencing of their tumors.

In precision cancer medicine the right therapy for the right patient at the right time all these things come together, the targeted therapies, the immunotherapy, even standard chemotherapy, all of that is part of precision cancer medicine.-Michael Kastan, MD, PhD

Immunotherapy aims to harness the power of the immune system to fight cancer. That can mean activating the immune system, energizing exhausted immune cells, or helping immune cells find cancer cells by guiding them there or by removing cancers good guy disguises.

Dukes Center for Cancer Immunotherapy supports these efforts by identifying promising basic science discoveries and building teams to translate those ideas into treatments.

"There are so many world-class basic research scientists here making discoveries..."-Scott Antonia, MD, PhD

...discoveries that are potentially translatable as immunotherapeutic strategies, said Scott Antonia, MD, PhD, professor of medicine and the centers founding director. Thats what motivated me to come to Duke, because of the great opportunity to interact with basic scientists to develop new immunotherapeutics and get them into the clinic.

Antonia believes immunotherapy has the potential to revolutionize cancer treatment, but more work remains to be done to realize its promise. The proof of principle is there, he said, but still only a relatively small fraction of people enjoy long-term survival. If we can hone immunotherapeutic approaches, thats our best opportunity.

Among the most exciting immunotherapy work being facilitated by the center involves removing a patients own T cells (a type of lymphocyte), manipulating them in the lab to make them more effective against tumors, then injecting them back into the patient.

T cells can be manipulated in the lab in a number of different ways. In one approach, called CAR T-cell therapy, the T cells are engineered with an addition of synthetic antibody fragments that bind to the patients tumor, effectively directing the T cells directly to the tumor cells.

In another approach, called tumor-infiltrating lymphocyte (TIL) adoptive cell therapy, the subset of a patients T cells that have already managed to find their way into the tumor are extracted and then grown to large numbers before being returned to the patient. Antonia and his colleagues recently published a paper demonstrating the effectiveness of TIL expansion in lung cancer. Were now doing the preparative work to develop clinical trials using this approach in brain tumors, and our intention is to expand into many other cancers as well, he said.

Antonia points out that innovations in CAR T-cell therapy and TIL therapy happening at Duke are possible because of collaborations with scientists in an array of disciplines, including antibody experts like Barton Haynes, MD, HS73-75, the Frederic M. Hanes Professor of Medicine, and Wilton Williams, PhD, associate professor of medicine and surgery, at the Duke Human Vaccine Institute, and biomedical engineers like Charles Gersbach, PhD, the John W. Strohbehn Distinguished Professor of Biomedical Engineering at the Pratt School of Engineering.

Furthermore, clinical trials for these kinds of cellular therapies require special facilities to engineer or expand the cells, which are provided by Dukes Marcus Center for Cellular Cures, led by Joanne Kurtzberg, MD, the Jerome S. Harris Distinguished Professor of Pediatrics, and Beth Shaz, MD, MBA, professor of pathology. Its been a very productive collaboration highlighting how Duke is uniquely positioned to develop immunotherapeutic strategies, Antonia said.

Targeted therapies exploit a tumors weak spot: a genetic mutation, for example. The benefit is that the treatment kills only cancer cells and not healthy cells. The prerequisite is knowing the genetics and biology of the specific tumor, no simple task.

Trudy Oliver, PhD05, who joined the Department of Pharmacology and Cancer Biology faculty as a Duke Science and Technology Scholar, studies cancer development and the biology of tumor subtypes, particularly squamous cell lung cancer and small cell lung cancer.

Even within small cell lung cancer, there are subsets that behave differently from each other, she said. Some of the treatments shes identified are in clinical trials

Our work suggests that when you tailor therapy to those subsets, you can make a difference in outcome.-Trudy Oliver, PhD'05

Some of the treatments shes identified are in clinical trials.

Sandeep Dave, MD, Wellcome Distinguished Professor of Medicine, is leading an ambitious project to analyze the genomics of the more than 100 different types of blood cancer. His project will streamline the diagnosis of blood cancer and uncover potential therapy targets.

All cancers arise from genetic alterations that allow cancer to survive and thrive at the expense of the host, he said. These genetic alterations are a double-edged sword they allow these cancer cells to grow, but on the other hand they do confer specific vulnerabilities that we can potentially exploit.

Dave said his background in computer science, genetics, and oncology helped him as he designed the project, which uses huge datasets.

Weve done the heavy lifting in terms of tool development and methodology, which is ripe to be applied to every other type of cancer."-Sandeep Dave, MD

Cancer disparities are caused by a complex interplay of elements, including access to health care and other resources, institutional barriers, structural racism, and biology, such as ancestry-related genetics. For example, some genetic biological factors and social elements contribute to disparities in many types of cancer.

Cancer treatment is approaching this personalized space where patients are no longer treated with a one-size-fits-all paradigm."-Tammara Watts, MD, PhD

"Its becoming increasingly apparent that there are differences in outcome with respect to race and ethnicity, said Tammara Watts, MD, PhD, associate professor of head and neck surgery & communication sciences, and associate director of equity, diversity, and inclusion at DCI. The very broad hypothesis is that there are genetic ancestry-related changes that may play a critical role in the disparate clinical outcomes we see every day in our cancer patients.

For example, self-identified white patients with throat cancer associated with the human papilloma virus (HPV) have better outcomes compared to self-identified Black patients, even when controlling for elements such as health care access, education, and socioeconomic status.

Watts is collaborating with bioinformatics experts at DCI to try to identify significant differences in gene expression among the two groups.

Im trying to tease out differences that may be impactful for disadvantaged patients based on race and ethnicity, she said. But there could be differences that emerge that could be useful for designing targeted treatments for a broad group of patients.

Thats because a targeted treatment for a particular genetic expression that might occur more commonly in Black people would help all patients with that expression, regardless of race or ethnicity.

Watts is far from alone in doing cancer disparity research at DCI. Tomi Akinyemiju, PhD, associate professor in population health sciences, uses epidemiology to study both biological factors and social elements that contribute to disparities in many types of cancer.

Jennifer Freedman, PhD, associate professor of medicine, Daniel George, MD92, professor of medicine, and Steven Patierno, PhD, professor of medicine and deputy director of DCI, are studying the molecular basis for why prostate, breast, and lung cancer tend to be more aggressive and lethal in patients who self-identify as Black. Patierno, who has been a national leader in cancer disparities research for more than 20 years, leads the Duke Cancer Disparities SPORE (Specialized Program of Research Excellence), funded by the National Cancer Institute. The SPORE grant supports these researchers as well as other DCI teams working on cancers of the breast, lung, stomach, and head and neck.

One of the things that impresses me is that [cancer disparities research] is a high priority within DCI, said Watts, who joined the faculty in 2019. These groups are actively engaged and collaborating and asking the questions that will drive change for patients who have worse outcomes that are related to ancestry.

Even better than a cancer cure is avoiding cancer altogether.

At DCI, Meira Epplein, PhD, associate professor in population health sciences, and Katherine Garman, MD02, MHS02, HS02-06, HS09, associate professor of medicine, are looking to decrease the incidence of stomach cancer by improving detection and treatment of the bacteria Helicobacter pylori, which can set off a cascade leading to stomach cancer. Epplein and Garman, also funded by the Duke Cancer Disparities SPORE grant, hope their work will reduce disparities because H. pylori infections and stomach cancer are both more prevalent among African Americans than whites.

When preventing cancer isnt successful, the next best thing is to detect and treat early. A relatively new concept in cancer care is interception, which means catching cancer just as, or even just before, it begins.

The point is to prevent it from progressing to full blown malignancy, said Patierno. In other words, stop the cancer from getting over its own goal line.

Patierno envisions a future where patients with pre-cancerous conditions or early cancer could take a pill to halt cancer development without killing cells in other words, a non-cytotoxic treatment, unlike standard chemotherapy.

We know its there, but were not going to poison it or burn it or cut it out because all of those have side effects. Were going to find a non-cytotoxic way to prevent it from progressing. Thats the goal.-Steven Patierno, PhD

Read About Alumni Making a Differencein Cancer Research and Care:

Changing theStatus Quo: Lori Pierce MD'85

Treatingthe WholePerson:Arif Kamal, MD,HS12, MHS15

Targetingthe Seeds ofCancer Growth:Eugenie S. Kleinerman, MD75, HS75

A DiscoveryThat Comes Outof Nowhere:Bill Kaelin, BS79, MD82

Story originally published in DukeMed Alumni News, Fall 2022.

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Developing New Tools to Fight Cancer - Duke University School of Medicine

DUBLIN--(BUSINESS WIRE)--The "Global Genetic Testing Market Research and Forecast, 2022-2028" report has been added to ResearchAndMarkets.com's offering.

The global genetic testing market is growing at a significant CAGR during the forecast period. The genetic disorder can be occurred by a change in one gene (monogenic disorder), by changes in multiple genes by a combination of environmental factors, and gene mutations, or by the destruction of chromosomes. Genetic testing is a medical test that is used for the identification of mutations in genes or chromosomes.

The key benefit of genetic testing is the chance to know the risk for a certain disease that possibly can be prevented, identify the disease or a type of disease, identify the cause of a disease, to determine options for a disease. The disease that can be identified by genetic testing includes, breast and ovarian cancer, Age-Related Macular Degeneration (AMD), bipolar disorder, Parkinson's disease, celiac disease, and psoriasis.

The global genetic testing market is projected to considerably grow in the upcoming year due to the prevalence of genetic disorders, cancer, and chronic disease. Moreover, continuous advancement by the medical companies in the genetic diagnostic field is also augmenting the market growth.

These companies are finding new and better tests for the accurate diagnosis of the most prevalent as well as rare diseases. Besides, the increase in awareness between people about health and the increased mortality rate due to genetic diseases across the globe is also a major factor increasing the need for demand for genetic testing.

Moreover, The adoption of (DTC) direct-to-consumer genetic testing kits in countries such as the US, China, and Japan, is increasing rapidly. With growing technological acceptances, awareness programs, and a drop in costs, the market for DTC-GT kits is likely to witness a significant boost over the forecast period. However, the lack of diagnostic infrastructure in emerging economies is a challenging factor for market growth.

Regional Outlooks

North America is estimated to contribute a significant share in the global genetic testing market due to the high awareness among the people about advanced treatment for healthcare, well-developed healthcare infrastructure, presence of key players, and availability of drugs.

Moreover, an increase in government initiatives for the enhancement of healthcare facilities and funding in research in the region is also a major factor for the significant market share of the region. In the US under the US CDC EGAPP, inventiveness has been taken by the government such as the Evaluation of Genomic Applications in Practice and Prevention which is also motivating the market growth.

One of the key goals of the initiative is to timely, offer objectively, and credible information that is linked to available scientific evidence. These statistics will allow healthcare workers and payers, customers, policymakers, and others to differentiate genetic tests that are safe and useful.

Asia-Pacific will have considerable growth in the global Genetic Testing Market

In Asia Pacific, the market is increasing due to government initiatives in research and the increasing prevalence of chronic diseases. Apart from cancer, genetic testing processes have also come in easy reach for the diagnosis of inherited cardiovascular diseases such as cardiac amyloidosis, Brugada syndrome, and familial dilated cardiomyopathy. As the region has a high incidence of cardiovascular diseases, significant scope for genetic testing can be witnessed in the region during the forecast period.

Market Players Outlook

The report covers the analysis of various players operating in the global genetic testing market. Some of the major players covered in the report include Abbott Laboratories, Myriad Genetics, Inc., F. Hoffmann-La Roche Ltd., Illumina, Inc., and Thermo Fisher Scientific, Inc. To survive in the market, these players adopt different marketing strategies such as mergers and acquisitions, product launches, and geographical expansion.

The Report Covers

Market Segmentation

Global Genetic Testing Market by Technology

Global Genetic Testing Market by Type

Global Genetic Testing Market by Disease

Company Profiles

For more information about this report visit https://www.researchandmarkets.com/r/fvmuud

About ResearchAndMarkets.com

ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

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Global Genetic Testing Market Research Report 2022 Featuring Major Players - Abbott Laboratories, Myriad Genetics, F. Hoffmann-La Roche, Illumina, and...

The outcomes from biologics and cell therapies hinge on what they secrete. More specifically, protein secretion has important impacts for both the quality and quantity of a therapeutic produced using bioprocessing, says Dino Di Carlo, PhD, the Armond and Elena Hairapetian chair in engineering and medicine at the University of California, Los Angeles.

For biologics, he continues, the rate at which producer cells secrete protein therapeuticsfor example, monoclonal antibodiesdrives the amount of therapeutic that can be produced per batch and ultimate costs of production; for cell therapies, secreted proteins are a key product attribute that defines a high-quality product.

A previous GEN story explained how secretion-based screening could improve cell therapies. Here, Di Carlo describes how he and his colleagues used single-cell sequencing information (SEC-seq) to link the secretions and transcriptomes for individual antibody-secreting cells.

The key finding from this work, Di Carlo says, is that gene transcripts are not necessarily correlated to secreted proteins, which makes the community rethink genetic modificationapproaches that just focus on overexpressing the gene for the target-secreted protein to achieve animproved therapeutic effect. For example, the SEC-seq study showed that the levels of mRNA transcripts for immunoglobulin G (IgG) proteins did not correlate with the amount of assembled and secreted IgGheavy and light chainin humanplasma cells.

Instead, in highly secreting cells, we found pathways upregulated that drive energy production, protein translation, protein trafficking, and response to misfolded proteins, Di Carlo explains. This suggests that having enough transcripts around to produce the secreted protein is not the bottleneck for high levels of secretion. As he adds, Other pathways are the likelybottleneck, and they are needed to make and traffic a lot of protein to the membrane to secrete it, as well as deal with mis-folded proteins that result from translation of large quantities of proteins.

Upon understanding the importance of secretions from biologics and cell-based therapies, what can a commercial bioprocessor do about it? One implication is for bioprocessors interested in the genetic modification of therapeutic cells to secrete more of a therapeutic protein, Di Carlo says. Our results suggest it is not sufficient to genetically modify your cell type of interest with just the gene to produce a secreted protein, because you may also need to drive these other associated pathways to enhance the level of secretion.

The SEC-seq method could also be applied in other ways. Bioprocessors could use this technique to identify the pathways that drive secretion of critical cytokines and growth factors for their therapeutic cell type of interest, Di Carlo says. For example, there may be differences in what drives high levels of secretion between the human plasma cells secreting IgG and natural killer cells secreting cytokines. This information could be used by a bioprocessor to improve the base cell types used for a therapeutic product or to perform quality control or production-batch sorting based on these factors.

For biologics, bioprocessors can use SEC-seq to uncover what drives higher secretion of a therapeutic protein by producer cell types, like CHO cells, HEK293 cells, etc., Di Carlo explains. The information obtained could help engineer the next generation of more efficient and productive producer cell lines.

So, making an effective biologic or cell therapy depends on what cells secrete. Fortunately, Di Carlos work will help bioprocessors better understand and improve that secretion.

Continued here:
Tracking Transcripts in Biologics and Cell Therapies - Genetic Engineering & Biotechnology News

CARLSBAD, Calif.--(BUSINESS WIRE)--Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, announced today that Brian M. Culley, Lineages Chief Executive Officer, will present at the Alliance for Regenerative Medicine 2022 Cell & Gene Meeting on the Mesa, on October 12th, 2022 at 2:15pm PT / 5:15pm ET at the Park Hyatt Aviara, Carlsbad, CA. Virtual meeting attendance is available and includes a livestream of Lineages presentation and the ability to view all conference sessions on-demand. Interested parties can visit the 2022 Cell & Gene Meeting on the Mesa website for full information on the conference, including registration.

The Cell & Gene Meeting on the Mesa is the sectors foremost annual conference bringing together senior executives and top decision-makers in the industry to advance cutting-edge research into cures. Tackling the commercialization hurdles facing the cell and gene therapy sector today, this meeting covers a wide range of topics from clinical trial design to alternative payment models to scale-up and supply chain platforms for advanced therapies. The program features expert-led panels, extensive partnering capabilities, exclusive networking opportunities, and dedicated presentations by the leading publicly traded and privately held companies in the space. This conference enables key partnerships through more than 3,000 one-on-one meetings while highlighting the significant clinical and commercial progress in the field.

About the Alliance for Regenerative Medicine

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies. ARM promotes legislative, regulatory, reimbursement and manufacturing initiatives to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-engineered therapies. In its 13-year history, ARM has become the global voice of the sector, representing the interests of 450+ members worldwide, including small and large companies, academic research institutions, major medical centers and patient groups.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include five allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelial cell therapy in development for the treatment of geographic atrophy secondary to age-related macular degeneration, is being developed under a worldwide collaboration with Roche and Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer; (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy; and (v) PNC1, a photoreceptor neural cell therapy for the treatment of vision loss due to photoreceptor dysfunction or damage. For more information, please visit http://www.lineagecell.com or follow the company on Twitter @LineageCell.

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Lineage to Present at Alliance for Regenerative Medicine 2022 Cell & Gene Meeting on the Mesa - Business Wire

Depression Treatment: How Genetic Testing Can Help Find the Right Medication

Depression Treatment: How Genetic Testing Can Help Find the Right Medication

17 October,2022 08:42 am

ISLAMABAD, (Online) - Thats according to a new studyTrusted Source conducted by the U.S. Department of Veterans Affairs (VA) and published today in the Journal of the American Medical Association.

In it, researchers report that pharmacogenetic testing might help medical professionals by providing helpful information on how a person metabolizes a medication. This information can help doctors and others avoid prescribing antidepressants that could produce undesirable outcomes.

Depression medication is sometimes determined through trial and error to find the best drug and dosage. The researchers say they hope genetic testing can minimize this by giving insight into how a person may metabolize a drug.

Researchers said genetic testing did not show how a person would react to a particular medication but instead looked at how a person metabolized a drug. A drug-gene interaction is an association between a drug and a generic variation that may impact a persons response to that drug. Learning more about drug-gene interactions could potentially provide information on whether to prescribe medication and whether a dosage adjustment is needed.

In the study, around 2,000 people from 22 VA medical centers diagnosed with clinical depression received medications to treat their symptoms. The participants were randomized, with one-half receiving usual care and one-half undergoing pharmacogenetic testing.

For those that received usual care, doctors prescribed medication without the benefit of seeing a genetic testing result. The researchers found that 59 percent of the patients whose doctors received the genetic testing results used medications with no drug-gene interaction. Only 26 percent of the control group received drugs with no drug-gene interaction.

The researchers said the findings show that doctors avoided medications with a predicted drug-gene interaction.

Most often, patients get tested after at least one or two drugs havent worked or they had severe side effects, said Dr. David A. Merrill, a psychiatrist and director of the Pacific Neuroscience Institutes Pacific Brain Health Center at Providence Saint Johns Health Center in California. There are real genetically driven differences in how people metabolize drugs. It helps select more tolerable options to know about their genetics ahead of time.

Researchers interviewed participants about their depression symptoms at 12 weeks and 24 weeks.

Through 12 weeks, the participants who had genetic testing were more likely to have depression remission than those in the control group.

At 24 weeks, the outcome was not as pronounced. The researchers said this showed that genetic testing could relieve depressive symptoms faster than if a person did not receive the testing.

What experts think

There is a place for pharmacogenetic testing when treating people with depression, according to Dr; Alex Dimitriu, an expert in psychiatry and sleep medicine and founder of Menlo Park Psychiatry & Sleep Medicine in California and BrainfoodMD.

Some situations that might call for genetic testing include treatment-resistant depression and more complex cases.

It tells me if someone will either rapidly or slowly metabolize a drug meaning the level of the drug will either be too low or too high depending on the persons metabolism, Dimitriu told Healthline. I have used it in a few rare cases to see what options remain.

To me, more important than pharmacogenetic testing is watching the symptoms and response in my patients, he continued. I see my patients often, especially when starting a new medicine, and we can go slow and watch how the patient is doing. If you start at a low dose and raise the dose slowly, with good monitoring and charting, you can readily see who responds too fast or too slow and at what dose.

Some doctors dont think the science is there yet and arent going to rush into using pharmacogenetic testing based on this study.

I used pharmacogenetic testing about ten years ago and the science is accurate. It tells you the persons genetic makeup, said Dr. Ernest Rasyida, a psychiatrist at Providence St. Josephs Hospital.

From a scientific point of view, he told Healthline, this was a great study. It showed that the doctor used the data 60 percent of the time.

That means that the doctor looked at the data and the medications in the green zone and chose not to use them for side effects or other reasons. Instead, they chose a drug in the red zone because of their clinical experience.

I would argue that if 40 percent of the time you are going to use your judgment and you should use your judgment then why get the test? he concluded.

In addition to depression, pharmacogenetic testing can also be used in the treatment of other non-mental health conditions, such as cancer and heart disease.

Experts say there is no risk to the patient when getting the test and the researchers said they believe it will likely benefit some patients substantially.

Pharmacogenetic results are well-known and have been for years, but the clinical practice of medicine is very conservative, so it takes a long time for clearly beneficial changes to become common practice, Merrill told Healthline. If 15 to 20 percent of patients started on a new drug can avoid a major gene-drug interaction by knowing their results, doing the test seems like a no-brainer to me.

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Depression Treatment: How Genetic Testing Can Help Find the Right Medication - Dunya News

Risky at-birth surgery saves baby with rare disorder

Doctors have performed a dramatic surgery to save a baby who was born with a life-threatening rare disorder that hampered his ability to breathe. (Sept. 21) (AP Video: Emma H. Tobin)

AP

Every baby born in the United States is pricked in the heel shortly after birth. A blood sample is then analyzed to look for one of 20 to 30 inherited diseases.

Early identification of a particular disease meanstreatment can start right away, potentially saving or extending thechild's life.

Now, doctors want to go even further: They want to look not just atblood, but atgenes.

A new effort announced Wednesday by a genetic testing company paired withresearchers at NewYork-Presbyterian/Columbia Universityaims to sequence 100,000 newborns in New York City over the next five years.

The sequencing would look for about 250 diseases that strike before age 5 and for which there are treatments or approaches that can make a difference in a child's life.

A similar effort in the United Kingdom is also examining the genes of 100,000 newborns, looking for diseases for which there is a treatment or a cure.

The programs promiseto bring treatments to babies before symptoms become obvious and at a time when something can be done to help them.

"The appetite for this is growing. The awareness of this is growing. We all see it as inevitable," said Dr. Robert Green, a medical geneticist atBrighamand Women's Hospital and Harvard Medical School, both in Boston."We are grossly underutilizing the life-saving benefits of genetics and we have to get past that."

This week,Green is hosting a conference in Boston, bringing together researchers and industry representatives from the U.S., U.K., European Union and Australia to set standards and discuss the challenges and opportunities presented byscaling upnewborn genetic sequencing.

This kind of early sequencing and treatment is possible now for the first time because of dramatic advances in diagnostics, therapies and digital data storage, as well as a reduction in the cost of sequencing, said Dr. Paul Kruszka, a clinical geneticist and chief medical officer of GeneDx at Sema4, which is leading the new program.

"We're entering the therapeutic era and leaving the diagnostic era," Kruszka said. "This potentially has the opportunity to change the way we practice medicine especially in rare disease."

Right now, families with rare diseases often search for a diagnosis for 5, 10 or even 20 years. If the child could be diagnosed at birth, he said, it would short-circuit that process and treatment could begin much earlier hopefully before the child suffers irreversible damage.

Before deciding whether every family should get access to genetic sequencing for their newborn,large studies like Sema4's are needed to justify the cost, Kruszka said.

The price of gene sequencing has dropped precipitiously, with one company, Illumina. announcing last week that its newest-generation sequencing machinescan run a complete sequence for about $200. Kruszka said Sema4 expects to still payabout $1,000 for each sequence of all 20,000 genes.

Gene sequencing at birth should be able to save money over the child's lifetime by preventing illness, Green said. The costs of sequencing are limited, he said, but the benefits will build up over the child's lifetime and may help family members, too.

Green and his team began analyzing the genetic sequences of newborns in 2013, and has found lots of useful information among the first 320 babies sequenced, he said. He now has funding to expand his sequencing researchto 1,000 newborns.

Large numbers are essential because most of the diseases being diagnosed are extremely rare.

Convincing parents to participate in a sequencing research trial "is not easy," Green said. Many are concerned about privacy and the discrimination their child might face if their genome were made public. And it can be a unpleasant for parents to consider the horrible diseases their perfect newborn might be harboring,he said.

"You've gone through all this pregancy and you're sitting there with a healthy baby (and I'm) offering you the opportunity to find out something that's devastating and terrifying," he said. "How fun is that?"

He doesn't think privacy needs to be a major parental concern. Companies can learn more useful information by tracking someone's cell phone or credit card than their genome and most common diseases are the result of many combinations of genes.

"Many people hear 'genetics' and worry somehow that that is a special kind of privacy threat," he said, adding that he doesn't think there is. "We haven't been paying attention to the medical benefits of genetic testing, particularly predictive genetic testing."

if people don't want to know, that's okay, too, Green said. "We canrespect people who don't want to know, but as also respect people who do want to know," he said. "Some families will say 'I treasure the precious ignorance.' Others will say 'If I could have known, I would have poured my heart and soul into clinical trials or spent more time with the child when she was healthy."

In a five-year review of their research, Green and his colleagues found that "terrible things didn't happen" when they sequenced newborn genomes.

Families, he said, "did not in fact have downstream distress," he said. "They did have appropriate medical follow-up and that there were amazing benefits to the babies and the families as a result of the surveillance and treatment."

The baby sequencing identified several parents who had inherited illnesses and received risk-reducing surgery, he said, as well as a baby who had a narrowed aorta that wouldn't have been detected if its genetics hadn't indicated the need for an echocardiogram.

"Even in a small sample we found much to act on," he said.

At Rady Children's Hospital in San Diego, they're trying to rapidly sequence the genomes of babies who already have problems and are being treated in one of 83 children's hospitals acrossCanada and the U.S.

Every morning, samples arrive by Fedex. In some cases, the baby is in such dire shape than an answer is needed immediately. For those children, "we've got to drop what we're doing and go,"said Dr. Stephen Kingsmore, the president and CEO of Rady's Institute for Genomic Medicine."Even a day can cost a child's life or brain function."

For babies who are stable, sequencing still happens rapidly, but a little less so."Every sample gets onto a sequencer the same day," he said.

So far, the institute, which is also collaborating on a newborn sequencing study in Greece,has been able to provide a 1,500 children with a diagnosis in the first weeks of life in addition to a life-saving treatment.

"That idea, that future is where a child never experiences a sick day, even though they have a fatal condition," the institute's former director of marketing,Graciela Sevilla,said earlier this year. "We'd love to see that on a regular basis."

Contact Weintraub at kweintraub@usatoday.com

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

Air pollution could be contributing to millions of premature births

Estimates in a new study say air pollution could be a factor in up to 3.4 million preterm births.Video provided by Newsy

Newslook

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Blood from a baby at birth can be gene sequenced to prevent diseases - USA TODAY

(Aylish Turner | Daily Trojan)

A mutation in a newly discovered microprotein might lead to a significant risk for Alzheimers disease, according to research from the Leonard Davis School of Gerontology. The discovery expanded the gene target to treat the disease and provided a new potential therapeutic solution to the incurable disease.

The newly-discovered protein, named SHMOOSE, is encoded by a gene that exists within the cells mitochondria, which is responsible for cells energy production. A mutation within this gene, which partially inactivates the SHMOOSE microprotein, is associated with a 30% increase in ones risk of developing Alzheimers disease. The mutated version of the protein has reportedly appeared within nearly a quarter of people of European ancestry.

Brendan Miller, a 2022 doctoral graduate who studied neuroscience and the studys first author, relied on big data techniques to identify genetic variations associated with disease risk, after analyses revealed that mutations are linked to increased risk of Alzheimers, brain atrophy and energy metabolism.

Researchers began studying the genes mutated and default forms and found that SHMOOSE is the first mitochondrial-DNA-encoded microprotein to be detected using both antibodies and mass spectrometry.

Miller said one of the biggest obstacles in the research process was the sheer amount of data that researchers had to compile to make these findings. Miller described this big data as taking up terabytes of storage, containing research gleaned from dozens of individuals. His team was able to overcome this by utilizing new and advanced technology, which allowed them to make discoveries not otherwise possible.

Computational power over the last ten years has grown exponentially. With that means youre going to see in the field of medicine and biology a lot of rapid discoveries, Miller said. At USC, we have infrastructure, and we have a lot of talented computational scientists to help us with that.

Being able to manipulate and understand big data was essential for the success of this project, Miller said.

The big challenge is starting from hundreds of potential gene targets and narrowing them down to one, Miller said. The way we did this was [by] implementing a lot of genetics data and omics data from similar individuals with different data types.

The study highlights the importance of the emerging field of microprotein studies. Microprotein, a small protein encoded from a small open reading frame, appears to modify energy signaling and metabolism in the central nervous system. A variety of studies have found microproteins in mitochondria of neurons and showed that SHMOOSE alters energy metabolism in the brain, in part by inhibiting the inner mitochondrial membrane.

When you look at microproteins, there are many hundreds of thousands of them, [which] creates a whole new dimension of things that need to be discovered, said Pinchas Cohen, a professor of gerontology, medicine and biological sciences and the senior author of the study.

There is currently no approved medicine for Alzheimers disease developed based on microproteins, while microprotein- or peptide-related treatments have been employed in treatments of diabetes, heart diseases and some other chronic illnesses. The therapeutic potential of microproteins in Alzheimers cases was thus exciting news for many researchers in the field.

Helena Chang Chui, chair and professor of neurology at Keck School of Medicine, said the paper is very rich and has significant potential impact for understanding the causes of Alzheimers.

Were getting a little bit closer with immunological approaches with monoclonal antibodies[and] antibodies against amyloid proteins, but theres been no particular no peptide treatments, Chui said.

Researchers are, on the whole, cautiously optimistic about the therapeutic potential of the study, Cohen said, and it is still too early to contemplate applying the findings of the study into therapeutic research. Cohen said he hopes that the team could use standard mouse models of Alzheimers and demonstrate that SHMOOSE does have benefits on the treatment of Alzheimers disease.

Then, as Cohen implied, the team might pick individuals who have the SHMOOSE mutation to do the research, which will lend to the precision medicine approaches.

The issue is that Alzhmeimers disease is very heterogeneous. [Its] not really one specific condition, its multiple conditions, each being a result of various genetic susceptibilities, that all present in a similar way, Cohen said. Thats why I believe that treatments that will be focused on the primary genetic abnormality, also known as precision medicine approaches, will be more efficacious.

Link:
Study finds microprotein correlated to Alzheimers risk - Daily Trojan Online

Passage Bio

PHILADELPHIA, Oct. 10, 2022 (GLOBE NEWSWIRE) -- Passage Bio, Inc. (Nasdaq: PASG), a clinical-stage genetic medicines company focused on developing transformative therapies for central nervous system (CNS) disorders, today announced the appointment of William Chou, M.D. as chief executive officer (CEO) and a member of the board, effective immediately. Edgar B. (Chip) Cale will resign his position as the companys interim CEO and will continue in his role as general counsel and corporate secretary. Maxine Gowen, Ph.D., will step down as interim executive chairwoman following a brief transition period and will then continue to serve as chairwoman.

The Board and I are delighted to welcome Will to Passage Bio to lead the company through an exciting phase of development, said Dr. Gowen. Wills depth of experience and success in developing and commercializing advanced therapeutics will be instrumental in establishing and solidifying the company as a leader in genetic medicines.

Dr. Chou is an accomplished executive with nearly twenty years of healthcare experience across a range of development and commercialization roles. Most recently, Dr. Chou served as CEO of Aruvant Sciences, a clinical-stage biopharmaceutical company focused on developing gene therapies for rare diseases.

I am thrilled to join the talented team at Passage Bio and build upon the companys many accomplishments and impressive capabilities, said Dr. Chou. With three ongoing clinical programs, we are poised to deliver multiple meaningful milestones over the coming quarters. As a clinician, it is my privilege to lead a company with tremendous potential to bring transformative therapies to patients with CNS disorders for which there are limited or no approved treatment options today.

Prior to joining Aruvant, Dr. Chou served in a variety of leadership roles at Novartis, including vice president, global disease lead for Novartis Cell and Gene Therapy unit where he oversaw the global commercial launch of Kymriah, the first CAR-T cell therapy. Prior to that role, Dr. Chou led the Kymriah lymphoma clinical development program to approvals in the United States, Europe, Australia, Canada and Japan. Before joining Novartis, Dr. Chou worked at the Boston Consulting Group where he focused on commercial and clinical pharmaceutical strategy.

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Dr. Chou holds an M.B.A. from the Yale School of Management, an M.D. from the University of Pittsburgh School of Medicine, and an A.B. in politics and economics from Princeton University. Dr. Chou completed his residency in internal medicine at Yale New Haven Hospital and his fellowship in geriatrics at Yale University.

About Passage Bio

Passage Bio (Nasdaq: PASG) is a clinical-stage genetic medicines company on a mission to provide life-transforming therapies for patients with CNS diseases with limited or no approved treatment options. Our portfolio spans pediatric and adult CNS indications, and we are currently advancing three clinical programs in GM1 gangliosidosis, Krabbe disease, and frontotemporal dementia with several additional programs in preclinical development. Based in Philadelphia, PA, our company has established a strategic collaboration and licensing agreement with the renowned University of Pennsylvanias Gene Therapy Program to conduct our discovery and IND-enabling preclinical work. Through this collaboration, we have enhanced access to a broad portfolio of gene therapy candidates and future gene therapy innovations that we then pair with our deep clinical, regulatory, manufacturing and commercial expertise to rapidly advance our robust pipeline of optimized gene therapies. As we work with speed and tenacity, we are always mindful of patients who may be able to benefit from our therapies. More information is available at http://www.passagebio.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, the Private Securities Litigation Reform Act of 1995, including, but not limited to: our expectations about timing and execution of anticipated milestones, including initiation of clinical trials and the availability of clinical data from such trials; our expectations about our collaborators and partners ability to execute key initiatives; our expectations about manufacturing plans and strategies; our expectations about cash runway; and the ability of our lead product candidates to treat their respective target monogenic CNS disorders. These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop and obtain regulatory approval for our product candidates; the timing and results of preclinical studies and clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; the risk that positive results in a preclinical study or clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; failure to protect and enforce our intellectual property, and other proprietary rights; our dependence on collaborators and other third parties for the development and manufacture of product candidates and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; and the other risks and uncertainties that are described in the Risk Factors section in documents the company files from time to time with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. Passage Bio undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

For further information, please contact:

Passage Bio Investors:Stuart HendersonPassage Bio267-866-0114shenderson@passagebio.com

Passage Bio Media:Mike BeyerSam Brown Inc. Healthcare Communications312-961-2502MikeBeyer@sambrown.com

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Passage Bio Announces Appointment of William Chou, M.D. as Chief Executive Officer - Yahoo Finance

Demand for viral-vector-based gene therapies has risen to unprecedented levels, thanks to their potential to help treat previously incurable diseases. The two vectors most in the spotlight? Lentiviral (LV) vectors and adeno-associated viral (AAV) vectors due to the increased research and positive clinical results they are seeing across a wide range of applications, including cancer, heart disease, and hematologic and genetic disorders. The more drug developers look to expand this range of therapeutic areas, the greater the demand for commercial-scale development. So its important to understand not only how these two vectors can be applied to drug development, but also the capabilities required for scale-up that allows us to bring these innovative therapies to patients.

LV vectors are derived from the single-stranded RNA retrovirus HIV-1, and have been used extensively because of their ability to infect non-dividing cells, efficiently integrate into the host genome, carry large transgene loads, and allow for long-term transgene expression. They are predominantly used as delivery vehicles for introducing genetic modifications into cell therapies, such as CAR-T, and HSC gene therapies. Importantly, recent regulatory approvals and clinical successes with LV vectors are spurring even more interest among drug developers.

Lets look at the benefits of LV vectors in more detail:

However, LV vectors also present two major risks to safety.

The first is a risk of accidental exposure because HIV can self-replicate during manufacturing thanks to the lentiviruss high mutation and recombination rate.Though research shows that the risk is low, it remains a major safety concern for lab engineers and workers during development. Before using a lentiviral vector system, a risk assessment must be completed and documented. Typically, lentiviral vectors may be safely handled using either BSL-2 or BSL-2 enhanced controls, depending upon the risk assessment.

The second risk is the potential for oncogenes to occur in cells through insertional mutagenesis. For this reason, lentiviral vectors are predominantly used for cell therapy applications with genetic modification of cells ex-vivo. Only limited use is seen for direct in vivo therapies.

Unlike their LV cousins, AAV vectors are single-stranded DNA parvoviruses that can replicate only in the presence of helper viruses, such as the adenovirus, herpes virus, human papillomavirus, and vaccinia virus. Following several landmark approvals, AAV vectors are currently being used for in vitro, ex vivo, and in vivo research. AAV therapies predominantly target rare genetic disorders for which the patient population tends to be highly limited. As the market is so small, drug developers feel immense pressure to be first to market to commercialize their therapies.

The biological elements of AAV vectors make them a very attractive candidate for gene therapy for several reasons:

As with LV vectors, AAV vectors come with several drawbacks that affect their applications and efficiency.

Firstly, AAV vectors are limited by their restricted capacity for insertion of transgene DNA; because of their relatively small transgene size, they are unable to deliver genes larger than 4.8 kilobytes. Secondly, the generation of neutralizing antibodies against AAV in non-human primates (NHP) and humans may attenuate the curative effects of AAV-mediated gene therapies and limit the size of patient populations suitable for these therapies. Thirdly, there are several different serotypes and capsids for AAVs, all of which have different production and purification requirements and vary greatly with respect to function and efficacy. Fourthly, AAV drug products have varying degrees of empty and partially filled capsids, and these have implications for safety and efficacy. Generally, the highest possible percentage of AAV particles with the full transgene DNA is desired, and this varies significantly depending on the production method, AAV serotype, and the transgene itself. The latter two factors introduce significant manufacturing challenges for AAV therapies.

Overall, the industrys collective ability to successfully scale up LVV and AAV vectors faces two challenges:

i) Manufacturing each viral vector currently requires different processes, so companies cannot apply a one-size-fits-all approach to their upstream and downstream processes. Therefore, manufacturing requires immense scientific and market expertise to make the informed decisions necessary for developing a robust plan.

ii) Given the industrys limited experience with commercial-scale viral vector supply, companies need to work closely with regulatory agencies. This can be especially challenging during the transition from preclinical to commercial, where complexities arise that can cause potential delays resulting in increased costs.

As demand continues to rise, pharma companies must understand how to navigate these challenges to continue delivering their life-saving medications.

Head of Commercial Development for Viral Vector, Cell and Gene Technologies (CGT) at Lonza

She works closely with the innovation, operations, engineering, strategic marketing, and business teams to enable prioritization, strategic development and commercialization of viral vector production services for CGT. Suparnas background is in Neuroscience, and she earned her PhD in Neuropharmacology from the University of Toronto. She has over 15 years of broad pharmaceutical and CDMO experience driving innovation, drug discovery, product and service development for CNS, oncology, and cell and gene therapy.

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The Pros and Cons of Lentiviral and Adeno-Associated Viral Vectors - The Medicine Maker

A protein that helps make neurons also works to reprogram scar tissue cells into heart muscle cells, especially in partnership with a second protein, according to a study led by Li Qian, PhD, at the UNC School of Medicine.

CHAPEL HILL, N.C. Scientists at the UNC School of Medicine have made a significant advance in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future medicines to heal damaged hearts.

In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that contributes to heart failure after a heart attack or because of heart disease. Turning fibroblasts into cardiomyocytes is being investigated as a potential future strategy for treating or even someday curing this common and deadly condition.

Surprisingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific.

Its an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming, said study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at UNC School of Medicine.

Scientists over the last 15 years have developed various techniques to reprogram adult cells to become stem cells, then to induce those stem cells to become adult cells of some other type. More recently, scientists have been finding ways to do this reprogramming more directly straight from one mature cell type to another. The hope has been that when these methods are made maximally safe, effective, and efficient, doctors will be able to use a simple injection into patients to reprogram harm-causing cells into beneficial ones.

Reprogramming fibroblasts has long been one of the important goals in the field, Qian said. Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes.

In the new study, Qians team, including co-first-authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their aim was to catalogue and compare the changes in cells gene activity patterns and gene-activity regulation factors during these three distinct reprogrammings.

Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. Soon they determined that this activation was due to Ascl1, one of the master-programmer transcription factor proteins that had been used to make the neurons.

Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they had been using for making cardiomyocytes, to see what would happen. They were astonished to find that it dramatically increased the efficiency of reprogramming the proportion of successfully reprogrammed cells by more than ten times. In fact, they found that they could now dispense with two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c.

In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but it shifts away from the pro-neuron role when accompanied by Mef2c. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes.

Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail, Qian said.

The results show that the major transcription factors used in direct cellular reprogramming arent necessarily exclusive to one targeted cell type.

Perhaps more importantly, they represent another step on the path towards future cell-reprogramming therapies for major disorders. Qian says that she and her team hope to make a two-in-one synthetic protein that contains the effective bits of both Ascl1 and Mef2c, and could be injected into failing hearts to mend them.

Cross-lineage Potential of Ascl1 Uncovered by Comparing Diverse Reprogramming Regulatomes was co-authored by Haofei Wang, Benjamin Keepers, Yunzhe Qian, Yifang Xie, Marazzano Colon, Jiandong Liu, and Li Qian. Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).

Media contact: Mark Derewicz, 919-923-0959

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Scientists Discover Protein Partners that Could Heal Heart Muscle | Newsroom - UNC Health and UNC School of Medicine

Biopharma focuses on streamlining biomanufacturing and supply chain issues to drive uptake of cell and gene therapies.

Cell and gene therapies (CGTs) offer significant advances in patient care by helping to treat or potentially cure a range of conditions that have been untouched by small molecule and biologic agents. Over the past two decades, more than 20 CGTs have been approved by FDA in the United States and many of these one-time treatments cost between US$375,00 and US$2 million a shot (1). Given the high financial outlay and patient expectations of these life-saving therapies, it is essential that manufacturers provide integrated services across the whole of the supply chain to ensure efficient biomanufacturing processes and seamless logistics to reduce barriers to uptake.

The following looks at the who, what, when, and why of biomanufacturing and logistics in CGTs in the bio/pharmaceutical industry in more detail.

According to market research, the global gene therapy market will reach US$9.0 billion by 2027 due to favorable reimbursement policies and guidelines, product approvals and fast-track designations, growing demand for chimeric antigen receptor (CAR) T cell-based gene therapies, and improvements in RNA, DNA, and oncolytic viral vectors (1).

In 2020, CGT manufacturers attracted approximately US$2.3 billion in investment funding (1). Key players in the CGT market include Amgen, Bristol-Myers Squibb Company, Dendreon, Gilead Sciences, Novartis, Organogenesis, Roche (Spark Therapeutics), Smith Nephew, and Vericel. In recent years, growth in the CGT market has fueled some high-profile mergers and acquisitions including bluebird bio/BioMarin, Celgene/Juno Therapeutics, Gilead Sciences/Kite, Novartis/AveXis and the CDMO CELLforCURE, Roche/Spark Therapeutics, and Smith & Nephew/Osiris Therapeutics.

Many bio/pharma companies are re-considering their commercialization strategies and have re-invested in R&D to standardize vector productions and purification, implement forward engineering techniques in cell therapies, and improve cryopreservation of cellular samples as well as exploring the development of off-the-shelf allogeneic cell solutions (2).

The successful development of CGTs has highlighted major bottlenecks in the manufacturing facilities, and at times, a shortage of raw materials (3). Pharma companies are now taking a close look at their internal capabilities and either investing in their own manufacturing facilities or outsourcing to contract development and manufacturing organizations (CDMOs) or contract manufacturing organizations (CMOs) to expand their manufacturing abilities (4). Recently, several CDMOsSamsung Biologics, Fujifilm Diosynth, Boehringer Ingelheim, and Lonzahave all expanded their biomanufacturing facilities to meet demand (5).

A major challenge for CGT manufacturers is the seamless delivery of advanced therapies. There is no room for error. If manufacturers cannot deliver the CGT therapy to the patient with ease, the efficacy of the product becomes obsolete. Many of these therapies are not off-the-shelf solutions and therefore require timely delivery and must be maintained at precise temperatures to remain viable. Thus, manufacturers must not only conform to regulations, but they must also put in place logistical processes and contingency plans to optimize tracking, packaging, cold storage, and transportation through the products journey. Time is of the essence, and several manufacturers have failed to meet patient demands, which have significant impacts on the applicability of these agents.

Several CAR T-cell therapies have now been approved; however, research indicates that a fifth of cancer patients who are eligible for CAR-T therapies pass away while waiting for a manufacturing slot (6). Initially, the manufacture of many of these autologous products took around a month, but certain agents can now be produced in fewer than two weeks (7). Companies are exploring new ways to reduce vein-to-vein time (collection and reinfusion) through the development of more advanced gene-transfer tools with CARs (such as transposon, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) among others, and the use of centralized organization with standardized apheresis centers (5). Others are exploring the use of the of allogeneic stem cells including Regen Biopharma, Escape Therapeutics, Lonza, Pluristem Therapeutics, and ViaCord (7).

Several gene therapies have also been approved, mainly in the treatment of rare disease (8). Many companies are evaluating novel gene therapy vectors to increase levels of gene expression/protein productions, reduce immunogenicity and improve durability including Astellas Gene Therapies, Bayer, ArrowHead Pharmaceuticals, Bayer, Bluebird Bio, Intellia Therapeutics, Kystal Biotech, MeiraGTx, Regenxbio, Roche, Rocket Pharmaceuticals, Sangamo Therapeutics, Vertex Pharmaceuticals, Verve Therapeutics, and Voyager Therapeutics (8).

While many biopharma companies have established their own in-house CGT good manufacturing practice (GMP) operation capabilities, others are looking to decentralize manufacturing and improve distribution by relying on external contracts with CDMOs and CMOs such as CELLforCURE, CCRM, Cell Therapies Pty Ltd (CTPL), Cellular Therapeutics Ltd (CTL), Eufets GmbH, Gravitas Biomanufacturing, Hitachi Chemical Advances Therapeutic Solutions, Lonza, MasTHerCell, MEDINET Co., Takara Bio, and XuXi PharmaTech (6, 9, 10).

The top 50 gene therapy start-up companies have attracted more than $11.6 billion in funds in recent years, with the top 10 companies generating US$5.3 billion in series A to D funding rounds (10). US-based Sana Biotechnology leads the field garnering US$700 million to develop scalable manufacturing for genetically engineered cells and its pipeline program, which include CAR-T cell-based therapies in oncology and CNS (Central Nervous System) disorders (11). In second place, Editas Medicine attracted $656.6 million to develop CRISPR nuclease gene editing technologies to develop gene therapies for rare disorders (12).

Overall, CGTs have attracted the pharma industrys attention as they provide an alternative route to target diseases that are poorly served by pharmaceutical and/or medical interventions, such as rare and orphan diseases. Private investors continue to pour money into this sector because a single shot has the potential to bring long-lasting clinical benefits to patients (13). In addition, regulators have approved several products and put in place fast track designation to speed up patient access to these life-saving medicines. Furthermore, healthcare providers have established reimbursement policies and manufacturers have negotiated value- and outcome-based contracts to reduce barriers to access to these premium priced products

On the downside, the manufacture of CGTs is labor intensive and expensive with manufacturing accounting for approximately 25% of operating expenses, plus there is still significant variation in the amount of product produced. On the medical side, many patients may not be suitable candidates for CGTs or not produce durable response due to pre-exposure to the viral vector, poor gene expression, and/or the development of immunogenicity due to pre-exposure to viral vectors. Those that can receive these therapies may suffer infusion site reactions, and unique adverse events such as cytokine release syndrome and neurological problems both of which can be fatal if not treated promptly (14).

Despite the considerable advances that have been made in the CGT field to date, there is still much work needed to enhance the durability of responses, increase biomanufacturing efficiencies and consistency and to implement a seamless supply chain that can ensure these agents are accessible, cost-effective, and a sustainable option to those in need.

Cleo Bern Hartley is a pharma consultant, former pharma analyst, and research scientist.

BioPharm InternationalVol. 35, No. 10October 2022Pages: 4951

When referring to this article, please cite it as C.B. Hartley, "Growth in Cell and Gene Therapy Market," BioPharm International 35 (10) 4951 (2022).

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Growth in Cell and Gene Therapy Market - BioPharm International

In 2018, when he was 13, Ethan Ralstons eyesight started to get blurry. The diagnosis was devastating. He had been born with Leber Hereditary Optic Neuropathy (lhon), a rare genetic disorder that eats away at the cells of the optic nerve until it causes blindness.

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Given that America and Europe between them see just 800 cases of lhon a year young Mr Ralston was very unlucky. In another way, though, he could be counted fortunate. GenSight, a French biotech company, had for years been working on a gene therapy for lhon. The condition is caused by a mutation in a gene called nd4 which causes the bodys cells to make a faulty protein. The therapy, called Lumevoq, sought to resolve the problem by adding the canonical version of nd4 to cells in the retina and optic nerve. By 2018 Lumevoq was in clinical trials. Shortly after his diagnosis Mr Ralston was treated with it.

Today his eyesight has almost returned to normal. He can work on a computer, drive a car, go bowling with his friends. He would seem to be cured.

Such stories are becoming increasingly common. In the 2010s a whole year might see only one new gene-therapy approval from regulators. This August alone saw two, one for beta thalassaemia and one for haemophilia a, both diseases of the blood. The Alliance for Regenerative Medicine, an international industry group for cell and gene therapies, says that 1,369 groups are developing such treatments and just over 2,000 clinical trials are under way. Most of those in their earliest stages and may well progress no further: many are cell therapies which do not require changes to the patients genes. Still, according to scientists from the Centre for Biomedical Innovation in Cambridge, Massachusetts, there are enough trials under way that 40-50 new gene therapies could be approved for clinical use by 2030.

A lot of these will be used in the fight against cancer. Removing from the body some of the t-cells which the immune system uses to fight cancer, giving them a gene that lets them recognise a cancer-specific trait and putting them back is the basis of car-t therapies, one of the hottest approaches around (the car stands for chimeric antigen receptor). But there will also be lots that tackle inherited diseases. There are clear signs that this surge has begun. Janet Lambert, the boss of the Alliance for Regenerative Medicine, anticipates that Europe and America will see a record number of such gene therapies approved this year (see table).

In a world where saying that something is in some person or other entitys dna has become a shorthand for seeing it as part of their very essence, dealing with inherited diseases this way looks truly revolutionary. It is one of the most compelling concepts in modern medicine as a recent review paper put it. The ability to provide someone with a single treatment that will alleviate a terrible condition for a decade or moreperhaps even for lifeis an intervention without any obvious parallel.

But it comes with a number of challenges. The techniques being used still carry risks. The therapies themselves are enormously expensive, not just because of the research required to develop themthat is expensive all across the biotech worldbut because the cost of making them is particularly high. What is more, some may face stiff competition from other approaches, some of them equally novel. These may allow some of the conditions gene therapy seeks to fix to be treated in cheaper ways.

This raises the possibility that, impressive as they are, gene therapies might be relegated to a niche treating a small number of patients in rich countries. That would be a poor outlook for millions around the world who suffer from more common genetic diseases, such as sickle-cell disease, and other conditions. It could also scupper the chances of gene therapy moving beyond the realm of single-gene disorders to tackle more complex conditions. For many more people to experience the sort of benefits that have changed Mr Ralstons prospects, the ability to produce miracles will not be enough. They have to be produced affordably in ways that can be adapted to conditions far removed from the elite hospitals where trials typically take place today.

To design a gene therapy, you need a gene you want to add to the patients cells and a way of getting it into them. Finding the first is, in principle, easy: thousands of diseases, most of the worst thankfully rare, come about because of a garbled copy of a single gene. That means they might in principle be alleviated by the addition of the normal version. The second is normally the job of a modified virus that can no longer reproduce but that can get a new gene into its target cells: a viral vector.

Sometimes cells are taken out of the body, transformed by a vector and put back in, as they are in car-t cancer therapies. Zynteglo, a gene therapy for beta thalassaemia made by bluebird bio, a startup with an aversion to capital letters, works this way. On August 17th it became the third gene therapy for an inherited disease to be approved by Americas Food and Drug Administration (fda). In other cases the vector does its work inside the body. Lumevoqauthorised for use in France in 2021, but not yet by the European Medicines Agency (ema) or the fdawas injected directly into Mr Ralstons eyes.

The first gene-therapy trial, which treated a single child with a specific and severe immunodeficiency called ada-scid, got under way in 1990. It did not lead quickly to a commercial product (a different gene therapy for ada-scid, Strimvelis, was eventually approved in 2016) but it paved the way for a number of successors. Unfortunately in 1999 the nascent field was rocked by the death of Jesse Gelsinger, an 18-year-old, four days after he had been given a gene intended to fix his inherited inability to metabolise ammonia.

His death was caused by his immune systems response to the adenovirus used as a vector. That knowledge drove the hunt for safer vectors; James Wilson, a gene-therapy pioneer at the University of Pennsylvania, where the trial during which Mr Gelsinger died was based, uncovered the potential of adeno-associated viruses (aav). These are widespread in humans and are not known to cause any sort of disease; they provoke little or no immune response. Similar advantages are sought by vaccine-makers when they look for vectors. (The Oxford AstraZeneca covid-19 vaccine works in this way, using an adenovirus to put dna describing a telltale viral protein into the bodys cells.)

For gene therapies, aavs have the big advantage of coming in more than 100 different flavours, or serotypes, each of which has different preferences when it comes to which sorts of cell to infect. Vectors derived from aavs are able to home in on specific tissues such as the optic nerve, or the central nervous system, or the muscles.

However, aav-based vectors are not without problems. A recent analysis of almost 150 gene-therapy trials using them found that 35% had seen serious adverse events, including brain-imaging findings of uncertain significance. Large doses of the vector have also been linked to safety concerns. In 2018 Dr Wilson warned that high doses of aav caused life-threatening toxicity in piglets and monkeys. At the same time he resigned from the scientific advisory board of Solid Biosciences, a gene-therapy firm focused on muscular dystrophy, citing emerging concerns about the possible risks of too much aav. The firm says his resignation was due to findings in experiments that were unrelated to its work. Nonetheless its regulatory filings acknowledge that the high dosing requirements for the therapy it is developing may increase the risk of side-effects.

In August Novartis, a Swiss drug company, reported two liver-related deaths in children who were treated with its gene therapy for spinal muscular atrophy (sma). Trials of a therapy being developed by Astellas, a Japanese drug company, for a rare muscle disease called x-linked myotubular myopathy produced some spectacular results, but also saw three children die with sepsis and gastrointestinal bleeding as a consequence of liver failure and a fourth from other liver-related complications.

Bernhardt Zeiher, who is about to retire as Astellass head of development, recently told Endpoints, an online publication, that the company thinks the deaths were caused by a combination of a reaction to the aav vector used and an underlying risk of liver disease. The transformational nature of the therapy itself, he added, means that the firm is committed to finding a way forward in the field.

There have also been concerns over the potential for some vectors to trigger cancers in the long term. You are giving [patients] quadrillions of vector particles, says David Lillicrap, a professor at Queens University in Kingston, Ontario, who works on haemophilia. A very, very small percentage are going to get into the host genome [in] susceptible areas. In 2020 a patient who was being treated for ada-scid with Strimvelis, which uses an rna-based retrovirus as a vector, developed leukaemia. Orchard Therapeutics, the company marketing Strimvelis, has said it may be attributable to the way the gene integrated itself into the genome.

Nicole Paulk of the University of California, San Francisco, says that despite some worrying headlines the aav vector is extraordinarily safe. She says it has been or is being used in over 250 clinical trials with tens of thousands of patients, and that, compared with cancer drugs, it has been remarkably well tolerated.

Given that patients can have terrible experiences with cancer drugs that might not seem reassuring. But there are two other factors to bear in mind. One is that the patients in gene-therapy trials are often very unwell to begin with, and may come into them on other quite arduous treatment regimes. Adverse events are to be expected. More importantly, they may have little if anything by way of other options.

Karen Pignet-Aiach is the founder and boss of Lysogene, a French gene-therapy firm which concentrates on errors in the central nervous system. Firms like hers, she says, have to battle to make sure that regulatory agencies stick to the principle that the risks attached to a treatment have to be balanced against the benefits that a therapy for something lethal and untreatable could bring. In 2020 Lysogene had to deal with the difficult death of a child during a trial, putting a temporary halt to its clinical work. Ms Pignet-Aiach says the death may have been caused by medication given outside the trial but that there was no link with the treatment that was actually being investigated. As to the possible benefits, when she says Our patients have nothing [else] available she knows what she is talking about: she lost a daughter to Sanfilippo syndrome, one of the disorders the company is tackling.

Hold-ups when patients die are understandable, but they increase the cost, and risk, of developing these medicines. And there are other hurdles. Because no one yet knows how many years of duty can be expected from gene therapies, long-term studies are needed; regulators will often insist on them continuing after approval. Because the conditions involved are often progressive and untreatable by other means there are real ethical concerns about randomising trials, something often seen as the best way to clear-cut results.

These problems go some way to explaining the remarkable price of the therapies which make it to marketand which, because of those prices, sometimes leave it soon afterwards. When Glybera, a therapy developed by uniQure, a Dutch company, to address an error in the way fat is processed in a particularly rare condition, got the nod from the ema in 2012 it became the first gene therapy to be approved by a stringent regulator. It also became the first medical treatment with a price tag of $1m. The first approval by the fda, in 2017, was for Luxturna, a gene therapy to prevent another form of progressive vision loss. Roche, a big-pharma company, priced it at $425,000. Per eye. In 2019 Zolgensma, Novatiss treatment for sma, went on sale at $2.1m. Last year the mother of a baby being treated with Zolgensma remarked that everyone who touched the drug, or was around it, had to be trained to handle it: it was like carrying gold. Libmeldy, approved by the ema in 2020 to treat a disorder which degrades the nervous system, costs 2.8m ($3.3m) a dose.

Pharmaceutical companies do not discuss the basis of drugs prices. In America the approach is typically taken to be an assessment of what the market will bear, which has led to an environment accustomed to high prices. The problem with gene therapies is that the price being charged seems in some cases well beyond what the market will bear.

Take Glybera, the first-approved therapy. Only a single dose was ever sold. It has been withdrawn from the European market. According to Stat, another online publication, after the ema approved Zynteglo in 2019 bluebird bio offered it in Germany for $1.8m a treatment; Germany offered to pay $950,000 in cases where it worked, $790,000 when it didnt. The firm subsequently withdrew it from the European market; it has done the same with eli-cell, which treats an irreversible nerve disease. The price it has set for Zynteglo in America is $2.8m.

Some companies are getting out of the market altogether, suggesting they see no way forward. Amicus Therapeutics, a biotech firm which had been working on a number of gene therapies at one point, got out of the field completely earlier this year. Within two years of having put the ada-scid therapy Strimvelis on the market in Europe, gsk, a big drug company, offloaded the treatment to Orchard.

If the makers are worried, so are the buyers. Health systems and insurance firms can cope with one or two such therapies at the far end of the price spectrum. Britains nhs, quite capable of ruling out therapies on the basis of cost, has bought both Zolgensma and Libmeldy (it negotiated a significant discount). But as the number of approved treatments grows the economics are looking more challenging.

A study published this February by the Aspen Institute, a think-tank, and the Blue Cross Blue Shield Association, an association of American insurance companies, looked at the expected arrival of 90 gene therapies and cell therapies. By 2031 the annual acquisition cost for 550,000 patients would be $30bn. With the countrys total prescription-drug bill currently at $577bn, that is relatively small; but it is still significant. Virtually all the buyers for health care in America have warned about the cost burden they expect as the numbers of these products grow.

I think everyone agrees that the pricing of gene therapies is a crisis, says Dr Paulk. The crisis has two main drivers: the amount of work needed to develop and make the therapies and the lack of good models for pricing one-off interventions which could obviate the need for lifelong treatment.

The costs of gene therapies are not just down to arduous research and development and long-drawn-out trials. Making the material which gets put into the patient is not for the faint of heart says Jay Bradner, president of the Novartis Institutes for BioMedical Research. Gene therapies are like snowflakes, says Dr Paulk. Every aav program and every lot is completely unique. Bespoke, though, does not mean small scale. She says that for diseases where you need to get the vector into a particularly large number of cells, such as Duchenne muscular dystrophy, It is not uncommon that we need to use at least a 50 litre, if not a 200 litre, bioreactor to make a single dose for a single patient.

Analysts at the Boston Consulting Group recently estimated that the cost of manufacturing gene therapies ranges from $100,000 to $500,000 per dose. A lot of this manufacturing is done by third parties, and the difficulties of the process can be seen in the limited capacity they offer. Biotech firms that want to get into gene therapy can have to wait up to three years for manufacturing capacity to become available, according to insiders.

On the other side of the coin is the difficulty of calculating benefits. If a $2m treatment really does provide decades of life then the cost per year is down in the tens of thousands of dollarshardly out of line with many other modern therapies. This has led some to suggest that payment might be in annual instalments. In the long term that could make the total larger, but it would spread it out. Another possible innovation is to couple such an approach with the option of stopping paying if the therapy stops working.

The question as to whether the therapy is worth the price has to be answered in the context of what if anything the competition can offer. Take sma, which is caused by a faulty version of a gene called smn1. Zolgensma treats this problem by providing cells with an extra copy of smn1 which works. A treatment called Spinraza uses a method that increases the amount of protein made from a very similar but normally much less productive gene, smn2: its active agent is a molecule called an antisense oligonucleotide.

Antisense treatments are being tried against various conditions which look as if they can be alleviated by getting an existing gene expressed more or less. They are not permanent; Spinraza needs to be administered every four months. Moreover, although the cost of manufacture is far lower than for gene therapies, they are still not cheap. Biogen, the biotech company that makes Spinraza, charges up to $125,000 per dose. But such treatments may well be easier to scale up, and thus see their costs reduced.

Haemophilia, for a form of which Roctavian, made by Biomarin, a biotech company, received ema approval on August 24th, is another condition where alternative approaches have made huge strides, according to Dr Lillicrap. One of the newest antibodies used in its treatment needs to be given only every two to four weeks, rather than every few days, as used to be the case. Artificial versions of the clotting factors haemophiliacs cannot make have been engineered so as to last longer in the blood. There are also clever new ways of lowering the expression of proteins which suppress coagulation.

It is not just what the competition can offer now that matters. It is what it might offer in five or ten years time. Spending a lot on a gene therapy today may prove a good investment if it provides many years of reasonably healthy life. But at the same time it is a bet against the real possibility that a cheaper and possibly better treatment is on the way.

The answer to that conundrum is to make sure that gene therapies get better and cheaper, too. Various companies are looking at ways to improve manufacturing. 64x Bio, based in San Francisco, is testing millions of possible cell lines to try and find those that will grow vectors like aav most efficiently. Others are looking at the vectors themselves, trying to make them less arousing to the immune system, better targeted and more likely to actually carry the gene of interest. Current procedures leave a lot of the vectors empty; increasing the proportion that is filled would reduce dose size and costs.

Ideas for making better things to put in the vectors abound. The field started with basic tools; would-be therapists could put a gene into the genome but had little control over where it went and thus how it might be controlled and what collateral damage it might cause. In the past decade, though, great advances have been made in gene editing, a set of techniques which allow the message in an existing gene to be rewritten. As Fyodor Urnov, a professor at the University of California, Berkeley, puts it, gene therapy is like adding a fifth wheel to a car with a flat tyre; gene editing is repairing the flat.

At present, gene editing is a particularly promising route for therapies in which blood-cell-making stem cells are removed, fiddled with and reinserted into the patients bone marrow. Two clinical trials in which this sort of editing is used against sickle-cell disease, which is brought about by mutations in haemoglobin which make red blood cells deformed and defective, are already well under way. One is for a treatment from Vertex Pharmaceuticals, based in Massachusetts and crispr Therapeutics, the other is by bluebird bio.

More than a dozen patients are reported to have been cured, and it is possible that one of the treatments could be ready for approval next year. There are other gene therapies for the condition at earlier stages. There is also, again, competition from other approaches. On August 8th Pfizer, another big drug company, announced its intention to acquire Global Blood Therapies, a biotech company, for $5.4bn. For that it gets Oxbryta, a drug that stops the mutant haemoglobins from sticking together, and some other therapies.

A similar gene-therapy approach is being used to tackle aids by editing into cells traits that make them immune to hiv. But here the price issue, already confounding, becomes all but lethal. Most people with aids, like most people with sickle-cell disease, live in low- and middle-income countries. According to Mike McCune of the Bill & Melinda Gates Foundation, in countries where antiretroviral therapy for aids costs between $70 and $200 a year an all-out cure for the disease, even if it were possible, would need to come in at $2,000 or less.

If this sounds staggeringly unlikely, it is worth considering that there is a partial precedent. The cost of making target-specific monoclonal antibodies was enormous when they were first developed. But between 1998 and 2009 manufacturing improvements brought about a 50-fold reduction in the cost of goods. Matching that would allow gene therapies to move into middle-income countries, if not low-income ones.

As Mr Ralston can testify, gene therapies border on the miraculous. But they remain miracles of science, their creation incredibly time-intensive [and] people-intensive, as Dr Paulk puts it. Now they must become routinely applicable miracles of medicine. That requires extending the range of conditions they address, learning how long they last and expanding the number of patients they help. In many ways that effort will be more demanding than the work to date. It will have to go well beyond the labs currently tinkering, the charities currently raising funds for rare diseases and the companies desperately trying to find a way to sell the remarkable things they have created. But their remarkable work has made it possible for that second miracle-making effort to begin.

Editors note (September 1st 2022): Due to an editing error, the print and earlier online versions of this article wrongly stated that Lumevoq had been approved by the ema and that Oxford AstraZeneca vaccine used an AAV vector rather than an adenovirus. Sorry.

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Gene therapies must become miracles of medicine | The Economist

This month, Insights & Outcomes digs into the nitty gritty of quantum potholes, foreign DNA, relapsing fever, and the thermodynamics of hydrogen binding.

As always, you can find more science and medicine research news on Yale News Science & Technology and Health & Medicine pages.

In some quantum mechanical systems, researchers say, the energy landscape is going to have a few potholes touching points where the state of the system is not defined. Understanding how these potholes, known as singularities, affect a quantum systems behavior is a key area of physics research.

In a new study in the journal Science, incoming Yale assistant professor of physics Charles D. Brown II and his collaborators found a new approach for probing certain types of quantum singularities.

For the study, Brown and co-authors from the University of California-Berkeley conducted a unique quantum simulation experiment with intersecting lasers that trap and manipulate ultra-cold atoms in crystals made of light. The researchers moved the atoms along trajectories that entered, turned, and exited singularities at linear touching points (called Dirac points) and quadratic touching points.

A quadratic band touching point is a point at which two energy bands have equal values but away from this point the energy values are non-equal, and the gap between the energy bands grows proportional to the square of the distance from the point.

The researchers found that the ultimate state of the system depended only on the entry and exit angles through the singularities.

We developed a distinct method to probe singularities, importantly including non-Dirac singularities, in ultracold atom quantum simulators, Brown said.

Brown is first author and co-corresponding author of the study. Dan Stamper-Kurn of the University of California-Berkeley is the senior and co-corresponding author.

Relapsing fever, a condition caused by bacterial infections transmitted by lice or tick bites, is characterized by recurrent bouts of fever, headache, and muscle aches. If left untreated, it can cause severe disability and even death.

Yet the condition which often afflicts people living in poorer regions of Africa, central Asia, and Central and South America remains a relatively unstudied disease.

In a new study, a team of Yale researchers analyzed different species of Borellia bacteria that cause many cases of relapsing fever and Lyme disease in humans, identifying a single molecule that allows two species of Borrelia to avoid immune system detection. They found that mice infected with relapsing fever but lacking the molecule CD55 had lower levels of the pathogen and a bolstered immune response.

While CD55 normally acts as a regulator of immune system response to protect potentially damaging response to host tissues, in cases of relapsing fever it is hijacked by bacteria to avoid detection and eradication, explained co-lead author Gunjan Arora, associate research scientist in the lab of senior author Erol Fikrig, the Waldemar Von Zedtwitz Professor of Medicine (Infectious Diseases) and Professor of Epidemiology (Microbial Diseases) and of Microbial Pathogenesis. The pathogens got very smart and used a molecule designed to balance our immune system response to survive in the host, Arora said.

Geoffrey Lynn, associate research scientist, is co-lead author of the study published in the journal mBio.

For decades, researchers studying the conversion of light energy into electrical or chemical energy such as in solar cells have focused on the movement of electrons, which are central to the process.

But in a new study in the journal Chem, Yale chemists James Mayer and Hyunho Noh take a different approach. They looked at energy conversion reactions as a type of whole atom transfer of hydrogen atoms, which have one electron and one proton, and are found in most energy conversion reactions.

For the study, Mayer, the Charlotte Fitch Roberts Professor of Chemistry in Yales Faculty of Arts and Sciences, and Noh, a postdoctoral associate in chemistry, measured the thermodynamics of hydrogen-atom binding to nickel oxide electrodes when in contact with three solvents: water, dimethylformamide, and acetonitrile.

Our work shows that the electron-only model is not sufficient, Mayer said. The other new approach this paper develops is that the solid/solution interface has a range of surface sites, with somewhat different strengths of chemical bonds. While this range of energies is well known in some areas of surface science, the importance of this effort has not been emphasized.

They found that the binding of hydrogen was the same no matter which solvent they used or what was dissolved in the solution, showing that this parameter is the best intrinsic property of the electrode, while the electron-only parameters vary strongly with the nature of the medium.

A medication commonly used to treat heart failure may also reduce alcohol drinking, especially among those diagnosed with alcohol use disorder, researchers from Yale School of Medicine and the National Institutes of Health Intramural Research Program (NIH IRP) report.

The effects of the drug spironolactone on drinking behavior in mice, rats, and humans were reported in the journal Molecular Psychiatry.

This is a remarkable example of bench to bedside team science showing that an inexpensive, off-patent drug, may help reduce alcohol consumption, said co-senior author Amy Justice, the C.N.H. Long Professor of Medicine and professor of public health.

In animal models of excessive alcohol drinking, researchers from the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) IRPs found that when administered to rats and mice, spironolactone reduced consumption of alcohol, and it did so in a dose dependent manner.

The Yale team, headed by Justice, then analyzed data from the U.S. Department of Veterans Affairs to assess the effects of spironolactone taken for at least 60 days on individuals reporting current alcohol use. Compared to similar individuals who did not receive the drug, those who took spironolactone reported greater decreases in alcohol consumption, the researchers found.

And those who had more severe alcohol problems, particularly those diagnosed with alcohol use disorder, benefitted the most, Justice said.

There are limited number of drugs that can help reduce harmful alcohol consumption, which costs the U.S. healthcare system $28 billion annually and another $179 billion in lost productivity, according to the Centers for Disease Control and Prevention.

Spironolactone is a medication in widespread use and a proven safety profile that is no longer on patent offering a ready additional tool to treat alcohol use disorder, the authors said.

All together, our findings provide strong justification for randomized clinical trials to further investigate the potential of this medication in patients with alcohol use disorder, said co-first author Christopher Rentsch, assistant professor at the Yale School of Medicine and London School of Hygiene & Tropical Medicine.

Lorenzo Leggio of the NIDA and NIAAA IRPs and Leandro Vendruscolo of the NIDA IRP are co-senior authors.

Yale scientist Emily Sandall will spend a year with the Office of Trade Policy & Geographic Affairs in the U.S. Department of Agriculture as a recipient of the American Association for the Advancement of Sciences Science & Technology Policy Fellowship.

Sandall is a postdoctoral researcher in the Department of Ecology and Evolutionary Biology, in Yales Faculty of Arts and Sciences.

Her research has focused primarily on insect biodiversity patterns, through geographic, morphological, and phylogenetic methods. As a postdoctoral research associate in the Yale Center for Biodiversity & Global Change, she examined global dragonfly biogeography and led a team of species experts. In her fellowship role, her research background in insect biodiversity, taxonomy, natural history, and data standards will enable her to share expertise on topics related to agricultural policy throughout the U.S. government, including species-level protections or restrictions. For instance, on topics related to an endangered or invasive species, she will be able to provide critical insights into scientific literature about how that affects trade agreements and provide summaries to negotiators and policymakers to inform their decisions.

Foreign DNA, or genetic material that comes from an organism of the same or different species, is key to the survival of bacteria, helping them resist antimicrobial agents and adapt to a variety of changing environments. Bacterial pathogens also often rely on foreign genes to cause disease in humans. But how do bacteria know which foreign genes to accept?

To answer this question, researchers in the lab of Eduardo Groisman, the Waldemar Von Zedtwitz Professor of Microbial Pathogenesis, zeroed in on the role of a widespread protein known to prevent the expression of foreign DNA. In doing so, they solved the question of how bacteria can overcome foreign gene silencing to access the benefits of foreign DNA.

Specifically, the researchers explored how bacteria can express genes otherwise suppressed by the foreign gene silencing protein H-NS. Because H-NS amounts were believed to remain constant, researchers had ascribed the overcoming of foreign gene silencing to other proteins. In the new study, however, Jeongjoon Choi, an associate research scientist, and Groisman found that the human pathogen Salmonella Typhimurium degrades H-NS when inside a mammalian host and they identified the enzyme responsible for H-NS degradation.

According to their findings, the researchers identified a mutant form of H-NS that resists degradation and found that the beneficial bacterium Escherichia coli cannot express foreign genes or colonize the gut of mice when it harbors the mutant H-NS.

The researchers demonstrated that H-NS degradation is essential for different bacterial species to express foreign genes, showing that beneficial E. coli and pathogenic Salmonella both use the same strategy to overcome gene silencing and thus adapt to the specific environments they face during infection. The research was published in the Proceedings of the National Academy of Sciences.

Creating new neuropsychiatric drug candidates from a virtual library

Study finds all African carnivores at risk for range loss

Yales Spielman wins $3 million Breakthrough Prize

The roots of biodiversity: how proteins differ across species

Jumping genes yield new clues to origins of neurodegenerative disease

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Insights & Outcomes: Foreign DNA, quantum potholes and relapsing fever - Yale News

University of Minnesota researchers recently led successful efforts to build the first genome for Pallass cat (Otocolobus manul), a small wild cat native to central Asia known for its grumpy facial expression. The cat, which faces growing challenges from climate change, habitat fragmentation, and poaching, had no available genetic resources to help with conservation prior to this study.

The study, published in NAR Genomics and Bioinformatics, was led by Nicole Flack, a doctoral candidate in the College of Veterinary Medicine, along with Christopher Faulk, a professor in the College of Food, Agricultural, and Natural Resource Sciences.

The researchers used blood samples from Tater, a 6-year-old Pallass cat who lives at the Utica Zoo in New York, to construct a high-quality diploid nuclear genome assembly, a representative map of genes for the species.

The study results include confirmation that the Pallass cat is more closely related to certain wild cat species and less related to house cat species than some previous studies have suggested.

An allele-specific methylation analysis the first of its kind in cats also sheds light on how gene expression is regulated in mammals through a process called genomic imprinting. Mammals inherit two copies of each gene from their parents; usually these copies are equally active, but imprinted genes have chemical tags that turn off one copy. These findings pave the way to a deeper understanding of growth, development and hybridization among cat species, which could have important implications for genetic diversity and conservation.

The genomic resources the study produced provide a comprehensive genetic reference for conservation efforts working to track the health of wild populations and optimize breeding programs for cats in captivity.

Im hopeful our work will help with Pallass cat conservation. Genetic diversity is a key factor in the health and trajectory of animal populations, but its difficult to study without anything to compare to, said Flack. Our reference genome will be useful for monitoring the health of the Pallass cat population, both in captive breeding programs and in the wild.

These resources will enable future research not only on Pallass cat, but on the health, disease and physiology of house cats and other species even translational work to humans. This is particularly true of the assessment of allele-specific methylation, because imprinting is a unique feature of genes shared across mammals, and has significant implications for our understanding of human growth and development. But it has been chronically understudied because of the limitations of existing technology limitations that nanopore sequencing overcomes.

Our small team was able to provide Taters high-quality diploid cat genome including epigenetic information while using minimal financial and lab resources, said Faulk. We hope to serve as a model for conservation and sequencing projects from pathogens to people, especially by low-resource groups on limited budgets.

Project funding was provided by the United States Department of Agriculture National Institute of Food and Agriculture, the Norn Group, the National Institutes of Health, and the National Science Foundation.

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About the College of Veterinary MedicineThe University of Minnesota College of Veterinary Medicine affects the lives of animals and people every day through educational, research, service, and outreach programs. Established in 1947, the University of Minnesota College of Veterinary Medicine is Minnesotas only veterinary college. Fully accredited, the college has graduated over 4,000 veterinarians and hundreds of scientists. The college is also home to the Veterinary Medical Center, the Veterinary Diagnostic Laboratory, the Leatherdale Equine Center and The Raptor Center. Learn more at vetmed.umn.edu.

About the College of Food, Agricultural and Natural Resource Sciences The University of Minnesotas College of Food, Agricultural and Natural Resource Sciences (CFANS) strives to inspire minds, nourish people, and sustainably enhance the natural environment. CFANS has a legacy of innovation, bringing discoveries to life through science and educating the next generation of leaders. Every day, students, faculty, and researchers use science to address the grand challenges of the world today and in the future. CFANS offers an unparalleled expanse of experiential learning opportunities for students and the community, with 12 academic departments, 10 research and outreach centers across the state, the Minnesota Landscape Arboretum, the Bell Museum of Natural History, and dozens of interdisciplinary centers. Learn more at cfans.umn.edu.

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U of M researchers map the genome of the world's grumpiest cat - UMN News

St. Jude Childrens Research Hospital scientist Madan Babu Mohan, Ph.D., Center of Excellence in Data-Driven Discovery director and member of the Department of Structural Biology, has been elected a Fellow of the Royal Society of London. The Royal Society is the oldest scientific academy in continuous existence.

Babu was selected to join the Royal Society for his pioneering data science-based strategies to reveal fundamental principles in biological systems. His scientific accomplishments include determining the molecular mechanisms governing G-protein-coupled receptor (GPCR) signaling, uncovering the roles of disordered protein regions in biology and disease, and establishing genome-scale principles of gene regulation.

One-third of all Food and Drug Administration-approved drugs target GPCRs, membrane proteins found on the surface of cells. Babus work has shown how genetic and isoform variability of GPCRs can influence drug responses. His most recent work investigated how GPCR selectivity for G-proteins is determined. Understanding this family of proteins is of tremendous interest to the development of novel therapeutics.

I am honored for our work to receive this recognition, Babu said. The science we have achieved is possible because of long-term support for fundamental research and the collaborative environment at St. Jude and the MRC Laboratory of Molecular Biology in Cambridge, England. I am grateful for the many contributions of my past and current colleagues, as well as my mentors and family.

Dr. Babus election to the Royal Society is well-earned, and we are all honored to call him a colleague, said James R. Downing, M.D., president and CEO of St. Jude. His investigations of GPCRs have the potential to have profound implications for pharmaceutical development. Through these discoveries, we can advance cures for pediatric cancer and other catastrophic diseases.

I am delighted to welcome our newest cohort of Fellows, said Sir Adrian Smith, President of the Royal Society. They are pioneering scientists and innovators from around the world who have confounded expectations and transformed our thinking.

Founded in the 1660s, the Royal Society is an independent scientific academy of the U.K. and the Commonwealth. Its Fellows have included many of the worlds most eminent scientists and technologists, representing a range of personalities, from Sir Isaac Newton and Benjamin Franklin to Dorothy Hodgkin and Robert Webster (St. Jude Infectious Diseases, emeritus).

This year sees 59 Fellows, 19 Foreign Members and two Honorary Fellows elected. Babus fellow U.S.-based new Fellows and Foreign Members include researchers at Google DeepMind, Harvard University, the Howard Hughes Medical Institute, the Institute for Advanced Study, Stanford University and the University of Chicago.

Babu joined the faculty of St. Jude in 2020, following a 14-year tenure as a program leader at the MRC Laboratory of Molecular Biology in Cambridge, England. He earned his Ph.D. in computational genomics from Cambridge University and his undergraduate degree from Anna University, Chennai, India. Babu completed a postdoctoral fellowship with the National Institutes of Health, Bethesda, Maryland.

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St. Jude scientist M. Madan Babu elected to the Royal Society of ... - St. Jude Children's Research Hospital

The poster and oral presentation winners of the Wayne State University School of Medicines ninth annual Vision Research Workshop have been announced.

The workshop, held Oct. 12, was presented by the Department of Ophthalmology, Visual and Anatomical Sciences, and the Kresge Eye Institute.

Presentation winners included:

Poster Presentations

First place: Nicholas Pryde, Assessment of NanodropperTM eyedropper attachment

Second place: Bing Ross, Mechanism of Preferential Calcification in Hydrophilic Versus Hydrophobic Acrylic Intraocular Lens

Third place: Pratima Suvas, Expression, Localization, and Characterization of CXCR4 and its ligand CXCL12 in herpes simplex virus-1 infected corneas

Oral Presentations

First place: Ashley Kramer, A comparative analysis of gene and protein expression in a zebrafish model of chronic photoreceptor degeneration

Second place: Jeremy Bohl, Long-distance cholinergic signaling contributes to direction selectivity in the mouse retina

Third place: Zain Hussain, Diagnostic and Treatment Patterns of Age-Related Macular Degeneration among Asian Medicare Beneficiaries

Mark Juzych, M.D., chair of the Department of Ophthalmology, Visual and Anatomical Sciences, and director of the Kresge Eye Institute, gave welcome remarks.Linda Hazlett, Ph.D., vice dean of Research and Graduate Programs and vice chair of the department, provided an overview of research.

The keynote speaker giving the annual Robert N. Frank, M.D., Clinical Translational Lecture, was Reza Dana, M.D., M.P.H., the Claes H. Dohlman Chair and vice chair for Academic Programs in Ophthalmology at Harvard Medical School, who presented New Ways of Doing Old Things: Translational Investigations in Management of Common Corneal and Ocular Surface Disorders.

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Winners of ninth annual Vision Research Workshop named - Wayne State University

Newswise PHILADELPHIAAdults with a genetic form of childhood-onset blindness experienced striking recoveries of night vision within days of receiving an experimental gene therapy, according to researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

The patients had Leber Congenital Amaurosis (LCA), a congenital blindness caused by mutations in the gene GUCY2D. The researchers, whose findings are reported in the journal iScience, delivered AAV gene therapy, which carries the DNA of the healthy version of the gene, into the retina of one eye for each of the patients in accordance with the clinical trial protocol. Within days of being treated, each patient showed large increases, in the treated eye, of visual functions mediated by rod-type photoreceptor cells. Rod cells are extremely sensitive to light and account for most of the human capacity for low-light vision.

These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness, said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology at Penn.

LCA is one of the most common congenital blindness conditions, affecting roughly one in 40,000 newborns. The degree of vision loss can vary from one LCA patient to another but all such patients have severe visual disability from the earliest months of life. There are more than two dozen genes whose dysfunction can cause LCA.

Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the phototransduction cascadethe process that converts light to neuronal signals. Prior imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, especially in rod-rich areas, hinting that rod-based phototransduction could work again if functional GUCY2D were present. Early results with low doses of the gene therapy, reported last year, were consistent with this idea.

The researchers used higher doses of the gene therapy in two patients, a 19- year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits. In daylight, the patients had some, albeit greatly impaired, visual function, but at night they were effectively blind, with light sensitivity on the order of 10,000 to 100,000 times less than normal.

The researchers administered the therapy to just one eye in each patient, so the treated eye could be compared to the untreated eye to gauge treatment effects. The retinal surgery was performed by Allen C. Ho, MD, a professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests revealed that, in both patients, the treated eyes became thousands of times more light-sensitive in low-light conditions, substantially correcting the original visual deficits. The researchers used, in all, nine complementary methods to measure the patients light sensitivity and functional vision. These included a test of room navigation skills in low-light conditions and a test of involuntary pupil responses to light. The tests consistently showed major improvements in rod-based, low-light vision, and the patients also noted functional improvements in their everyday lives, such as can [now] make out objects and people in the dark.

Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy, said study co-author Artur V. Cideciyan, PhD, a research professor of Ophthalmology at Penn.

To the researchers, the results confirm that GUCY2D gene therapy to restores rod-based photoreceptor functionsand suggest that GUCY2DLCA patients with more severe rod-based dysfunction are likely to benefit most dramatically from the therapy. The practical message is that there should be an emphasis on rod vision measurements at screening of LCA candidates and in monitoring them throughout a treatment trial.

The findings, the researchers said, also underscore the remarkable fact that in some patients with severe congenital vision loss, the retinal cell networks that mediate vision remain largely alive and intact, and need only the resupply of a missing protein to start working again, more or less immediately.

The ongoing clinical trial is registered at clinicaltrials.gov as trial NCT03920007.

Support for the research was provided by Atsena Therapeutics, Inc., the developer of the GUCY2D gene therapy; the National Institutes of Health (R01 EY11522); and by a CURE Formula grant from the Pennsylvania Department of Health.

Read more:
Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness - Newswise

Its natural for women to worry about breast cancer, especially since many people know someone who was touched by the disease. While there is no foolproof way to prevent breast cancer, there are things you can do to lower your risk. Some factors you cant change, but knowing what can help is key to lowering your risk of breast cancer.

Breast cancer is the second most common cancer among women in the U.S.some types of skin cancer are the most common. Between 1989 and 2020, breast cancer death rates decreased by 43%, but racial and ethnic inequities still exist. While breast cancer incidence is lower among Black women than white women, the death rate is 40% higher among Black women than white women, according to the American Cancer Society. That is because about one in five Black women with breast cancer have triple-negative breast cancermore than any other racial or ethnic group. Meanwhile, Asian American and Pacific Islanders have the lowest death rate from breast cancer while Native Americans and Alaska Natives have the lowest rates of developing breast cancer. And while rare, men can get breast cancer too.

The AMAsWhat Doctors Wish Patients Knew series provides physicians with a platform to share what they want patients to understand about todays health care headlines.

In this installment, Jill Jin, MD, an internist at Northwestern Medicine and clinical assistant professor of medicine at Northwestern University Feinberg School of Medicine, took time to discuss what patients need to know about what to do to reduce their risk of breast cancer. She is also a senior physician adviser for the AMA and an associate editor forJAMA.

Know the risk factors

While risk factors for breast cancer are broad, we think primarily about agearound the age of menopause and after menopause is when breast cancer risk goes up in women, said Dr. Jin. Family history, of course, is another big one. That includes genetic mutations that we know of such as BRCA1 and BRCA2.

Theres also this whole concept of estrogen exposure, which can be both endogenouswithin the body or how much your body producesversus exogenous, from medications she said. Then other things like alcohol and smoking are thought to be associated somewhat with breast cancer as well.

Start screening between 40 and 50

Overall, the recommended age to start screening for breast cancer in average-risk women would be anywhere from 40 to 50 years old, said Dr. Jin. It is important to convey to patients that most professional societies do recommend later than 40, either 45 or 50, as the age to start screening. But most physicians are still starting on the earlier end of this spectrum because it can be a tough sell for patients to say, wait until 50 years old when, to be honest, most people around them are probably getting screened earlier.

Almost everyone knows somebody these days who has had breast cancer, whether its a friend or a family member, and when you have that personal connection its scary, she added. Thats why I usually tell women who are at average riskwho dont have family history of breast cancerthat I am comfortable waiting until 45 years old to start screening.

If they do have a family history of breast cancer or other risk factors, we certainly can and should start screening earlier, Dr. Jin said. Its very individualized at the end of the day.

Different screening tests are available

There are several different screening modalities, said Dr. Jin, noting that a mammogram is the most common one. Other methods of screening include ultrasounds, as well as a breast magnetic resonance imaging.

But for most people, we start with mammograms, she said.

Earlier screening isnt always better

It always begins with getting to know the patient, asking about their history and their lifestyleits definitely an individualized risk assessment first, said Dr. Jin. And if there is nothing that suggests they are at higher risk than average, then you can have a discussion with patients about potentially waiting to start screening.

It comes down to the benefits versus the harms of screening, she added, noting the younger you start screening, the more lives you will save because you will catch more cancers at earlier stages, especially the more aggressive ones.

But on the flip side, the younger people are, the more you pick up things that are not cancer, which is called a false positive finding. Younger women have denser breast tissue, and when breast tissue is dense, it is very hard to differentiate normal tissue from something that may look like cancer, Dr. Jin explained. And then you go down this whole path of follow-up testing which includes additional mammograms and sometimes biopsy, which very often ends up being an unnecessary biopsy because everything will turn out normal.

This causes a lot of anxiety. It upends patients lives for a couple months while this whole process is going on, and that amount of anxiety affects many other parts of patients livesit is not trivial, she added. And then you do it all over again the next year. The younger you start, the more the potential harms of these false positives start to outweigh the potential benefit of earlier diagnosis.

Maintain a healthy lifestyle

For all womenreally for everyoneit is important to maintain a healthy lifestyle, said Dr. Jin. That means eating a balanced diet, not drinking too much alcohol, not smoking, maintaining regular physical activity and a normal body mass index.

All of those things are likely helpful for prevention of not just breast cancer, but other cancers as well, along with cardiovascular diseasea lot of things, she added.

There are medications to reduce risk

Chemoprevention, or the use of medications, is another option to reduce breast-cancer risk, said Dr. Jin. For chemoprevention, there are two classes of medications that are used. One is called selective estrogen receptor modulators, or SERMs.

Tamoxifen is probably the most common one that is used. SERMs medications block the effects of estrogen in the breast, she added. Another class is called aromatase inhibitors. Those are usually used in older women after menopause and stop other hormones in the body from becoming estrogen.

However, both have other side effects. While tamoxifen blocks the effects of estrogen in breast tissue, it can actually enhance estrogen effects in other parts of the body, so we do worry about blood clots as well as uterine cancer, said Dr. Jin. And then aromatase inhibitors can cause other side effects related to low estrogen such as hot flashes, bone pain, decreased bone density, and increased risk of osteoporosis and fractures.

Thats why we dont use these medications in everyone to decrease breast cancer risk, and reserve them for high-risk women only. Again, as with every decision in medicine, we want to make sure the balance of potential benefits versus harms is in favor of benefits, she said.

Surgical prevention is also an option

The other kind of prevention would be surgical prevention, said Dr. Jin. This is also done for women who are high risk, most commonly because of the BRCA gene mutation.

People who have a known BRCA gene mutation, which puts them at an increased risk for both breast and ovarian cancer, are candidates for surgery to remove the breasts. Thats called prophylactic mastectomy, she said. They also may be candidates for surgery to remove the ovaries to decrease the risk of ovarian cancer as well.

Test for the BRCA gene mutation

There are calculators that can be used to calculate whether someone, based on their family history and ethnicity, should get genetic testing for the BRCA gene mutation, which is a blood test said Dr. Jin. If you have a first-degree family membersuch as your mom or siblingwho has breast cancer and is known to have BRCA, then you should get tested for it.

If you just have a family history of breast cancer with unknown BRCA status, thats when the calculators come into play, she added, noting they look at how many first-degree and second-degree relatives, whether you are of Ashkenazi Jewish descent, and certain other risk factors to decide whether you should get the genetic testing.

Breastfeeding may reduce risk

While there are no clinical trials on this topic, there is observational data that does suggest that breastfeeding is protective against breast cancer, said Dr. Jin. The same goes for having children versus not having children; pregnancy does seem to be protective as well.

Were not saying go get pregnant and breastfeed to reduce your risk of having breast cancerits not practical, she added. But it does seem to be an association.

Birth control is OK to take

This is also somewhat controversial, but overall, the link between birth control and breast cancer is very small to none, Dr. Jin said. When I talk with my patients about this, I share that using birth control pills most likely does not increase the risk of breast cancer in a clinically significant way.

Furthermore, this very small potential increase in risk is limited to the time that youre actually taking birth-control pills, she said. So, its not a permanent effect. Its temporary.

Be cautious with self-breast exams

There has not been any good evidence to show that self-screening has any overall benefit in mortality, said Dr. Jin. Breasts are just lumpy to begin with and a lot of people end up feeling lumps that just end up being normal breast tissue.

And you may end up, again, going down that path of all the imaging and the biopsies and in the end, it is nothing, she added. So, self exams are not recommended by clinical guidelines.

However, some people are going to be wanting to do that anyways and that is fine. If someone really wants to stay on top of their body, I will explain that breasts can feel lumpy or bumpy, and what they are looking for is a change from baseline. At the end of the day, you still know your own breasts and your own body the best, said Dr. Jin. So, if you feel something that is different, that you have not felt before, then you should let me know and we can decide at that point what to do,

If they are in the office with me, I am happy to do a quick exam of the breast and tell them this is what your normal breast tissue feels like, dont be alarmed if you feel this or if you feel this. It is just normal.

Dont hesitate to talk to your doctor

While screening is recommended to start between 40 and 50 years old, if at any point you do notice something like a lump or you see something weird on the skin or if you have pain or any symptoms that are different than normal, that takes you out of the typical screening category, she emphasized. As with all cancer screening, when a symptom is detected that is different, and you should never hesitate to bring that up to your doctor.

See the article here:
What doctors wish patients knew about breast-cancer prevention - American Medical Association

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.

Methods: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 61013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.

Results: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.

Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

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Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A

ZUG, Switzerland and BOSTON, Sept. 28, 2022 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today announced that the U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation to CTX130, the Companys wholly-owned allogeneic CAR T cell therapy targeting CD70, for the treatment of Mycosis Fungoides and Szary Syndrome (MF/SS).

The RMAT designation is an important milestone for the CTX130 program that recognizes the transformative potential of our cell therapy in patients with T-cell lymphomas based upon encouraging clinical data to date, said Phuong Khanh (P.K.) Morrow, M.D., FACP, Chief Medical Officer of CRISPR Therapeutics. "We continue to work with a sense of urgency to bring our broad portfolio of allogeneic cell therapies to patients in need.

Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the drug development and review processes for promising pipeline products, including genetic therapies. A regenerative medicine therapy is eligible for RMAT designation if it is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such disease or condition. Similar to Breakthrough Therapy designation, RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of the biologics license application (BLA) and other opportunities to expedite development and review.

About CTX130 and COBALT TrialsCTX130, a wholly-owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting Cluster of Differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX130 is being investigated in two ongoing independent Phase 1 single-arm, multi-center, open-label clinical trials that are designed to assess the safety and efficacy of several dose levels of CTX130 in adult patients. The COBALT-LYM trial is evaluating the safety and efficacy of CTX130 for the treatment of relapsed or refractory T or B cell malignancies. The COBALT-RCC trial is evaluating the safety and efficacy of CTX130 for the treatment of relapsed or refractory renal cell carcinoma. CTX130 has received Orphan Drug and Regenerative Medicine Advanced Therapy designations from the FDA.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Boston, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

CRISPR Forward-Looking StatementThis press release may contain a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Morrow in this press release, as well as regarding CRISPR Therapeutics expectations about any or all of the following: (i) the status of clinical trials and discussions with regulatory authorities related to product candidates under development by CRISPR Therapeutics including, without limitation, expectations regarding the benefits of RMAT designation; and (ii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words believes, anticipates, plans, expects and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the potential for initial and preliminary data from any clinical trial and initial data from a limited number of patients not to be indicative of final trial results; the potential that clinical trial results may not be favorable; potential impacts due to the coronavirus pandemic, such as the timing and progress of clinical trials; that future competitive or other market factors may adversely affect the commercial potential for CRISPR Therapeutics product candidates; uncertainties regarding the intellectual property protection for CRISPR Therapeutics technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics most recent annual report on Form 10-K, quarterly report on Form 10-Q and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at http://www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.

CRISPR THERAPEUTICS standard character mark and design logo, CTX130 and COBALT are trademarks and registered trademarks of CRISPR Therapeutics AG. All other trademarks and registered trademarks are the property of their respective owners.

Investor Contact:Susan Kim+1-617-307-7503susan.kim@crisprtx.com

Media Contact:Rachel Eides+1-617-315-4493rachel.eides@crisprtx.com

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CRISPR Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX130 for the Treatment of Cutaneous T-Cell...