]]> High costs, data management issues and recruitment problems are some of the main challenges for personalised medicine in clinical development. Credit: US Air Force/Kemberly Groue Genome sequencing costs are falling fast, opening the playing field for developing highly personalised drug candidates. Personalised medicine in the 21st century offers the promise of therapies customised based on the study of what truly makes us unique: our DNA.

The importance of the individual has been widely established in medicine since time immemorial. The well-worn adage that physicians should treat the patient, not the disease has been around since the 19th century, and the awareness of that message is far older than that. Even Hippocrates, the father of Western medicine who treated patients in the fifth century BC, stressed the importance of treating each patient as an individual.

For the sweet [medicines] do not benefit everyone, nor do the astringent ones, nor are all patients able to drink the same things, Hippocrates wrote.

Hippocrates might have tailored his rudimentary treatments based on the patients age, physique and other easily observable factors, but personalised medicine in the 21st century offers the promise of therapies customised based on the study of what truly makes us unique: our DNA.

Advancements in genomics, proteomics, data analysis and other fields both medical and technical are gradually facilitating the development of laser-focused drugs, as well as the ability to predict peoples personal risk factors for particular diseases and how individual responses to various treatments might differ.

After years of anticipation, there is now evidence that governments around the world have clocked the importance of personalised medicine and are driving efforts to the build the genetic data sets and biobanks that are required to push the science forward. Former US President Barack Obama launched the Precision Medicine Initiative to great fanfare in 2015; the scheme has since evolved into the All of Us research programme, which aims to gather health data from more than a million US volunteer-citizens to unlock new insights.

In the UK, the 100,000 Genomes Project reached its goal of sequencing 100,000 whole genomes from 85,000 NHS patients with cancer or rare diseases. Genomics England has noted that so far, analysis of this data has revealed actionable findings in around one in four rare disease patients, while about 50% of cancer cases suggest the potential for a therapy or clinical trial.

You can match a blood transfusion to a blood type that was an important discovery, said Obama at the launch of the Precision Medicines Initiative, summarising the broad appeal of personalised therapies and diagnostics. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?

The stage might be set for personalised healthcare to dramatically transform public health, but few in the medical field would deny that the world is hardly ready yet. Transitioning from the traditional one-cure-fits-all treatment model to new processes that leverage patients genetics, lifestyles and environmental risk factors is an immense task that presents challenges in both the laboratory and the clinic.

Oncology is, by a landslide, the field that has been most impacted by developments in precision medicine; around 90% of the top-marketed precision treatments approved in 2018 were cancer therapies, while other therapeutic areas have lagged far behind. The majority of approved precision medicines in oncology achieve something of a halfway house between the old way and the new they fall short of being tailored to a specific individual, but they allow for more detailed stratification of patients by the oncogenic mutations of their tumours, which may be driving cancer cell survival and growth.

Common examples of these mutations are HER-2 in certain breast and stomach cancers, BRAF in melanoma and EGFR in lung cancer. High expression of these proteins at cancer sites can be targeted by precision treatments, such as Roches monoclonal antibody Herceptin (trastuzumab) for HER-2, Genentechs BRAF inhibitor Zelboraf (vemurafenib), and Roches EGFR inhibitor Tagrisso (osimertinib). Regulators such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are also increasingly approving tumour-agnostic treatments the first and most famous of which is Mercks immunotherapy Keytruda (pembrolizumab) which target specific biomarkers regardless of tumour location.

But despite the availability of a growing menu of personalised cancer treatments, actually matching patients up to the right therapy can be difficult. According to a survey of US acute care organisations conducted by Definitive Healthcare and published in December 2019, just over 20% had established precision medicine programmes. Investment in genomic testing is vital to quickly get patients on the best treatment course, but financial and operational barriers remain.

The foremost among these is the cost associated with genomic sequencing and the use of companion diagnostic devices, cited by 28% of Definitive Healthcares respondents as the biggest challenge for already-established precision medicine schemes. Lack of expertise is another obstacle, as many physicians may struggle to accurately interpret test results without specialist assistance another major cost driver for clinics and hospital departments trying to build pathology teams that are up-to-date with the newest tests. A 2018 survey of 160 oncologists by Cardinal Health found that 60% of physicians who dont use genomic tests avoid them because of the difficulty of interpreting the data.

In clinical research and development, too, there are growing pains associated with moving the pharmaceutical pipeline towards drugs targeting smaller patient sub-groups. Again, cost is a central issue companion diagnostics dont come cheap, finding and validating biomarkers to guide targeted therapies is a lengthy task, and analysing vast amounts of data often requires new teams with specialised knowledge.

The expense of incorporating a host of new processes into innovative trial designs not to mention the cost of manufacturing cell and gene therapies obviously has an impact on the list price of personalised drugs that win approval. This is most clearly seen in the eye-watering prices of some of the worlds first truly individualised cancer treatments, chimeric antigen receptor T-cell (CAR-T) therapies.

Treatments such as Novartiss Kymriah and Gileads Yescarta remove T-cells from the patients blood, modify them to target tumour cell antigens and then infuse them back into the blood stream. These therapies have achieved impressive results in rare and advanced cancers, but cost upwards of $400,000 per patient, limiting their reimbursement options among both private and public payers. Promising advances in CAR-T manufacturing and potential off-the-shelf T-cell production could help bring these costs down in the years to come, but for now the problem remains.

As for the broader clinical trial eco-system, these studies have been historically set up to assess a drug candidates safety and efficacy in an increasingly large segment of the patient population, building evidence towards the regulatory approval process. Bringing a personalised medicine through the clinical development process is a new paradigm in a number of ways; as well as the aforementioned cost drivers, there can be an extra enrolment burden to identify and recruit patients this is already a common cause of trial failure, but its all the more difficult when youre looking to access a small patient sub-group with the appropriate biological profile.

The difficulty of providing sufficient evidence of safety and efficacy can also present issues where current regulations struggle to accommodate new innovations in personalised medicine. Smaller trial designs present statistical problems in terms of understanding a drugs definitive risk-benefit profile, and while some personalised applications can be discovered as part of larger trials that fail to meet their endpoints outside of a select patient group with particular biomarkers, many current regulations dont accept post hoc analysis and would require an entirely new trial.

Personalised medicine developers desire better guidance on how best to design a successful clinical trial for a personalised therapy, because absent guidance, they risk presenting suboptimal evidence regarding stratification options, reads a 2017 study on personalised medicine barriers, published in the Journal of Law and Biosciences. Designing clinical trials for differently responding subgroups (for example, biomarker-positive and biomarker-negative groups) requires additional time and resources. Companies are reluctant to make this investment without a commensurate increase in the certainty of regulatory approval.

The increasing use of surrogate endpoints, conditional approvals and real-world data is helping to address these issues, but theyre not yet an ideal solution. Conditional approvals rely on very careful post-marketing observation and analysis, while the value of surrogate endpoints has been questioned, adding to the tension between accelerating approvals and ensuring patient safety.

The ultimate benefits of creating more personalised treatments are clear, and their advantages for human health could, in the long-term, be matched by their economic returns. After all, quickly treating patients with the right therapy for them or, even better, using knowledge of a patients genetic risk profile to prevent illness in the first place would be a huge financial gain for overburdened health systems.

Todays costs are gradually falling, as NIH data on DNA sequencing costs demonstrate. But there is still a long way to go before we can wave goodbye to the blanket drug development that has dominated modern pharma for decades, even in the advanced field of oncology, let alone other therapeutic areas. Only a sustained and holistic push from regulators, drug developers, clinicians, governments and others will be enough to bring us over the line.

View post:
Precision medicine in 2020: what barriers remain for drug developers? - pharmaceutical-technology.com

Former CEO of Freeline Therapeutics, Ltd. has outstanding international drug development, commercialization expertise, with focus on rare disease, gene therapy

Renovacor, Inc, a preclinical-stage biopharmaceutical company focused on developing transformative gene therapy-based treatments for cardiovascular disease, today announced the addition of Dr. Anne Prener to both the companys board of directors and scientific advisory board.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20200224005120/en/

Anne Prener, M.D., Ph.D. Appointed to Renovacor Board of Directors and Scientific Advisory Board (Photo: Business Wire)

Dr. Prener has a proven track record of building and leading high-performing global teams for both preclinical and clinical stage biotech companies. Her 25+ years of experience across several therapeutic areas has focused on rare diseases and gene therapy. Most recently, Dr. Prener served as CEO of Freeline Therapeutics, Ltd., where she scaled the company from the preclinical stage to a fully-integrated biotechnology organization, which included a broad, internally developed pipeline, two programs in clinical development and a commercial-scale, high-quality CMC and manufacturing platform. Prior to that, Dr. Prener was CEO for Gyroscope, a gene therapy company focused on addressing important retinal diseases with novel approaches. She helped build the company from start, including hiring the clinical, regulatory and scientific teams, developed medical and commercial strategy and served as a leading board director of the company. Overall, Dr. Prener has been instrumental in bringing six biologics through development, approval and launch preparations, of which one new treatment for hemophilia took only 4.5 years from first human dose to approval.

"We are delighted to have Anne join both the board of directors and scientific advisory board at a time when our industry has a pressing need for more women in high-impact leadership and mentorship roles," said Renovacor CEO Magdalene Cook. "Anne is not only a brilliant scientist in her own right, but her experience as CEO at two prior gene therapy companies will be invaluable and highly relevant to the opportunities and challenges we will face as we build Renovacor. I know Anne will be an engaged and effective advisor and will help us develop foundational long-term strategies."

"I look forward to working with such distinguished colleagues in a uniquely positioned company in the rare disease gene therapy space. The cardiovascular clinical indication is a virtually untouched one, with many exciting possibilities," said Anne Prener, M.D., Ph.D. "My role on the board of directors and scientific advisory board will be hands-on. I will engage with Dr. Cook and her team bringing my experience to bear on pivotal near term initiatives, key to Renovacors success, from manufacturing to preclinical and clinical planning, building a pipeline, and progressing the long term strategic goals of the company."

Dr. Prener joins Renovacors world-class scientific advisory board, which also includes Arthur M. Feldman, MD, PhD, Laura H. Carnell Professor of Medicine (Cardiology) at the Lewis Katz School of Medicine at Temple University, and Founder, Renovacor; Michael Bristow, MD, PhD, Professor of Medicine-Cardiology, University of Colorado, School of Medicine, and Co-founder, President and CEO, ARCABiopharma; Douglas Mann, MD, Lewin Professor of Medicine, Director of Cardiovascular Division, Washington University School of Medicine; Dennis McNamara, MD, Professor of Medicine and Director of the Heart Failure Center, University of Pittsburgh Medical Center; and Joseph Glorioso III, PhD, Professor in the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine.

Story continues

A Commitment to Improving Treatment of Genetically Derived Cardiovascular DiseasesRenovacors lead program is a recombinant adeno-associated virus (AAV)-based gene therapy for patients suffering from dilated cardiomyopathy (DCM) due to mutations in the BAG3 gene, based on discoveries made by Renovacor Founder, Dr. Arthur M. Feldman. Dilated cardiomyopathy is a condition affecting over 3 million patients in the US and growing steadily. Many patients develop DCM due to ischemic heart disease. Recently subpopulations have been identified that develop DCM due to mutations in specific genes that have been shown to result in the development of DCM. One of these specific genes is the Bcl2-associated athanogene 3 (BAG3) gene. The prevalence of disease causing BAG3 haploinsufficiency is estimated at approximately 35,000 individuals in the United States, representing an orphan disease by FDA guidelines. Currently DCM patients with a BAG3 mutation are treated with standard of care for heart failure. Despite improvements in pharmacotherapy and care, the five-year survival of a patient with DCM is only 50%. Development of a BAG3 gene replacement therapy for patients with DCM that carry BAG3 mutations could potentially prevent progression of disease in this otherwise healthy population of young adults.

About RenovacorRenovacor is a preclinical stage biotechnology company whose mission is to develop improved therapies for genetically derived cardiovascular diseases. The company is currently developing a gene therapy for a rare, familial form of dilated cardiomyopathy. Renovacors lead gene therapy product aims to restore cardiac function in patients with symptomatic heart failure due to BAG3 gene mutation. For further information about Renovacor, please visit http://www.renovacorinc.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200224005120/en/

Contacts

Renovacor: Magdalene Cook, MDCEO, Renovacor203-524-0788mcook@renovacorinc.com

For Media Requests: Samantha Choinski603-489-5964LaVoieHealth Scienceschoinski@lavoiehealthscience.com

Here is the original post:
Anne Prener, M.D., Ph.D. Appointed to Renovacor Board of Directors and Scientific Advisory Board - Yahoo Finance

MEDFORD/SOMERVILLE, Mass. (February 4, 2020)Researchers led by biologists at Tufts University have discovered that the brains of developing embryos provide signals to a nascent immune system that help it ward off infections and significantly improve the embryos ability to survive a bacterial challenge. Using frog embryos, which continue to develop with their brains removed, the researchers found that embryos without a brain are not able to marshall the forces of immune cells to an injury or infection site, leading the embryo to succumb to an infection more quickly. By contrast, the presence of a brain crucially helps direct immune cells to the site of injury to overcome the bacterial threat. The study was published today in NPJ Regenerative Medicine.

In a developing embryo, both brain and immune system are not fully formed. The immune system, for its part, consists mostly of an innate system of cells that respond immediately to infection and do not require training or produce antibodies. Nevertheless, these cells require signals that prompt them to move toward an infection site and trigger a response.

The research team found that the brain appears to contribute to the signals that guide the nascent immune system. When brainless frog embryos were infected with E. coli, only about 16% of embryos survived, while the presence of a brain protected more than 50% from the infection. By following markers of immune cells, researchers confirmed that the effect is not due to the missing brain somehow hampering immune system development because the composition of the immune cells remained the same with or without a brain. Instead, they found that the effect was due to the brain sending signals to the immune cells to move toward the site of an infection.

We found that macrophages innate immune system cells that can swallow up bacteria and destroy them to reduce the burden of an infection do not migrate appropriately without the presence of the brain said Michael Levin, Vannevar Bush Professor of Biology at Tufts Universitys School or Arts and Sciences and Associate Faculty at Harvards Wyss Institute, director of the Allen Discovery Center at Tufts and corresponding author of the study. Without the brain and its neurotransmitter signals, gene expression and innate immune system activity go awry, resulting in increased susceptibility to bacterial pathogens.

Other roles for the embryonic brain signaling during infection may include inducing cellular responses, for example preventing cell death or reducing inflammation, that help protect against the harmful effects of the infection.

Immune system abberations were also observed in brainless embryos that were further developed. When the researchers tracked myeloid cells, a class of immune cells that includes macrophages, neutrophils and others, after an injury, they found that the myeloid cells in brainless embryos gathered in locations far from the injury site. By contrast, myeloid cells in normal embryos with intact brains would pile up at the injury site to assist in healing. In fact, in the brainless embryo, the myeloid cells tended to cluster around abnormal, disorganized peripheral nerve networks, also a by-product of brain absence, as demonstrated in earlier studies.

An examination of aberrations in genetic expression in brainless embryos also pointed to the reduction of the neurotransmitter dopamine (a signaling chemical used in the brain for learning and motivation), and that dopamine may play a role in activating immune cells to migrate in the early stages of an infection. The absence of an immune cell quorum at the infection site leads the brainless embryos to become more susectible to its lethal effects.

Our results demonstrate the deep interconnections within the bacteria-brain-body axis: the early brain is able to sense the pathogenic bacteria and to elaborate a response targeted to fight against the cellular and molecular consequences of the infection, said Celia Herrera Rincon, Research Scientist II at the Allen Discovery Center at Tufts, and first author of the study.

Other authors of this study include: Jean-Francois Par, Christina Harrison, Alina Fischer, and Sophia Jannetty at the Allen Discovery Center at Tufts; Christopher Martyniuk, associate professor in the Department of Physiological Sciences at University of Florida; and Alexandre Dinis and Vishal Keshari, graduate students, and Richard Novak, senior staff engineer at the Wyss Institute for Biologically Inspired Engineering, Harvard Universiy.

This research was supported by the Templeton World Charity Foundation Independent Research Fellowship (TWCF0241) and the Allen Discovery Center program through The Paul G. Allen Frontiers Group (12171), as well as The Defense Advanced Research Projects Agency(DARPA, W911NF-16-C-0050), and the National Institutes of Health (AR055993, AR061988). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Herrera-Rincon, C., Par, J-F, Martyniuk, C.J., Jannetty, S.K., Harrison, C., Fischer, A., Dinis, A., Keshari, V., Novak, R., and Levin, M. An in vivo brainbacteria interface:

the developing brain as a key regulator of innate immunity. NPJ Regenerative Medicine (31 Jan 2020) DOI: 10.1038/s41536-020-0087-2

###

About Tufts University

Tufts University, located on campuses in Boston, Medford/Somerville and Grafton, Massachusetts, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

Visit link:
Brain links to embryonic immunity, guiding response of the troops that battle infections - Tufts Now

The past decade has seen some major advances for the medical industry, from cancer vaccines to CRISPR technology. Read on for a glimpse of the most memorable highlights.

Every year, Hepatitis C causes around 400,000 deaths around the world. In 2010 human trials started on a breakthrough medication called Sofosbuvir, which offered a 12-week treatment program that blocks the action of proteins and enzymes that support the virus.

In 2012, biologists Emmanuelle Charpentierand JenniferDoudnaproposed CRISPR-Cas9enzymes be utilised to edit genomes. This sparked the advent of the revolutionary gene-editing tool known as CRISPR and empowered scientists with the ability to modify DNA and genes. From managing malaria outbreaks to growing agricultural crops, CRISPR is one of the most significant scientific breakthroughs of the decade.

In 2013 researchers at Cornell University took 3D printing beyond consumer goods and branched out into human body parts. They successfully printed an outer ear that functioned and resembled the real thing. Later in the year researchers from the University of Pennsylvania printed 3D blood vessels. By 2020, San Diego based company Organovo is planning to print human livers.

Following a severe facial injury, American firefighter Patrick Hardison thought he would be left scarred and deformed for the rest of his life. In 2015 surgeons at the NYU Langone Medical Centre carried out the most advanced face transplant in history, using 3D modelling to replace ear canals, bones and other elements of the face.

2017 was a landmark year for gene therapy, with scientists harnessing the technology to treat diseases like cancer. Instead of treating the symptoms, gene therapy allows scientists to modify DNA to treat cancers like leukemia and breast cancer.

Stanford University made headlines in 2018 when a team of researchers announced they had successfully eliminated cancerous tumours in mice with a vaccine. "I dont think theres a limit to the type of tumour we could potentially treat, as long as it has been infiltrated by the immune system," said Ronald Levy, MD, senior author of the study and Professor of Oncology at the Stanford Health Centre.

Breast cancer claims more than 11,000 lives a year in the UK, though thanks to a new blood test developed by researchers at the University of Nottingham, experts are expecting the figure to fall. The test detects autoantibodies and could allow doctors to diagnose breast cancer as early as five years before a lump appears.

Want to know more about the latest medical breakthroughs? Don't miss 'A New Approach Concentration Measurement of Bases and Acids using a Refractometer' which spotlights the latest technologies from Austrian based company Anton Paar.

See more here:
Science in the 2010s Medicine - Labmate Online

It's a lesson Breteni Morgan-Berg has been learning again and again after a whirlwind year in the spotlight. Her 7-year-old daughter, Kamiyah, has an exceedingly rare gene mutation that causes her to collapse multiple times a day. Kamiyah's illness, a mutation of a gene known as KCNMA1, got diagnosed last year after extensive medical sleuthing.

Kamiyah's condition made her a star in an episode of "Diagnosis," the Netflix medical detective documentary series based on the New York Times column of the same name. But while her time in the limelight didn't cure her gene mutation that remains a work in progress. Instead, it grew her family: researchers dedicated to find her a treatment, and other families dealing with the same gene mutation who thought they too were alone.

The media exposure also gave Morgan-Berg and Kamiyah a louder voice. They're known now, Kamiyah's condition a known issue. That helps too, when seeking assistance, when Morgan-Berg is making another call for help, or one more emailed request.

If theres anything Netflix and the New York Times did for us granted I pushed myself to that point and thats how we got there but it makes it much harder to ignore," Morgan-Berg said.

Kamiyah, and her appearance on the Netflix show, has catalyzed a growing network of support in the medical community. Dr. Lisa Sanders, the model for the brilliant, medical mystery solving doctor-detective main character in the show "House, M.D.," featured Kamiyah in her Diagnosis column in the New York Times prior to the collaboration with Netflix. She's just a text message away.

Dr. Sotirios Keros was a early and crucial part of Kamiyah's medical family. He got to know her in 2018 after a colleague referred the child with the then-undiagnosed condition to him.

For Kamiyah, Keros couldn't have been at a better place in a better time. A New York resident, Keros regularly commuted to Sioux Falls to work as assistant professor in pediatric neurology at Sanford Childrens Hospital and the University of South Dakota, where there was a shortage of professionals with his expertise. His specialized background in neurology and ion channel physiology meant when he saw Kamiyah's condition, what she was suffering from was clear, he said.

Keros got Kamiyah's gene mutation on a special rare disease database known as CoRDS, hosted by Sanford Health. He also co-founded a foundation the KCNMA1 Channelopathy International Advocacy Organization meant to help support the research into the KCNMA1 mutation and helping connect those with the condition with researchers and each other.

Kamiyah appearance on Netflix didn't trigger an avalanche of donations into the foundation ("Nope, nope, nope, nope"), said Keros. That funding might come in time, as a result of family fundraising and growing awareness of the condition. But the foundation is serving a more immediate purpose, acting as a crucial link between those struggling with the condition giving them a place to turn.

"The reason we started the foundation was this exact reason: to give people education and just a place to turn," he said. "Some diseases, like this one, there really isnt any treatment, but just being involved with other people is its own kind of help."

Another key member of Kamiyah's support team is Dr. Andrea Meredith, a researcher at the University of Maryland School of Medicine, who first heard about Kamiyah in Sanders' column. She was stunned to later learn the gene that causes Kamiyah's condition was the exact same one she was currently researching. Previously, she had only heard of one such patient an anonymous Chinese family documented in a 2005 paper.

"When Kamiyahs mom gave us genetics report I almost fell over because one of the mutations we had picked out of the publicly available database, with no other information other than the sequence change, ended up being the mutation that she had," Meredith said. Her work involves growing mice genetically modified with Kamiyah's condition, a key component of further research.

Meredith, too, has grown close to Morgan-Berg and her family, and helped co-found the KCNMA1 foundation with Keros. Kamiyah's photos are all over Meredith's lab, Morgan-Berg said. Meredith has a daughter who is slightly older than Kamiyah, and the two families met up in New York when Kamiyah and Morgan-Berg were making media appearances in connection to the Netflix show.

One of the most powerful things about meeting Kamiyah in person was the ability to see that sweetness and its amazing how she has that childlike innocence and sweetness, yet shes afflicted by these very powerful symptoms," Meredith said.

Meredith is now working to secure funding from the National Institutes of Health to expand her lab, due to the sheer volume of people contacting her seeking help.

"She has no idea what she means to us," Morgan-Berg said.

Also helping Kamiyah, quietly, is Massachusetts-based Q-State Biosciences. Q-State had no comment about its work with Kamiyah: "Q-State is still in the early stages of research on this project, and cannot provide details right now," said a spokesperson.

But Morgan-Berg said Q-State's work involves matching Kamiyah's genetic profile against available drugs to see if there's anything that could help possibly the most immediately promising work, if they find something.

With the good came the bad. Kamiyah's attention from the New York Times column and Netflix show brought out the worst in some people, Morgan-Berg said. Online trolls attacked Kamiyah's family, specifically her mother, accusing her of being a terrible wife, a fame-seeking welfare mom and worse.

"Terrible, horrible things you cant even make up yourself. Trolls just come out of the woodwork," she said.

Morgan-Berg locked down her Facebook account to shield herself from the worst commenters, but that didn't keep them all away.

She worried the Netflix show might make it seem that Kamiyah's condition was cured and everything was fine now. But she knows that's not the case, and she wishes others did, too.

The research grinds on, a silver-bullet solution hasn't shown up, and the big media exposure didn't solve her family's biggest immediate problem: negotiating the tangled web of bureaucracies to get Kamiyah help she needs now, trained care providers who can help take care of a growing girl, protecting her from her own body.

Its hard enough to be told that Kamiyah is going to die before they can help us, that the information that we give on Kamiyah could help someone else," said Morgan-Berg. "But the fact is that we cant even get help with the quality of life we have left.

Morgan-Berg is required to interview and hire the care providers first, then seek funding. But because Kamiyah's condition is so rare, it can be difficult to obtain what she needs through insurance. Morgan-Berg said she's applied for coverage from the care providers multiple times, and gotten turned down each time, putting her in a quandary: Let the caregivers go, or pay for them out of pocket?

It's an ongoing battle that makes her dream of moving to Denmark to be close to friends she met online, whose son Atle has the same condition as Kamiyah. She presses on, powered by her family, friends and the growing network of others with the same condition and medical professional dedicated to finding answers.

"I dont want to look back and think, 'I could have done more. I want to know Ive done everything humanly possible,'" Morgan-Berg said.

Go here to see the original:
After Netflix show on rare illness, a new family bonds - West Central Tribune

The first step consisted of genetically modifying a laboratory cell line in which the researchers could monitor the levels of fluorescent MeCP2 as they inhibited molecules that might be involved in its regulation. First author Dr. Laura Lombardi, a postdoctoral researcher in the Zoghbi lab at the Howard Hughes Medical Institute, developed this cell line and then used it to systematically inhibit one by one the nearly 900 kinase and phosphatase genes whose activity could be potentially inhibited with drugs.

We wanted to determine which ones of those hundreds of genes would reduce the level of MeCP2 when inhibited, Lombardi said. If we found one whose inhibition would result in a reduction of MeCP2 levels, then we would look for a drug that we could use.

The researchers identified four genes than when inhibited lowered MeCP2 level. Then, Lombardi and her colleagues moved on to the next step, testing how reduction of one or more of these genes would affect MeCP2 levels in mice. They showed that mice lacking the gene for the kinase HIPK2 or having reduced phosphatase PP2A had decreased levels of MeCP2 in the brain.

These results gave us the proof of principle that it is possible to go from screening in a cell line to find something that would work in the brain, Lombardi said.

Most interestingly, treating animal models of MECP2 duplication syndrome with drugs that inhibit phosphatase PP2A was sufficient to partially rescue some of the motor abnormalities in the mouse model of the disease.

This strategy would allow us to find more regulators of MeCP2, Zoghbi said. We cannot rely on just one. If we have several to choose from, we can select the best and safest ones to move to the clinic.

Beyond MeCP2, there are many other genes that cause a medical condition because they are either duplicated or decreased. The strategy Zoghbi and her colleagues used here also can be applied to these other conditions to try to restore the normal levels of the affected proteins and possibly reduce or eliminate the symptoms.

Other contributors to this work include Manar Zaghlula, Yehezkel Sztainberg, Steven A. Baker, Tiemo J. Klisch, Amy A. Tang and Eric J. Huang.

This project was funded by the National Institutes of Health (5R01NS057819), the Rett Syndrome Research Trust and 401K Project from MECP2 duplication syndrome families, and the Howard Hughes Medical Institute. This work also was made possible by the following Baylor College of Medicine core facilities: Cell-Based Assay Screening Service (NIH, P30 CA125123), Cytometry and Cell Sorting Core (National Institute of Allergy and Infectious Diseases, P30AI036211; National Cancer Institute P30CA125123; and National Center for Research Resources, S10RR024574), Pathway Discovery Proteomics Core, the DNA Sequencing and Gene Vector Core (Diabetes and Endocrinology Research Center, DK079638), and the mouse behavioral core of the Intellectual and Developmental Disabilities Research Center (NIH, U54 HD083092 from the National Institute of Child Health and Human Development).

The full study can be found inScience Translational Medicine.

Read the original here:
Test reveals possible treatments for disorders involving MeCP2 - Baylor College of Medicine News (press release)

Nov. 2, 2019 13:30 UTC

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Veracyte, Inc. (Nasdaq: VCYT) today announced new data that advance understanding of the frequency, positive predictive value and co-occurrence of genomic alterations that are targeted by newly available and investigational precision medicine therapies for thyroid cancer. The findings were enabled by Afirma Xpression Atlas analyses, which uses RNA sequencing, of Veracytes extensive biorepository of thyroid nodule fine needle aspiration (FNA) samples from patients undergoing evaluation for thyroid cancer. The data were presented this week during the 89th Annual Meeting of the American Thyroid Association (ATA).

In one study, researchers assessed the frequency of ALK, BRAF, NTRK and RET fusions in nearly 48,000 consecutive patients whose thyroid nodule FNA samples were deemed indeterminate, suspicious for malignancy or malignant (Bethesda III/IV, V and VI categories, respectively) by cytopathology. The researchers found that 425 (0.89 percent) of the FNA samples harbored one of the alterations, with NTRK fusions the most common at 0.38 percent, followed by RET (0.32 percent), BRAF (0.13 percent) and ALK (0.06 percent). Additionally, RNA whole transcriptome sequencing demonstrated differences in the prevalence of these four fusions across Bethesda categories, with Bethesda V being the highest.

NTRK fusion inhibitors have received pan-cancer FDA approval and clinical trials have included selective inhibitors of ALK, BRAF, NTRK and RET, which makes their detection in patients with thyroid cancer of interest to physicians, said Mimi I. Hu, M.D., professor at The University of Texas MD Anderson Cancer Center, who presented the findings in a poster. As our understanding of the role of genomics in thyroid cancer advances, this information offers the potential to optimize initial treatment, predict response to treatment and prioritize selective targeted therapy should systemic treatment be needed.

In another study, researchers evaluated the positive predictive value of the NTRK, RET, BRAF and ALK fusions in 58 patients with indeterminate thyroid nodules (Bethesda III/IV categories) from Veracytes biorepository for whom surgical pathology diagnoses were available. They found that NTRK and RET fusions were associated with malignancy in 28 of 30 nodules, while risk of malignancy was lower among nodules with ALK (67 percent) or BRAF (75 percent). In a third study, researchers found that when using RNA sequencing data on a large sample of nearly 48,000 thyroid nodule FNA samples (Bethesda categories III-VI), they identified 263 co-occurrences of gene fusions and variants that were previously considered mutually exclusive.

The findings from these three studies underscore the power of our extensive biorepository of thyroid nodule FNA samples and our optimized RNA sequencing platform to advance understanding of the genomic underpinnings of thyroid cancer and to better capture the biology of thyroid lesions, said Richard T. Kloos, M.D., senior medical director, endocrinology, at Veracyte. As precision medicine therapies that target specific gene alterations emerge, understanding individual patients genomic profiles becomes increasingly important to physicians. Our Afirma Xpression Atlas provides this information at the same time as initial diagnosis with the Afirma Genomic Sequencing Classifier, or GSC, to help inform treatment decisions.

Also during the ATA meeting, Veracyte unveiled its new Afirma patient report, which in addition to identifying patients with benign or suspicious-for-cancer nodules among those deemed indeterminate by cytopathology, based on Afirma GSC results, now provides individualized and actionable variant and fusion information on each patient. This information includes: risk of malignancy, associated neoplasm type, relative risk of lymph node metastasis and extrathyroidal extension; availability of FDA-approved therapy; and genetic counseling and germline testing considerations. This information is also provided for patients with cytopathology results that are suspicious for malignancy or malignant (Bethesda V and VI).

About Afirma

The Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas provide physicians with a comprehensive solution for a complex landscape in thyroid nodule diagnosis. The Afirma GSC was developed with RNA whole-transcriptome sequencing and machine learning and helps identify patients with benign thyroid nodules among those with indeterminate cytopathology results in order to help patients avoid unnecessary diagnostic thyroid surgery. The Afirma Xpression Atlas provides physicians with genomic alteration content from the same fine needle aspiration samples that are used in Afirma GSC testing and may help physicians decide with greater confidence on the surgical or therapeutic pathway for their patients. The Afirma Xpression Atlas includes 761 DNA variants and 130 RNA fusion partners in over 500 genes that are associated with thyroid cancer.

About Veracyte

Veracyte (Nasdaq: VCYT) is a leading genomic diagnostics company that improves patient care by providing answers to clinical questions that inform diagnosis and treatment decisions without the need for costly, risky surgeries that are often unnecessary. The company's products uniquely combine RNA whole-transcriptome sequencing and machine learning to deliver results that give patients and physicians a clear path forward. Since its founding in 2008, Veracyte has commercialized seven genomic tests and is transforming the diagnosis of thyroid cancer, lung cancer and idiopathic pulmonary fibrosis. Veracyte is based in South San Francisco, California. For more information, please visit http://www.veracyte.com and follow the company on Twitter (@veracyte).

Cautionary Note Regarding Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: "anticipate," "intend," "plan," "expect," "believe," "should," "may," "will" and similar references to future periods. Examples of forward-looking statements include, among others, the ability of Veracytes Afirma Xpression Atlas to analyze FNA samples to help diagnose thyroid cancer, the expected impacts of Veracytes collaboration with Johnson & Johnson in developing interventions for lung cancer, on Veracytes financial and operating results, on the timing of the commercialization of the Percepta classifier, and on the size of Veracytes addressable market. Forward-looking statements are neither historical facts nor assurances of future performance, but are based only on our current beliefs, expectations and assumptions. These statements involve risks and uncertainties, which could cause actual results to differ materially from our predictions, and include, but are not limited to: our ability to achieve milestones under the collaboration agreement with Johnson & Johnson; our ability to achieve and maintain Medicare coverage for our tests; the benefits of our tests and the applicability of clinical results to actual outcomes; the laws and regulations applicable to our business, including potential regulation by the Food and Drug Administration or other regulatory bodies; our ability to successfully achieve and maintain adoption of and reimbursement for our products; the amount by which use of our products are able to reduce invasive procedures and misdiagnosis, and reduce healthcare costs; the occurrence and outcomes of clinical studies; and other risks set forth in our filings with the Securities and Exchange Commission, including the risks set forth in our quarterly report on Form 10-Q for the quarter ended September 30, 2019. These forward-looking statements speak only as of the date hereof and Veracyte specifically disclaims any obligation to update these forward-looking statements or reasons why actual results might differ, whether as a result of new information, future events or otherwise, except as required by law.

Veracyte, Afirma, Percepta, Envisia and the Veracyte logo are trademarks of Veracyte, Inc.

View source version on businesswire.com: https://www.businesswire.com/news/home/20191102005007/en/

Read more from the original source:
Veracyte Announces New Data That Advance Understanding of Genomic Alterations Targeted by Precision Medicine Therapies for Thyroid Cancer - BioSpace

The National Institute of Health (NIH) has awarded the Willowbrook-based Institute for Basic Research (IBR) a $1.95 million grant over five years to support the study of rare diseases linked to genetic abnormalities.

Although the state-operated facility has expanded its mission in recent years, scientific research into developmental disabilities has been at the core of IBRs work since its founding more than five decades ago.

In that tradition, the NIH award will fund research led by Dr. Gholson Lyon, an IBR psychiatrist and scientist who heads the Genomic Medicine Laboratory in the Department of Human Genetics.

The grantprovides science investigators who have demonstrated ability to make major contributions to medical science the freedom to embark on ambitious, creative, and/or longer-term research projects, the New York State Office for People With Developmental Disabilities (OPWDD) said in a press release.

According to OPWDD, the research will further understanding of the genetic basis for rare diseases that include Ogden syndrome, which was discovered and named by Dr. Lyon.

Occurring in an estimated one of 1,000,000 births, Ogden syndrome is characterized by craniofacial abnormalities, hypotonia, global developmental delays, cryptorchidism, cardiac anomalies, and cardiac arrhythmias, says OPWDD.

The disease is connected to mutation of the NAA10 gene, which affects the bodys proteins and the ability of cells to proliferate. In addition to Ogden Syndrome, Dr. Lyons clinical studies will also focus on other diseases tied to NAA10, and a related gene, NAA15.

These diseases have a profound impact on families, said Dr. Lyon. I am grateful for this support from OPWDD and [the National Institute of Healths National Institute of General Medical Sciences].

Dr. Lyon also works with families at IBRs George A. Jervis Clinic, which offers diagnostic and consultative services for children and adults with intellectual and developmental disabilities.

In addition to Ogden syndrome and related diseases, Dr. Lyon also researches Fragile X syndrome, autism syndromes, and investigates the physiological basis of neuropsychiatric conditions, with the goal of expanding access to preventive services and treatment for those disorders, according to his online bio.

IBR Acting Director Joseph J. Maturi said, Dr. Lyons extensive medical and scientific training and experience will help him successfully undertake these ambitious and important studies."

Continued here:
Willowbrook-based research facility receives $1.95 million grant to study rare diseases - SILive.com

National Institutes of Health (press release)

NIAID scientists discover rare genetic susceptibility to common cold National Institutes of Health (press release) The case, published online today in the Journal of Experimental Medicine, reveals an important mechanism by which the immune system responds to these viruses, say the study authors. Several weeks after birth, the child began experiencing life ... and more »

Original post:
NIAID scientists discover rare genetic susceptibility to common cold - National Institutes of Health (press release)

Cleveland Clinic's Medical Innovation Summit to focus on genomics and precision medicine Crain's Cleveland Business Topics for panels, discussions and other sessions include: gene therapy and gene editing markets, investors' perspective on precision medicine, reimbursement strategies for genomic innovation, artificial intelligence and customized implants and ...

Visit link:
Cleveland Clinic's Medical Innovation Summit to focus on genomics and precision medicine - Crain's Cleveland Business

As companies like 23andMe and Ancestry.com help make genetic testing commonplace, you would think that we would become better at ensuring protections for the privacy of that data. Instead, multiple Congressional actions threaten to erode already-weak protections against genetic discrimination. But its not just a dystopian Gattaca future where citizens are discriminated against based on their genes that we need to be worried aboutone researcher is concerned that our inadequate genetic privacy laws will stymy science.

Its inhibiting both clinical care and research, Robert Green, a medical geneticist at Harvard Medical School, told Gizmodo.

Greens work focuses on how genomic medicine impacts peoples health and behavior. One thing hes particularly interested in is what makes people inclined to say yes to a genetic test. And hes observed one particularly big reason why people seem to be saying no: fears of genetic discrimination.

For Green and other geneticists, that makes their work harder to doresearch to, say, track how a particular gene affects a certain condition requires thousands of people to undergo genome sequencing, and the harder it is to attract those numbers, the longer it takes to do the work. Ultimately, this could mean treatments taking more time to get to patients.

But fears of genetic discrimination could also impact the health of those patients directly, if they refuse testing that could help doctors treat them.

People are concerned that if they find theyre carrying a risky gene and it goes into their medical record, it will have a bad impact in some way, Green said. Which they should be.

In 2008, Congress passed the Genetic Information and Nondiscrimination Act,(or GINA) to prohibit health insurers and employers from either requiring genetic testing or using it in making decisions about things like deductibles. The protections of GINA already do not apply to life insurance, long-term care, or disability insurance, meaning those companies are free to ask for genetic information and reject people deemed too risky. The Affordable Care Act, now in the midst of being replaced, solved another problem with GINA, protecting against discrimination for preexisting conditions revealed via genetic tests. Another bill, HR1313, currently under review in the House, would allow employers to request that employees undergo genetic testing, with the risk of paying hefty fines if they refuse.

Were injecting terrible opportunities for discrimination into the workplace, Green said.

Green has just started looking at how this impacts health care and research outcomes. In one project, early data suggests the impact may be significant.

As part of a major NIH-funded study looking at how genetic sequencing of infants impact health care, Green and his colleagues offered the parents of more than 2,500 newborns free genetic sequencing for their child. Of those, parents of 325 newborns agreed to attend an information session. Only 57 wound up participating.

Greens group is continuing to research why parents say yes or no to genetic testing. So far, Green tells Gizmodo, his investigation has revealed that privacy concerns play a role, possible a major one.

People decline genetic tests because of concerns over privacy and genetic discrimination, especially insurance discrimination, he said. This is stymying biomedical research and peoples access to healthcare.

While many are frustrated by inadequate genetic privacy protections, insurers and employers argue that theres a business reason for revealing genetic information. With more information on the risks of covering patients, insurers might be able to offer a more affordable, efficient product.

Green said that the UK offers a good example of how the US might approach its problem. There, insurers and the government have reached an agreement that both guarantees the right to insurance, and the rights of insurers to access information that may impact risk. The agreement states that insurers must establish a higher bar than typical when basing risk assessment on genetic testing data. In other words, they cant see that youre a carrier for a gene that might lead you to develop a disease, and immediately treat that gene as a preexisting condition. It also ensures consumers cant be pressured into taking a test, that tests taken in the course of medical research are exempt from being shared with insurers, and that people cant be asked to share the genetic testing information of relatives.

There are ways can we satisfy business needs of companies and also satisfy the privacy of consumers, Green said. But right now, we in the genetics community are actually aghast.

Read more from the original source:
Are Our Terrible Genetic Privacy Laws Hurting Science? - Gizmodo

April 10, 2017 Drug responses are known to vary based on the genetic profiles of patients. This is why personalized medicine is highly desirable to prevent adverse effects. Credit: lightwise / 123rf

Drug-induced hypersensitivity reactions (DIHRs) are serious and life threatening. A common example is the use of the antiepileptic drug carbamazepine, but the mechanisms that trigger it are unclear. Current scientific consensus holds that people who have a specific variation of the 'human leukocyte antigen B' (HLA-B) gene, which provides the code for making a protein that plays a critical role in the immune system, are more at risk of DIHR. However, the mechanism linking this gene to DIHR is currently unknown. As this specific variation, called HLA-B*15:02, is fairly common in people of South-East Asian descent, this is a serious problem for clinicians in the region.

Researchers at Universiti Teknologi MARA Selangor in Malaysia used computer modelling to mimic and analyse how the protein encoded by HLA-B*15:02 interacts with a range of antiepileptic medications. The researchers used various software to mimic how drugs interact with a specific region of the HLA protein that is crucial for its normal functionality. Since the HLA complex acts like a sort of identity card in our cells, anything interacting with it other than our own immune cells can cause problems.

Carbamazepine and another eight out of 26 antiepileptic drugs (AEDs) that were tested were found to bind strongly to the HLA complex in the simulation model. The team believes this strong binding is behind DIHRs in patients who carry the variant gene.

The remaining AEDs that did not show strong binding interactions with the HLA-B*15:02 complex, including clonazepam, nitrazepam and stiripentol, could be safer options for patients that have already developed adverse reactions to other antiepileptic drugs.

Testing for HLA-B*15:02, which can be done in as few as four hours, should be incorporated into clinical practice as soon as possible, recommends the study's lead researcher Mohd Zaki Salleh.

Explore further: Some psychotic disorders may be induced by drugs designed to combat effects of epilepsy

Rice University researchers are starting to understand how protein fragments influence the fiber aggregation suspected as a cause of Huntington's disease.

Researchers from King's College London have discovered a specific class of inhibitory neurons in the cerebral cortex which plays a key role in how the brain encodes spatial information. The findings are published in the journal ...

Huntington's disease is an inherited brain disorder that is uniformly fatal, but researchers at Johns Hopkins believe they have made a big discovery about how the disease progresses that could lead to a way to stop it.

Scientists have known that a lack of sleep can interfere with the ability to learn and make memories. Now, a group of University of Michigan researchers have found how sleep deprivation affects memory-making in the brain.

Neurons derived from two different types of precursor cells that later develop into neurons in the medial amygdala - one of the interconnected structures in the brain involved in emotion, motivation and memory - help to program ...

A surgical technique that sends electrical impulses to a specific area of the brain reduces the "tics," or involuntary movements and vocal outbursts, experienced by young adults with severe cases of Tourette syndrome, according ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

See the article here:
The gene that turns epilepsy treatment deadly - Medical Xpress

Over five years, the University of South Florida received more than$260 million in federal funding from the National Institutes of Health; money which helped propel the Tampa campus as a leader in medical research.

But officials with the USF Health Morsani College of Medicine and Congresswoman Kathy Castor say that the innovative breakthroughs throughout the USF medical system would be seriously in peril if PresidentDonald Trump gets his way in his recently unveiled budget and cuts funding to the NIH by 18percent.

I foresee a very challenging environment if the NIH budget is cut because young scientists and even scientists who are established will have a very hard time maintaining their labs, said Dr.Samuel Wickline, the founding director of the USF Health Heart Institute, and Professor of Cardiovascular Sciences. We could see a decrement instead of an increment who would be interested in coming here otherwise.

Wickline was one of four doctors with the USF College of Medicine who conferredwithCastorat theUSF Health Byrd Alzheimers Institute in Tampa on Monday, informing her of the work they are doing. Wickline said that the Byrd Institute relies almost 100 percent on NIH funding,

Overall, NIH invested more than $32 billion annually in 2016 for medical research to benefit the American people.

About 30 percent of the grant money that goes out is used for indirect expenses, which, as you know, means that money goes for something other than the research thats being done, Health and Human Services Secretary Tom Price told reporters last month, justifying the proposed 18 percent cut to NIH funding for the 2018 budget.

Both Republicans and Democrats have criticized the presidents proposal to cut NIH funding.

You dont pretend to balance the budget by cutting lifesaving biomedical research when the real cause of the federal debt is runaway entitlement spending, said Tennessee Republican Senator Lamar Alexander,the chairman of the Senate Health, Education, Labor and Pensions Committee, immediately after the NIH proposed cuts were announced.

Castor says that Republicans and Democrats will work together to ensure the cuts dont go through.

We in the Congress intend to work in a bipartisan way to make sure that doesnt happen, that the treatments and cures and the research stay on track that these young scientists have the promise of continuing their grant funding their research moving forward, she said.

USFs Morsani College of Medicine attracts students from around the country and the world who want to enroll there because of its reputation as a research university. saidHana Totary-Jain, Ph.D., an assistant Professor of Molecular Pharmacology and Physiology.

Totary-John came from Israel to USF to study.

NIH funding has to be steady, Totary-Jain insisted, So scientists, instead of worrying about new grants and getting new money, can really focus on innovation and on the research that we do and bringing in new breakthroughs inall these fields.

Congress passed a bill late last year that gave the NIH an additional $4.8 billion over the next five years. That included $1.8 billion for former Vice President Joe Bidens cancer moonshot, another $1.5 billion when to President Obamasprecision medicine initiative to develop targeted gene therapies and $1.5 billion to the Brain Initiative to develop Alzheimers treatments.

Standing back and watching the news conference wasDr. Stephen Liggett, the vice dean for research at the Morsani College of Medicine. He said it was crucial that Congress find a way to be consistent in its funding for NIH grants.

You cant start a project and then turn it off, he said. If you look at the graph of the NIH budget, if it were left alone by Congress and simply increased by three percent per year, starting from 1970 theres a beautiful curve that puts it higher than we are now.

comments

Excerpt from:
Kathy Castor visits USF College of Medicine, pledges to fight Donald Trump's NIH funding cuts - SaintPetersBlog (blog)

Emotional, social, and psychiatric problems in children and adolescents have been linked to higher levels of genetic vulnerability for adult depression, according to University of Queensland scientists. They made the finding Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42998 Individuals: A Meta-Analysis, which appears inJAMA Psychiatry, while analyzing the genetic data of more than 42,000 children and adolescents from seven cohorts across five European countries.

Christel Middeldorp, MD, PhD, a child and adolescent psychiatrist at the Child Health Research Centre at the University of Queensland, said that researchers have also found a link with a higher genetic vulnerability for insomnia, neuroticism, and body mass index.

By contrast, study participants with higher genetic scores for educational attainment and emotional wellbeing were found to have reduced childhood problems, she pointed out.

We calculated a persons level of genetic vulnerability by adding up the number of risk genes they had for a specific disorder or trait, and then made adjustments based on the level of importance of each gene. We found the relationship was mostly similar across ages.

Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits. To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders, write the investigators.

This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the U.K., the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019.

Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI).

Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.

The results indicate there are shared genetic factors that affect a range of psychiatric and related traits across a persons lifespan. Around 50 percent of children and adolescents with psychiatric problems, such as attention deficit hyper-activity disorder (ADHD), continue to experience mental disorders as adults, and are at risk of disengaging with their school community among other social and emotional problems, added Middeldorp.

Our findings are important as they suggest this continuity between childhood and adult traits is partly explained by genetic risk, she continued. Individuals at risk of being affected should be the focus of attention and targeted treatment. Although genetic vulnerability is not accurate enough at this stage to make individual predictions about how a persons symptoms will develop over time, it may become so in the future, in combination with other risk factors.

Middeldorp believes that this study and others may support precision medicine by providing targeted treatments to children at the highest risk of persistent emotional and social problems.

Go here to read the rest:
Childhood Psychopathology Linked to Higher Levels of Genetic Vulnerability of Adult Depression - Clinical OMICs News

(The Conversation is an independent and nonprofit source of news, analysis and commentary from academic experts.)

Richard Gunderman, Indiana University

(THE CONVERSATION) Pandemic: Its a scary word.

But the world has seen pandemics before, and worse ones, too. Consider the influenza pandemic of 1918, often referred to erroneously as the Spanish flu. Misconceptions about it may be fueling unfounded fears about COVID-19, and now is an especially good time to correct them.

In the pandemic of 1918, between 50 and 100 million people are thought to have died, representing as much as 5% of the worlds population. Half a billion people were infected.

Especially remarkable was the 1918 flus predilection for taking the lives of otherwise healthy young adults, as opposed to children and the elderly, who usually suffer most. Some have called it the greatest pandemic in history.

The 1918 flu pandemic has been a regular subject of speculation over the last century. Historians and scientists have advanced numerous hypotheses regarding its origin, spread and consequences. As a result, many harbor misconceptions about it.

By correcting these 10 misconceptions, everyone can better understand what actually happened and help mitigate COVID-19s toll.

1. The pandemic originated in Spain

No one believes the so-called Spanish flu originated in Spain.

The pandemic likely acquired this nickname because of World War I, which was in full swing at the time. The major countries involved in the war were keen to avoid encouraging their enemies, so reports of the extent of the flu were suppressed in Germany, Austria, France, the United Kingdom and the U.S. By contrast, neutral Spain had no need to keep the flu under wraps. That created the false impression that Spain was bearing the brunt of the disease.

In fact, the geographic origin of the flu is debated to this day, though hypotheses have suggested East Asia, Europe and even Kansas.

2. The pandemic was the work of a super-virus

The 1918 flu spread rapidly, killing 25 million people in just the first six months. This led some to fear the end of mankind, and has long fueled the supposition that the strain of influenza was particularly lethal.

However, more recent study suggests that the virus itself, though more lethal than other strains, was not fundamentally different from those that caused epidemics in other years.

Much of the high death rate can be attributed to crowding in military camps and urban environments, as well as poor nutrition and sanitation, which suffered during wartime. Its now thought that many of the deaths were due to the development of bacterial pneumonias in lungs weakened by influenza.

3. The first wave of the pandemic was most lethal

Actually, the initial wave of deaths from the pandemic in the first half of 1918 was relatively low.

It was in the second wave, from October through December of that year, that the highest death rates were observed. A third wave in spring of 1919 was more lethal than the first but less so than the second.

Scientists now believe that the marked increase in deaths in the second wave was caused by conditions that favored the spread of a deadlier strain. People with mild cases stayed home, but those with severe cases were often crowded together in hospitals and camps, increasing transmission of a more lethal form of the virus.

4. The virus killed most people who were infected with it

In fact, the vast majority of the people who contracted the 1918 flu survived. National death rates among the infected generally did not exceed 20%.

However, death rates varied among different groups. In the U.S., deaths were particularly high among Native American populations, perhaps due to lower rates of exposure to past strains of influenza. In some cases, entire Native communities were wiped out.

Of course, even a 20% death rate vastly exceeds a typical flu, which kills less than 1% of those infected.

5. Therapies of the day had little impact on the disease

No specific anti-viral therapies were available during the 1918 flu. Thats still largely true today, where most medical care for the flu aims to support patients, rather than cure them.

One hypothesis suggests that many flu deaths could actually be attributed to aspirin poisoning. Medical authorities at the time recommended large doses of aspirin of up to 30 grams per day. Today, about four grams would be considered the maximum safe daily dose. Large doses of aspirin can lead to many of the pandemics symptoms, including bleeding.

However, death rates seem to have been equally high in some places in the world where aspirin was not so readily available, so the debate continues.

6. The pandemic dominated the days news

Public health officials, law enforcement officers and politicians had reasons to underplay the severity of the 1918 flu, which resulted in less coverage in the press. In addition to the fear that full disclosure might embolden enemies during wartime, they wanted to preserve public order and avoid panic.

However, officials did respond. At the height of the pandemic, quarantines were instituted in many cities. Some were forced to restrict essential services, including police and fire.

7. The pandemic changed the course of World War I

Its unlikely that the flu changed the outcome of World War I, because combatants on both sides of the battlefield were relatively equally affected.

However, there is little doubt that the war profoundly influenced the course of the pandemic. Concentrating millions of troops created ideal circumstances for the development of more aggressive strains of the virus and its spread around the globe.

8. Widespread immunization ended the pandemic

Immunization against the flu was not practiced in 1918, and thus played no role in ending the pandemic.

Exposure to prior strains of the flu may have offered some protection. For example, soldiers who had served in the military for years suffered lower rates of death than new recruits.

In addition, the rapidly mutating virus likely evolved over time into less lethal strains. This is predicted by models of natural selection. Because highly lethal strains kill their host rapidly, they cannot spread as easily as less lethal strains.

9. The genes of the virus have never been sequenced

In 2005, researchers announced that they had successfully determined the gene sequence of the 1918 influenza virus. The virus was recovered from the body of a flu victim buried in the permafrost of Alaska, as well as from samples of American soldiers who fell ill at the time.

Two years later, monkeys infected with the virus were found to exhibit the symptoms observed during the pandemic. Studies suggest that the monkeys died when their immune systems overreacted to the virus, a so-called cytokine storm. Scientists now believe that a similar immune system overreaction contributed to high death rates among otherwise healthy young adults in 1918.

10. The world is no better prepared today than it was in 1918

Severe epidemics tend to occur every few decades, and the latest one is upon us.

Today scientists know more about how to isolate and handle large numbers of ill and dying patients, and physicians can prescribe antibiotics, not available in 1918, to combat secondary bacterial infections. To such common-sense practices as social distancing and hand-washing, contemporary medicine can add the creation of vaccinations and anti-viral drugs.

For the foreseeable future, viral epidemics will remain a regular feature of human life. As a society, we can only hope that we have learned the great pandemics lessons sufficiently well to quell the current COVID-19 challenge.

This is an updated version of a story that originally ran on Jan. 11, 2018.

This article is republished from The Conversation under a Creative Commons license. Read the original article here: https://theconversation.com/10-misconceptions-about-the-1918-flu-the-greatest-pandemic-in-history-133994.

See the article here:
10 misconceptions about the 1918 flu, the 'greatest pandemic in history' - Shelton Herald

MEDICAL displays arent always the biggest attraction at museums. The sight of rusty amputation saws or devices for inexplicable procedures is enough to have most adults heading straight for the knitting and needlework section. They dont have to be like this, though.

I used to think the finest example must be the Hunterian Museum in London. Being located in the middle of the Royal College of Surgeons, which unfortunately is undergoing a major renovation, means it wont be open again until next year.

Malaysia provided a ground-breaking alternative in 2019. Al-Tibb: Healing Traditions in the Islamic World at the Islamic Arts Museum Malaysia provided almost a year of insights but is over now.

The catalogue is still a treasure store of information and images, much of which was the result of collaborating with Wellcome Institute one of the UKs greatest contributions to medical knowledge. For those who want to view Islamic healing in the flesh, so to speak, some of the exhibits are on permanent display in Taman Tasik Perdana.

In the meantime, the Science Museum has opened a new gallery, which turns out to be the largest of its type in the world. With the assistance of the Wellcome Institute, once again, there is still some of the chill factor although the squeamish can avoid anything too nightmarish. Children dont seem to mind the reality of human anatomy as much as adults. Its easy to distract them anyway.

LEARNING EXPERIENCE

Marc Quinn's bronze sculpture, The Self-conscious Gene is 3.5 metres tall.

At the entrance is the largest indoor sculpture Ive ever seen. Im not entirely sure what its purpose is, apart from distracting young visitors from some of the anatomical waxworks that are located nearby.

The statue, The Self-conscious Gene, is by Marc Quinn. When you look at it carefully, it becomes clearer that this is a giant with tattoos; potentially as frightening as the waxworks although somehow it isnt. Its actually quite fun if you ignore the ink, and we should be grateful that Quinn hasnt repeated his usual specialty sculpture made from his own frozen blood.

Most of the displays are more informative than The Self-conscious Gene. This is a learning experience, and I have to say there were a lot of probable medical students doing the rounds when I visited. A number of them looked like they might even be from Malaysia. There are certainly a lot of Malaysians at Imperial College just down the road.

A 15th century amputation saw.

The globalism of this London neighbourhood, and of medicine in general, is reflected in the displays. The grim stuff at the entrance to the gallery consists mostly of home-grown horrors.

Once youve got past them, you can relax a bit and look at medical solutions from every part of the world. This is a huge relief for art lovers, who can easily be diverted from the simulated operating theatre to look at objects with healing powers from every culture.

The variety of sculptures is stunning, with something from every major belief system that I can think of, except Islam and Judaism. Muslims and Jews have always preferred to focus on the message more than the medium, especially if the medium is a three-dimensional humanoid.

Hindus, Buddhists, Christians, Taoists, Jains and the innumerable tribal faiths of the planet have resorted to ingenious sculptural forms to provide some comfort in their distress, or to ward off imminent danger.

A ceramic wall tile giving thanks to the Madonna and Child for recovery from a vicious-looking dog bite.

Some of the most touching items are the ex-voto offerings made to deities in gratitude for a swift recovery. Mexico has a massive number of these, but the most eye-catching in the new gallery are from 18th century Italy.

One in particular seems to be a thank you for relief from a dog bite. Another one shows evil spirits being expelled, which was a common obsession in the past. Blessing someone after sneezing is a relic of those times when it was thought that demons were got rid of in coughs and sneezes.

Inspired by Islamic medicine, the practical shape of the waisted albarello jar became popular in Europe.

There are items from the Islamic world in the gallery, although there could have been more, considering the debt thats owed to Muslim medical writers and practitioners. Among the inevitable objects are albarello jars. Used by apothecaries, they originally came from the Middle East. The shape is the most distinctive thing about them; theyre waisted in the middle to make them easier to grasp from shelves full of jars placed so close to each other its hard to grip them.

PERFECT TIMING

A talismanic medicine bowl from Iran.

Most of the displays show the international nature of medicine. There are items from as far apart as China and South Africa. It is one field where thinking is often similar and collaboration has been more noticeable than in, for example, warfare.

Some of the most moving displays do relate to warfare from a purely medical point of view. The surgery in the First World War trenches that has been re-created here could be from any of the sides involved. The effect is no less chilling.

A sample of the actual penicillin mould created by Alexander Fleming.

Combat has seen some of the greatest advances in medical science as well as huge quantities of human misery. Even as an onlooker, we can ease off on the panic slightly when we catch sight of anaesthetics and major painkillers such as morphine.

Nothing brings people together better than a global pandemic. The timing of this new display is perfect. As we might be heading for a health crisis at the moment, its worth a visit to Medicine: The Wellcome Galleries. Only by knowledge and cooperation can viruses be combated. Looking at the history of medicine is a good start.

Follow Lucien de Guise on Instagram @crossxcultural

Read the original here:
A timely art exhibition in the midst of a global pandemic - New Straits Times

Visit the News Hub

Detailed genetic road map will guide research into TB treatments, vaccines

A new study led by Washington University School of Medicine in St. Louis lays out a genetic road map of immune responses to tuberculosis (TB) infection across three species. Pictured is a TB-infected human lung. TB is shown in green, and immune cells surrounding the TB bacteria are shown in red and white.

Tuberculosis (TB) is one of the worlds most vexing public health problems. About 1.5 million people died from this bacterial lung infection in 2018, and the World Health Organization (WHO) estimates that one-quarter of the worlds population some 2 billion people, mostly in developing countries are infected with the bacteria that causes TB.

For decades, scientists have been studying the deadly disease in mice and other animal models to develop drug therapies and vaccines to treat or prevent the infection. But findings in animals with TB dont always translate well to people with the disease, leaving scientists puzzled by the discrepancies.

Now, a new study led by Washington University School of Medicine in St. Louis offers a genetic road map detailing the similarities and differences in immune responses to TB across three species mice, macaques and humans. According to the researchers, the insight into the immune pathways that are activated in diverse models of TB infection will serve as a valuable tool for scientists studying and working to eradicate the disease.

The research, appearing Jan. 29 in the journal Science Translational Medicine, is a collaboration between Washington University; the Texas Biomedical Research Institute in San Antonio; and the University of Cape Town in South Africa.

For many years, scientists have been frustrated by the fact that animal models of TB especially the genetically identical mice so often studied dont really reflect what we see in people with TB infections, said co-senior author Shabaana A. Khader, PhD, a professor of molecular microbiology at Washington University. This study is important because now we show in great detail where these animal models overlap with humans with TB and where they dont.

Unlike many previous mouse studies, the new research involved genetically diverse mice that more closely recapitulate the wide range of TB infection severity in humans: Some infected individuals show no symptoms; others show intermediate degrees of severity; and still others develop extreme inflammation of the lungs.

With co-author Deepak Kaushal, PhD, at the Texas Biomedical Research Institute, the researchers compared the genetic and immune responses to TB infection in these diverse mice with the responses of TB-infected macaques in the Kaushal lab. And with co-author Thomas J. Scriba, PhD, of the University of Cape Town, the research team analyzed blood samples from adolescents in Western Cape, South Africa, who are enrolled in a clinical trial investigating TB infection. The samples from people allowed the researchers to analyze and compare data from the mice and macaques with a range of responses to TB infection in young people.

Past research from this long-running clinical trial identified a group of 16 genes whose activation patterns predicted the onset of TB disease more than a year before diagnosis. These genes called a human TB gene signature differed significantly in their activation patterns between young people who developed symptoms of TB and those who didnt.

In macaques, primates closely related to humans, scientists have long assumed that TB infection closely resembles such infection in people.

Our data demonstrate that 100% of the genes previously identified as a human TB gene signature overlap in macaques and people, said co-senior author Makedonka Mitreva, PhD, a professor of medicine and of genetics at Washington University and a researcher at the universitys McDonnell Genome Institute. Its important to have the definitive data showing it to be true.

There was significant overlap between humans and mice as well, according to the researchers, including co-first authors Mushtaq Ahmed, PhD, an assistant professor of molecular microbiology in Khaders lab; Shyamala Thirunavukkarasu, PhD, a staff scientist in Khaders lab; and Bruce A. Rosa, PhD, an assistant professor of medicine in Mitrevas lab. But they also identified genetic pathways that differed between mice and humans, providing detailed analysis of areas where TB in mice is unlikely to point to meaningful insight into human TB infection.

Until now, we have studied mouse models to understand TB disease progression, not knowing where the mouse disease translates to human disease and where it doesnt, Khader said. Now, we have shown that many areas do translate but that there are important aspects of TB infection that dont. If you are using mouse models to develop TB vaccines or other therapeutics that target areas that dont overlap, you likely wont succeed.

Added Mitreva, Our study will inform researchers when they may need to move to a different animal model to study their genetic or molecular pathways of interest.

The researchers studied in detail the genes that increase in expression in people who develop severe TB disease. Of 16 such genes identified in people, they were able to study 12 in mice. Four of the genes could not be studied because mice dont have equivalent versions of such genes or, when such genes were eliminated, the mouse embryos died during development.

The scientists found that the 12 genes fall into three categories: those that provide protection against TB infection; those that lead to greater susceptibility to TB infection; and those that had no effect either way. Such information will be useful in seeking future therapeutics that could, for example, boost effects of protective genes or shut down harmful ones.

According to Khader and Mitreva, their team plans to use the new knowledge to better understand TB infections that have become drug-resistant, a growing problem in places where the disease is endemic. In addition, they will harness the information to help understand why the TB vaccine often administered to high-risk groups of people works well in some individuals but not others.

With the studys raw data publicly available, Khader and Mitreva said they are hopeful it will serve as a valuable resource to TB research and immunology communities worldwide.

This work was supported by Washington University in St. Louis; the National Institutes of Health (NIH), grant numbers HL105427, AI111914-02, AI123780, AI134236-02, U19 AI91036 and U19AI106772; the Department of Molecular Microbiology at Washington University; and a Stephen I. Morse Fellowship; the Department of Medicine at the University of Rochester Medical Center.

Scriba is a co-inventor of a patent of the 16-gene signature for TB susceptibility from the Adolescent Cohort Study (ACS).

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

Read more here:
Immune responses to tuberculosis mapped across 3 species - Washington University School of Medicine in St. Louis

More than a year ago, the world was shocked by Chinese biophysicist He Jiankui's attempt to use CRISPR technology to modify human embryos and make them resistant to HIV, which led to the birth of twins Lulu and Nana.

Now, crucial details have been revealed in a recent release of excerpts from the study, which have triggered a series of concerns about how Lulu and Nana's genome was modified.

CRISPR is a technique that allows scientists to make precise edits to any DNA by altering its sequence.

When using CRISPR, you may be trying to "knock out" a gene by rendering it inactive, or trying to achieve specific modifications, such as introducing or removing a desired piece of DNA.

Gene editing with the CRISPR system relies on an association of two proteins. One of the proteins, called Cas9, is responsible for "cutting" the DNA. The other protein is a short RNA (ribonucleic acid) molecule which works as a "guide" that brings Cas9 to the position where it is supposed to cut.

The system also needs help from the cells being edited. DNA damage is frequent, so cells regularly have to repair the DNA lesions. The associated repair mechanisms are what introduce the deletions, insertions or modifications when performing gene editing.

Jiankui and his colleagues were targeting a gene called CCR5, which is necessary for the HIV virus to enter into white blood cells (lymphocytes) and infect our body.

One variant of CCR5, called CCR5 32, is missing a particular string of 32 "letters" of DNA code. This variant naturally occurs in the human population, and results in a high level of resistance to the most common type of HIV virus.

Jankui's team wanted to recreate this mutation using CRISPR on human embryos, in a bid to render them resistant to HIV infection. But this did not go as planned, and there are several ways they may have failed.

First, despite claiming in the abstract of their unpublished article that they reproduced the human CCR5 mutation, in reality the team tried to modify CCR5 close to the 32 mutation.

As a result, they generated different mutations, of which the effects are unknown. It may or may not confer HIV resistance, and may or may not have other consequences.

Worryingly, they did not test any of this, and went ahead with implanting the embryos. This is unjustifiable.

A second source of errors could have been that the editing was not perfectly efficient. This means that not all cells in the embryos were necessarily edited.

When an organism has a mixture of edited and unedited cells, it is called a "mosaic". While the available data are still limited, it seems that both Lulu and Nana are mosaic.

This makes it even less likely that the gene-edited babies would be resistant to HIV infection. The risk of mosaicism should have been another reason not to implant the embryos.

Moreover, editing can have unintended impacts elsewhere in the genome.

When designing a CRISPR experiment, you choose the "guide" RNA so that its sequence is unique to the gene you are targeting. However, "off-target" cuts can still happen elsewhere in the genome, at places that have a similar sequence.

Jiankui and his team tested cells from the edited embryos, and reported only one off-target modification. However, that testing required sampling the cells, which were therefore no longer part of the embryos - which continued developing.

Thus, the remaining cells in the embryos had not been tested, and may have had different off-target modifications.

This is not the team's fault, as there will always be limitations in detecting off-target and mosaicism, and we can only get a partial picture.

However, that partial picture should have made them pause.

Above, we have described several risks associated with the modifications made on the embryos, which could be passed on to future generations.

Embryo editing is only ethically justifiable in cases where the benefits clearly outweigh the risks.

Technical issues aside, Jiankui's team did not even address an unmet medical need.

While the twins' father was HIV-positive, there is already a well-established way to prevent an HIV-positive father from infecting embryos. This "sperm washing" method was actually used by the team.

The only benefit of the attempted gene modification, if proven, would have been a reduced risk of HIV infection for the twins later in life.

But there are safer existing ways to control the risk of infection, such as condoms and mandatory testing of blood donations.

Gene editing has endless applications. It can be used to make plants such as the Cavendish banana more resistant to devastating diseases. It can play an important role in the adaptation to climate change.

In health, we are already seeing promising results with the editing of somatic cells (that is, non-heritable modifications of the patient's own cells) in beta thalassemia and sickle cell disease.

However, we are just not ready for human embryo editing. Our techniques are not mature enough, and no case has been made for a widespread need that other techniques, such as preimplantation genetic testing, could not address.

There is also much work still needed on governance. There have been individual calls for a moratorium on embryo editing, and expert panels from the World Health Organisation to UNESCO.

Yet, no consensus has emerged.

It is important these discussions move in unison to a second phase, where other stakeholders, such as patient groups, are more broadly consulted (and informed). Engagement with the public is also crucial.

Dimitri Perrin, Senior Lecturer, Queensland University of Technology and Gaetan Burgio, Geneticist and Group Leader, The John Curtin School of Medical Research, Australian National University.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Go here to see the original:
New Details About The Infamous 'CRISPR Babies' Experiment Have Just Been Revealed - ScienceAlert

Novartis $9.7 billion acquisition of The Medicines Company (MDCO), which the companies announced Sunday after days of rumors, is a story of second acts.

It represents a new chance for a type of cholesterol-lowering drug that was once predicted to generate many billions of dollars in annual sales, but has so far disappointed drug makers and investors, to dominate the landscape for heart medicines. Its also a triumphant final act for Clive Meanwell, who founded The Medicines Company in 1996 and ran it through a quarter-century roller-coaster ride that saw the firm become a Wall Street darling, fall from favor, and, in the past year, reach new highs. And its a second act for The Medicines Companys current CEO, who previously spent almost four years as the chief executive of Purdue Pharma, the company whose name has become synonymous with the opioid epidemic.

The deal also represents another victory for Alexander Denner of Sarissa Capital, who took control of The Medicines Companys board last March and is chairman of the companys board of directors.

advertisement

Not so long ago, The Medicines Company was at a crossroads due to the loss of its key revenue driver, Denner said in a press release. I am proud of the companys transformation under a reconstituted board into a lean, highly focused team successfully advancing an exciting new therapy and creating tremendous value for patients and shareholders.

The Medicines Companys rise, fall, and subsequent rise also tells the story of how the industry has shied away from heart drugs, which a little more than a decade ago were the biggest sellers among all medicines, even as the heart disease remains the biggest global killer.

Were hoping to reimagine treatment of the leading global cause of death, Novartis (NVS) CEO Vas Narasimhan tweeted after the deal was announced. This could be a strong step forward in @Novartiss transformation into a focused medicines company.

Acquiring The Medicines Company fulfills Narasimhans goal of finding outside deals to bolster Novartis growth. Novartis has previously pulled off a turnaround of a heart failure drug, Entresto, that initially looked like a flop, and it will be able to use the same sales force to sell The Medicines Companys drug, inclisiran.

But the deal appears to assume inclisiran will generate more than $2 billion in annual sales, according to a note to investors from Umer Raffat at Evercore ISI, because The Medicines Company splits profits from the medicine with the biotechnology firm Alnylam, which originally invented it. Inclisiran is a type of cholesterol drug called a PCSK9 inhibitor. The two previous PCSK9 drugs, which generate annual sales of less than $1 billion, were given either once every two weeks or monthly. Inclisirans advantage is that it is given twice a year, and the cost of a years treatment is expected to be less.

But a big study on whether the new medicine decreases heart attacks and strokes has not yet finished. Novartis deal represents a bet that lowering cholesterol, which was the drug industrys past, will also be its future.

The Medicines Company first caught investors attention due to a drug called Angiomax, a blood thinner that was used in some heart procedures. The drug was approved in 2000, and within a few years was generating hundreds of millions of dollars in sales.

One of the biggest dramas around the drug was not medical but legal. In 2001, The Medicines Company had missed a deadline for extending its patent by days, and lobbied hard for a law (critics called it the dog ate my homework act) that would give it more exclusivity. Its a draconian penalty for an administrative mistake, Meanwell told the New York Times in 2010. He won, and Angiomax sales peaked at $635 million in 2014.

But after that, the companys sales did plummet, falling to just $45 million in 2016. The Medicines Company had always been based around licensing drugs invented elsewhere and marketing them, and Meanwell searched for another hit. Options included another blood thinner, several antibiotics, and a Pfizer (PFE) drug that had once been heralded as artery Drano but eventually failed due to mixed results. But by 2017, it became clear that the best option was a drug Meanwell had licensed from a small biotechnology company.

Alnylam was founded in 2002 around a technology that would win a Nobel Prize in 2006: a process called RNA interference, or RNAi, which could be used to block one of the central processes of life: the production of proteins based on recipes in DNA. This, it seemed, could be a new way of making drugs. (Alnylam, which now sports a $12 billion market cap, just had a second RNAi drug approved.) The drug Meanwell licensed prevents the PCSK9 gene from making a protein that is key to increasing the amount of cholesterol, including low-density lipoprotein, or LDL, in the blood. LDL increases the risk of heart attacks and strokes.

PCSK9 drugs had already had time in the spotlight. The PCSK9 gene caught drug companies attention in 2006 when a paper in the New England Journal of Medicine showed that mutations in the gene lowered LDL and prevented heart disease. One gene, found in African Americans, lowered the risk of heart attacks, strokes, and related problems by 88%. There were even patients with shockingly low LDL levels who seemed perfectly healthy. One, a Texas aerobics instructor, had an LDL of 14 milligrams per deciliter, just one-seventh of the normal level of 100 mg/dL.

Amgen (AMGN) and Regeneron, which was collaborating with the French drug giant Sanofi (SNY), bet on their own PCSK9 drugs. Regenerons Praluent was approved in April 2015; Amgens Repatha followed that August. It looked like the stage was set for an old-fashioned drug company marketing war. An executive at CVS (CVS) predicted that the drugs could cost the American health system $150 billion a year. Previous cholesterol drugs, like Pfizers Lipitor and Mercks Zocor, had, after all, been among the best-selling drugs of all time.

Instead, the drugs faced resistance due to their $14,000-a-year prices and the fact that they were shots. Even after both drugs had been shown to lower the risk of heart attacks and strokes, sales did not take off. In March 2018, Regeneron offered to lower the cost of Praluent to $8,000 a year or less by offering rebates to insurers. That October, Amgen cut Repathas price to $5,850. This February, Regeneron matched Amgens move. Sales have increased, but are still low. Repatha sales increased 40% from a year ago in the third quarter of 2019 to $168 million. In the same period, Praluent sales decreased 12% to $70 million.

But by 2017, Meanwell was betting on his PCSK9 drug, inclisiran. He sold off The Medicines Companys other assets, and focused entirely on running trials for the new cholesterol-lowering drug. Its possible that the fact that patients cant forget to take the drug every two weeks could yield bigger reductions in heart attacks and strokes than previous PCSK9s; having a drug that works so long will also mean that if any side effects do emerge, they will be more serious. A 15,000-patient study looking at the long-term effects of the medicine is ongoing.

In December, Meanwell became chief innovation officer, ceding the CEO job to Mark Timney, who had served as Purdues CEO from 2014 to 2017. At the time, Denner, the chairman, said that Timneys leadership will serve the Company well as it embarks on its next strategic phase. When asked about Timneys time with Purdue, a Medicines Company spokesperson reiterated that Timney has, in fact, served the company well during this important strategic phase.

In the third quarter of 2019, Novartis heart failure drug Entresto saw sales jump 60% to $430 million. Now well see if the company can pull off a similar turnaround in the fortunes of PCSK9 drugs.

Original post:
With $9.7b buy, Novartis bets that heart drugs are coming back - STAT

When University of Toronto Professor Michael Ohh was scouting postdoctoral positions at Harvard Medical School in the mid-1990s, a group of Canadians that often gathered to talk science told him to check out the molecular oncology floor at the Dana-Farber Cancer Institute, run by legendary virologist David Livingston.

It turned out to be good advice.

Ohh met with three young investigators Livingston had trained and hired, including the clinician-scientist William Kaelin Jr. The floor was full of bright and driven people, and the electricity in the air was palpable, recalls Ohh, now a professor of laboratory medicine and pathobiologyand of biochemistry at U of T.

Ohh spent the next five years in Kaelins lab and co-authored several papers on how cells respond to changes in oxygen levels research that contributed to Kaelin being awarded the 2019 Nobel Prize in Physiology or Medicine.

The work also set the stage for Ohhs career as an independent scientist in Toronto, and it continues to bear fruit and hold promise for treatments of cancer and other diseases.

One of the most significant things I learned in Bills lab was a rigorous approach to science, says Ohh. He really wanted you to nail the mechanism with a series of elegant experiments and he understood that process is highly competitive with other labs. He often said, Science is a contact sport.

Ohh calls his time in Kaelins lab a tour of duty unbearably stressful at times, but balanced by the excitement of doing fascinating science with talented people.

Kaelins lab was focused on three tumour suppressor genes. Two were well known, but the third was a newly discovered gene called VHL that had been shown to cause von Hippel-Lindau syndrome, a rare hereditary disorder in which patients develop multiple benign and cancerous tumours.

Only a handful of labs in the world studied VHL at the time and virtually nothing was known about its function. We tried a guilt-by-association approach, looking for proteins with which VHL interacted in the hope that these might shed clues to VHL function, says Ohh.

By the late 1990s, they had found several and determined that those proteins are part of a larger complex that likely targets other proteins for destruction.

They showed that without a functional VHL protein, these complexes are unable to degrade another protein called hypoxia-inducible factor (HIF), which in turn spurs tumour cell survival and growth even in low-oxygen microenvironments.

The mechanism at play in von Hippel-Lindau syndrome, in other words, also impacts how all cells sense and adapt to oxygen deprivation. The worlds of hypoxia and VHL collided in that discovery, says Ohh.

Researchers have since developed ways to control how cells sense and adapt to changes in oxygen, and are applying those findings for various conditions. A drug based on this approach is in clinical trial for various cancer types, and the findings also look promising in pre-clinical research for cardiovascular disease and anemia.

Ohhs lab in Toronto has just figured out why certain people with mutations in another HIF gene get cancer and/or polycythemia (an excess of red blood cells). Recent clinical reports have detailed the plight of people with this mutation, and clinicians are now asking Ohhs lab if they can help predict what disease their patients will eventually develop, so they can better monitor their patients for these conditions.

Early detection is critical for outcomes in cancer treatment, so this is useful, highly personalized medicine, says Ohh. And its an extension of the work we did 20 years ago, which is gratifying.

Ohh and his lab are also looking at evolutionary aspects of this molecular pathway. They are studying evolutionary diversions of the pathway among different animals over millions of years to see which genetic sequences and motifs are conserved.

Insights into these diversions could offer ways to understand the precise mechanisms and critical regions of HIF and VHL by which cells better respond to oxygen fluctuations.

Great science isnt the only product of the Kaelin lab. Ohh met his wife Meredith Irwin there when she was a research trainee, and they have been together for two decades. Irwin is a professor of pediatrics, medical biophysics and laboratory medicine and pathobiology at U of T, as well as a clinician-scientist at The Hospital for Sick Children.

Irwin was born and raised in New York, studied at the Massachusetts Institute of Technology and Harvard, and trained at Boston Childrens Hospital and Dana-Farber for more than a decade.

The couple travelled to Boston for Kaelins 60th birthday two years ago. They asked us to give talks, and afterward Bill made a comment about me stealing an American to Canada, says Ohh. We really are very happy here in Toronto.

Go here to read the rest:
'Science is a contact sport': What one U of T researcher learned in the lab of Nobel laureate William Kaelin - News@UofT