Category Archives: Gene Medicine

May 11, 2017 by Molly Peterson Findings from Leslie Lyons study could help feline preservationists implement breeding strategies in captivity for rare and endangered species such as the African black-footed cat. Credit: Cleveland Zoo

Whole genome sequencing (WGS), which is the process of determining an organism's complete DNA sequence, can be used to identify DNA anomalies that cause disease. Identifying disease-causing DNA abnormalities allows clinicians to better predict an effective course of treatment for the patient. Now, in a series of recent studies, scientists at the University of Missouri are using whole genome sequencing through the 99 Lives Cat Genome Sequencing Consortium to identify genetic variants that cause rare diseases, such as progressive retinal atrophy and Niemann-Pick type 1, a fatal disorder in domestic cats. Findings from the study could help feline preservationists implement breeding strategies in captivity for rare and endangered species such as the African black-footed cat.

The 99 Lives project was established at Mizzou by Leslie Lyons, the Gilbreath-McLorn Endowed Professor of Comparative Medicine in the College of Veterinary Medicine, to improve health care for cats through research. The database has genetically sequenced more than 50 felines and includes DNA from cats with and without known genetic health problems. The goal of the database is to identify DNA that causes genetic disorders and have a better understanding of how to treat diseases.

In the first study, Lyons and her team used the 99 Lives consortium to identify a genetic mutation that causes blindness in the African black-footed cat, an endangered species often found in U.S. zoos. The team sequenced three cats two unaffected parents and an affected offspring to determine if the mutation was inherited or spontaneous. The genetic mutation identified was located the IQCB1 gene and is associated with progressive retinal atrophy, an inherited degenerative retinal disorder that leads to blindness. The affected cat had two copies of the genetic mutation, indicating that it was an inherited disorder.

"African black-footed cats are closely related to domestic cats, so it was a good opportunity to use the 99 Lives database," Lyons said. "When sequencing DNA, we are looking for the high priority variants, or genetic mutations that result in disease. Variants in the IQCB1 gene are known to cause retinal degeneration in humans. We evaluated each gene of the African black-footed cat, one at a time, to look for the genetic mutation that is associated with vision loss."

In another study representing the first time precision medicine has been applied to feline health, Lyons and her team used whole genome sequencing and the 99 Lives consortium to identify a lysosomal disorder in a 36-week-old silver tabby kitten that was referred to the MU Veterinary Health Center. The kitten was found to have two copies of a mutation in the NPC1 gene, which causes Niemman-Pick type 1, a fatal disorder. The NCP1 gene identified is not a known variant in humans; it is a rare mutation to the feline population.

"Genetics of the patient is a critical aspect of an individual's health care for some diseases," Lyons said. "Continued collaboration with geneticists and veterinarians could lead to the rapid discovery of undiagnosed genetic conditions in cats. The goal of genetic testing is to identify disease early, so that effective and proactive treatment can be administered to patients."

Identification of both the IQCB1 gene in the African black-footed cat and the NCP1 in the silver tabby will help to diagnose other cats and allow them to receive appropriate treatment. Using results of the black-footed cat study, zookeepers will be implementing species survival plans to help manage the cats in captivity in North America.

Explore further: Linking human genome sequences to health data will change clinical medicine, says expert

More information: Annie Oh et al. Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes), Scientific Reports (2017). DOI: 10.1038/srep43918

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Rare feline genetic disorders identified through whole genome sequencing - Medical Xpress

"With a long-standing heritage in rare disease, including hemophilia, Pfizer is an ideal partner for our Hemophilia A program," said Dr. Sandy Macrae, Sangamo's Chief Executive Officer. "We believe Pfizer's end-to-end gene therapy capabilities will enable comprehensive development and commercialization of SB-525, which could potentially benefit Hemophilia A patients around the world. This collaboration also marks an important milestone for Sangamo as we continue to make progress in the translation of our ground-breaking research into new genomic therapies to treat serious, genetically tractable diseases."

Under the terms of the collaboration agreement, Sangamo will receive a $70 million upfront payment from Pfizer. Sangamo will be responsible for conducting the SB-525 Phase 1/2 clinical study and certain manufacturing activities. Pfizer will be operationally and financially responsible for subsequent research, development, manufacturing and commercialization activities for SB-525 and additional products, if any. Sangamo is eligible to receive potential milestone payments of up to $475 million, including up to $300 million for the development and commercialization of SB-525 and up to $175 million for additional Hemophilia A gene therapy product candidates that may be developed under the collaboration. Sangamo will also receive tiered double-digit royalties on net sales. Additionally, Sangamo will be collaborating with Pfizer on manufacturing and technical operations utilizing viral delivery vectors.

Gene therapy is a potentially transformational technology for patients, focused on highly specialized, one-time, treatments that address the root cause of diseases caused by genetic mutation. The technology involves introducing genetic material into the body to deliver a correct copy of a gene to a patient's cells to compensate for a defective one. The genetic material can be delivered to the cells by a variety of means, most frequently using a viral vector such as rAAV. There have been no gene therapy products approved in the U.S. to date.

Hemophilia A is a rare blood disorder caused by a genetic mutation resulting in insufficient activity of Factor VIII, a blood clotting protein the body uses to stop bleeding. There are approximately 16,000 patients in the U.S. and more than 150,000 worldwide with Hemophilia A. SB-525 is comprised of a rAAV vector carrying a Factor VIII gene construct driven by a proprietary, synthetic, liver-specific promoter. The U.S. Food and Drug Administration has cleared initiation of human clinical trials for SB-525, which also has been granted orphan drug designation. Sangamo is on track this quarter to start a Phase 1/2 clinical trial to evaluate safety and to measure blood levels of Factor VIII protein and other efficacy endpoints.

Conference CallSangamo will host a conference call today, May 10, 2017 at 5:00 p.m. ET, which will be open to the public, to discuss the details of the collaboration and the Company's first quarter business and financial results. The call will also be webcast live and can be accessed via a link the Sangamo Therapeutics website in the Investors and Media section under Events and Presentations. A replay of the webcast will also be available for one week after the call.

The conference call dial-in numbers are (877) 377-7553 for domestic callers and (678) 894-3968 for international callers. The conference ID number for the call is 15225000. For those unable to listen in at the designated time, a conference call replay will be available for one week following the conference call, from approximately 8:00 p.m. ET on May 10, 2017 to 11:59 p.m. ET on May 17, 2017. The conference call replay numbers for domestic and international callers are (855) 859-2056 and (404) 537-3406, respectively. The conference ID number for the replay is 15225000.

About Sangamo Therapeutics Sangamo Therapeutics, Inc. is focused on translating ground-breaking science into genomic therapies that transform patients' lives using the company's industry leading platform technologies in genome editing, gene therapy, gene regulation and cell therapy. The Company is advancing Phase 1/2 clinical programs in Hemophilia A and Hemophilia B, and lysosomal storage disorders MPS I and MPS II. Sangamo has a strategic collaboration with Pfizer for Hemophilia A, with Bioverativ Inc. for hemoglobinopathies, including beta thalassemia and sickle cell disease, and with Shire International GmbH to develop therapeutics for Huntington's disease. In addition, it has established strategic partnerships with companies in non-therapeutic applications of its technology, including Sigma-Aldrich Corporation and Dow AgroSciences. For more information about Sangamo, visit the Company's website at http://www.sangamo.com.

Forward Looking Statements This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation references relating to the collaboration agreement with Pfizer, potential milestone payments and royalties under the collaboration agreement, ability of the collaboration to advance and commercialize SB-525 as a treatment for Hemophilia A, research and development of therapeutic applications of Sangamo's genomic therapy platforms, the expected timing of clinical trials of lead programs, including SB-525 and the release of data from these trials, the impact of Sangamo's clinical trials on the field of genetic medicine and the benefit of orphan drug status. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to substantial dependence on the clinical success of lead therapeutic programs, the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo Therapeutics, Inc. assumes no obligation to update the forward-looking information contained in this press release.

Pfizer and Rare DiseaseRare disease includes some of the most serious of all illnesses and impacts millions of patients worldwide,i representing an opportunity to apply our knowledge and expertise to help make a significant impact on addressing unmet medical needs. The Pfizer focus on rare disease builds on more than two decades of experience, a dedicated research unit focusing on rare disease, and a global portfolio of multiple medicines within a number of disease areas of focus, including hematology, neuroscience, and inherited metabolic disorders.ii

Pfizer Rare Disease combines pioneering science and deep understanding of how diseases work with insights from innovative strategic collaborations with academic researchers, patients, and other companies to deliver transformative treatments and solutions. We innovate every day leveraging our global footprint to accelerate the development and delivery of groundbreaking medicines and the hope of cures.

Click here to learn more about our Rare Disease portfolio and how we empower patients, engage communities in our clinical development programs, and support programs that heighten disease awareness and meet the needs of patient families.

Pfizer Inc: Working together for a healthier worldAt Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. For more information, please visit us at http://www.pfizer.com. In addition, to learn more, follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

Pfizer Disclosure Notice: The information contained in this release is as of May 10, 2017. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about an investigational Hemophilia A agent, SB-525, including its potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical study commencement and completion dates as well as the possibility of unfavorable study results, including unfavorable new clinical data and additional analyses of existing clinical data; risks associated with initial data, including the risk that the final results of the Phase I/2 study for SB-525 and/or additional clinical trials may be different from (including less favorable than) the initial data results and may not support further clinical development; whether and when any applications may be filed with regulatory authorities for SB-525; whether and when regulatory authorities may approve any such applications, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of SB-525; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors That May Affect Future Results", as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at http://www.sec.gov and http://www.pfizer.com.

i Rare Disease: Facts and Statistics. http://globalgenes.org/rare-diseases-facts-statistics. Accessed September 7, 2016. ii Pfizer Inc. Rare Disease. http://www.pfizer.com/health-and-wellness/health-topics/rare-diseases/areas-of-focus. Accessed December 20, 2016.

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Sangamo Therapeutics And Pfizer Announce Collaboration For Hemophilia A Gene Therapy - PR Newswire (press release)

WEST HAVEN >> Our genes define our individuality, including what diseases to which we may be susceptible.

In just a few days, gene-sequencing machines can map all of a persons genes, revealing the cause of a genetic illness and even suggesting the best possible treatment.

On Monday, the Yale School of Medicine, partnering with Yale New Haven Hospital, took the next step toward personalized medicine, cutting the ribbon on its Center for Genome Analysis on Yales West Campus.

Dr. Murat Gunel, professor of genetics and neuroscience in the medical school, gave a vivid example of how gene sequencing can save lives:

About three months ago a baby was born in New Haven with a really, really significant skin disease that we had to transfer him to the intensive care unit. And he was dying, and we didnt know what was wrong with him, Gunel said. In six days we were able to sequence his genome, understand his disease and he is at home playing with his mother now.

The baby suffered from dystrophic epidermolysis bullosa, which makes the skin extremely fragile, and its caused by a mutation in just one gene: COL7A1. Gunel said Dr. Keith Choate first saw the baby on a Saturday and by Friday had the diagnosis. This is a daily occurrence, Gunel said.

Choate said the genetic analysis showed the infant had a mild case of the disease, which was limited to the hands and feet. He is receiving advanced wound care, Choate said.

The pair of NovaSeq 6000 gene-sequencing machines that are churning out this information with three more on the way will help researchers find treatments and cures for cancers, prenatal diseases and others at a faster and faster pace.

Of 20,000 genes in the human genome, 57 have been identified for which preventive measures can be taken or treatment can be prescribed if an abnormality or mutation is found. For example, mutations in the BRCA1 or BRCA2 genes increase a womans risk of developing breast or uterine cancer.

We are sequencing every cancer at Smilow now, understanding what is specific for that cancer and giving treatment specific to that individual, Gunel said. We want to take from these specific diseases not only for prenatal, not only for newborn, not only for cancer, but [to] understand the health of an individual. We want to make Connecticut the healthiest state in the nation by sequencing and understanding the differences between all of us.

Dr. Robert Alpern, dean of the Yale School of Medicine, said, The idea is that you can know the total sequence of a patient and then follow their history, their health, what happens to them and then correlate them together so that someday we will be able to predict everything about ones health just from their DNA sequence.

Yale has done so much for New Haven, so much for New Haven County and now so much for this country, said Senate Republican President Pro Tem Len Fasano of North Haven.

Referring to the ability to map a persons genome within days, Fasano said, You can take that and figure out how the environment affects different lives by looking at different gene structure, comparing to different parts of the country or whether its an urban area versus a suburban area. The research that can stem from this is pretty amazing when you think of it.

The growing field also is a boon to the states economy. Senate Democratic President Pro Tem Martin Looney of New Haven said, This commitment to the advancement of health and medicine will have far-reaching and positive impacts on our economy and overall well-being for years to come. We know were going to need data scientists, health information specialists, clinical analysts, genomic counselors, to name just a few of the specialties that are going to create huge opportunities for new employment in our state.

Marna Borgstrom, CEO of Yale New Haven Health, which includes the hospital, said, Theres great work being done here and our interest has been, who does this apply to and how can we make this available to patients? And with our partners at the medical school were committed to providing unparalleled value to people we serve, and part of value is giving people outcomes that are meaningful to them.

And so you start to think about areas like prenatal diagnoses, like certain newborn diseases, difficult cancers and the ability to take all of the drugs and the treatments and the information thats out there but actually create a specialized plan for each patient as each patients going to respond differently, she said.

Call Ed Stannard at 203-680-9382.

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Gene sequencing at Yale finding personalized root of disease; new center opens in West Haven - Litchfield County Times

Our next group of correspondents stood out due to their vocations: In one way or another, their chosen careers brought them into the subculture of scientific thinking. These readers tended to be more favorably disposed to gene editing than others.

Take this reader, a semi-retired school psychologist and a lover of science whose daughter plans to become a clinical geneticist:

I agree with the premise of your article [that prophylactic gene editing could soon be mandatory] and am not frightened by it at all. Scientific advances have not, cannot, and should not be stopped. Since the first civilizations science has been dragging religion and society reluctantly along into a more technologically advanced future. What we gain from this seems always to be more than what we have lost.

A medical student who hopes one day to do gene editing was likewise eager for a future where it is used to cure diseaseand even to direct the way that humans evolve:

Modern medicine, in its current form, is basically the answer to the question: What is the best way to treat diseases whose cures cannot and will not ever be found? Treating someone with cystic fibrosis, for instance, is an admirable thing to do, but its also an exercise in futility: That patient will undoubtedly die prematurely. Anything besides excising the mutant gene and replacing it with a normal copy is treading water and delaying the inevitable (though, obviously, the patients must still be treated).

In modern societies, infectious diseases and trauma are more or less under control (relative to developing countries and bygone eras). Curing genetic diseases (cancer loosely being included in this category) are currently a dead end. So, logically, addressing this head-on is the only next step.

I view gene therapy and editing as the way of the future, not only of medicine but also of humanity in general. It will start as the means for cures of currently incurable diseases. Eventually, it will be a means by which we can continue to evolve ourselves as a species. If 3.5 billion years of evolution churned our species out through the natural selection of random mutations, how much better can we do with logic and molecular precision? In my opinion, anything that can widely (and, potentially, permanently) change mankind and society for the better should be done.

I wish I shared the correspondents confidence that logic and molecular precision will serve humanity better in this realm than the decentralized systems of dating and mating have done so far. Reflecting on the decisions that literally every bygone generation might have made if able to edit genes, I fear that our choices will prove as imprudent in hindsightand thats not even accounting for unintended consequences.

The next reader is working to earn his Masters degree in Biochemistry:

It is not unreasonable to imagine that in the near future gene editing will be a safe and effective means of preventing genetic diseases. It is also not unreasonable to imagine that in the case of many diseases, such as sickle-cell anemia or cystic fibrosis, which are caused by small mutations in a single gene coding for a functionally important protein, gene editing would be likely to prevent the disease without affecting the child in any other way. For these diseases, once it is demonstrated that gene editing works the way that it is supposed to, I think parents should be punished for failing to employ gene editing. I think that if it had been demonstrated that gene editing was safe, effective, and selective, refusal to use this technique to prevent disease would essentially amount to fear and mistrust of the scientific and medical communities. I really dont think thats a valid reason to allow another person to be afflicted by a preventable disease.

However, I draw a distinction here between expecting parents to make edits that will definitely prevent a debilitating disease, and expecting edits that reduce the risk of a disease that the child may or may not have ended up getting. I certainly wouldnt be opposed to parents editing genes to reduce the chance of cancer, but I wouldnt really expect it. There are a number of behaviors that we know reduce cancer risk which we dont really expect parents to push on their kids. For example, parents could probably reduce cancer risk in their children by some small fraction by giving them grape juice every day or something like that. I dont really expect parents to do that. If you cant blame parents for not giving their kids grape juice you really cant blame them for not editing the kids genome.

At the same time, he adds, we can really only justify using gene editing for medical purposes:

We are a long way from understanding our biology well enough to be able to make genome modifications to enhance intelligence or beauty or athleticism without risking horrible unforeseen side effects. But even if we did have the ability to do that, I still dont think it would be justified because I dont think we can tie these traits to an increased sense of happiness or fulfillment.

I am short and scrawny, and Im perfectly happy with that. I know plenty of people who are perfectly content with being as dumb as rocks. I know plenty of smart people who are miserable. So, Ill grant that I am basing my opinion here on a biased personal experience, but I really dont think that we can say that it really is in the best interests of the child to alter superficial traits.

When discussing a childs future, people often talk as if the parents preference is the most important thing. But parents dont own their children. Parents are stewards of their children. I think that making designer babies would be an example of parents making self-serving decisions, rather than making decisions in the best interests of the child. I dont think that is justifiable.

The next correspondent is a biochemistry grad student who works in a research group that specializes in genome-editing technology, and cautions against its near-term limits:

If gene therapy with Cas9 were at some future time as cheap, easy, and safe as an antibiotic treatment, then yes, I would support punishments for parents who forewent a cure for their children. In some cases, a genetic disorder is very similar to other macro-level disorders, e.g. genes can be broken in the same sense that a wrist is broken. While wrists can come in many healthy shapes and sizes and colors, broken in two is not one of them; likewise, while genetic diversity is important and natural and cant always be cleanly mapped to disease, some genetic mutations are incontrovertibly damaging and lead to illness and suffering. Refusing a simple medical treatment for a disorder with a clear singular genetic root cause (of which there are fewer than one might think) would be as unethical as refusing to set a broken wrist.

But I dont think gene therapy will be as cheap, easy, or safe as antibiotics in our lifetimerather, my opinion is that gene therapy will be expensive, invasive, and risky (at least relative to an antibiotic pill) for the foreseeable future. I dont expect gene therapy to become routine in the same way that oral therapies are, and so choosing not to subject your child to gene editing cannot be chalked up to negligence. (A contemporary example: Sovaldi is a drug that essentially cures Hepatitis C, but it costs $200,000 and there are other treatmentscould you imagine a parent being prosecuted for refusing to pay for Sovaldi?)

Why am I so down on gene therapy?

First of all, regarding cost, the clamor surrounding the Cas9 patent dispute should give you an idea of how profitable the players in this field expect gene therapy to be. Gene therapy will always be more expensive than an oral antibiotic because the treatment requires many more steps (each of which is far costlier), is much lower throughput, and will require specialized care and oversight. For similar reasons, it will not be nearly as convenient for patients as filling a prescription. And as Ive written elsewhere, our current early-generation gene-therapy tools and limited understanding of the link between genetics and disease means that gene therapy carries unprecedented safety risks. (For example, no currently approved therapy could cause permanent heritable genetic changes.)

These risks shouldnt disqualify gene therapy as a possible future treatment, but they could certainly give the most informed and adventurous patient pause. In short, I believe technical limitations and cost and safety concerns will delay the debate over mandatory gene editing for decades at least. More pressing to discuss are the multitude of other ways that gene editing and GMOs affect modern life and medicine.

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Thoughts on Gene Editing From the Science Community - The Atlantic

May 09, 2017 09:13 ET | Source: Admera Health, LLC

SOUTH PLAINFIELD, N.J. and ROCHESTER, N.Y., May 09, 2017 (GLOBE NEWSWIRE) -- Today, the University of Rochester School of Medicine and Dentistry and Admera Health announced that enrollment had commenced in a randomized clinical study evaluating the use of pharmacogenomics to guide pain management decisions related to acute dental surgery. Specifically, the study is seeking to determine if a preoperative chair-side pharmacogenomic algorithm can significantly enhance the efficacy of surgical pain management and to characterize the association between gene-drug interactions and clinical outcomes.

Admera Health, a molecular diagnostic company, will extract and sequence DNA samples provided by the University of Rochester. Sequencing will utilize Admeras PGxOne Plus test, a 50 gene Next Generation Sequencing panel that interrogates nearly 200 different variants and provides recommendations for over 220 drugs based on an individuals unique genetic makeup.

It is well understood in the medical community that most acute surgical pain methods have shown inconsistent effects on pain relief and rely excessively on opioid use, which has associated dependency issues, as stated by Admera CEO and President Guanghui Hu. With the implementation of our PGxOne Plus test, we are confident that this study will demonstrate improved patient outcomes, similar to the way pharmacogenomics has been clinically validated in other therapeutic areas such as cardiovascular health, oncology, and psychiatric care. That is why we are excited to be working with the University of Rochester for this study.

According to the CDC, opioid-involved deaths continue to increase and have reached epidemic status. In March, a United States Senate committee opened a probe into the practices of the top manufacturers of opioid drugs.

About Admera Health

Admera Health is a CLIA-certified and CAP-accredited advanced molecular diagnostics company focused on personalized medicine, non-invasive cancer testing, digital health, and providing research use only services. Research and development efforts are dedicated to developing cutting-edge diagnostics that span the continuum of care. Utilizing next generation technology platforms and advanced bioinformatics, Admera Health seeks to redefine disease screening, diagnosis, treatment, monitoring, and management through its innovative, personalized solutions. It is our mission to deliver transformative, valuable solutions for patients, physicians, and clinical researchers. We are committed to improving the health and well-being of our global community through the direct delivery of personalized, medically actionable results.

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University of Rochester School of Medicine and Dentistry Collaborate with Admera Health in a Clinical Study ... - GlobeNewswire (press release)

Although the odds of developing breast cancer are nearly identical for black and white women, black women are 42 percent more likely to die from the disease. This mortality gapdriven by social and environmental, as well as biological factorscontinues to persist.

A large, multi-institutional study, published May 4 in JAMA Oncology, was designed to understand this gap by beginning to unravel the germline genetic variations and tumor biological differences between black and white women with breast cancer. This is the first ancestry-based comprehensive analysis of multiple platforms of genomic and proteomic data of its kind, the authors note.

Findings from this study could lead to more personalized risk assessment for women of African heritage and hasten the development of novel approaches designed to diagnose specific subtypes of aggressive breast cancers early and treat them effectively.

One new finding is that black women with hormone receptor positive, HER2-negative breast cancer had a higher risk-of-recurrence score than white women. The study also confirmed that black patients were typically diagnosed at a younger age and were more likely to develop aggressive breast-cancer subtypes, including basal-like or triple-negative cancerstumors lacking estrogen receptors, progesterone receptors and HER2as well as other aggressive tumor subtypes.

People have long associated breast cancer mortality in black women with poverty, or stress, or lack of access to care, but our results show that much of the increased risk for black women can be attributed to tumor biological differences, which are probably genetically determined, said study author Olufunmilayo Olopade,the Walter L. Palmer Distinguished Service Professor in Medicine and Human Genetics at the University of Chicago.

The good news, she said, is that as we learn more about these genetic variations, we can combine that information with clinical data to stratify risk and better predict recurrencesespecially for highly treatable cancersand develop interventions to improve treatment outcomes.

This is a great example of how team science and investments in science can accelerate progress in identifying the best therapies for the most aggressive breast cancers, said co-author Charles Perou, a member of the University of North Carolina Lineberger Comprehensive Cancer Center and professor of genetics, and pathology & laboratory medicine at the UNC School of Medicine.

In the largest dataset to date that has good representation of tumors from black women, we did not find much difference between the somatic mutations driving tumors in black and white women, he added. Yet black women were more likely to develop aggressive molecular subtypes of breast cancer. Now we provide data showing that differences in germline genetics may be responsible for up to 40 percent of the likelihood of developing one tumor subtype versus another.

The study used DNA data collected from 930 women154 of predominantly African ancestry and 776 of European ancestryavailable through The Cancer Genome Atlas, established by the National Cancer Institute and the National Human Genome Research Institute. The researchers combed through the data methodically, looking for racial differences in germline variations, somatic mutations, subtypes of breast cancers, survival time, as well as gene expression, protein expression and DNA methylation patterns.

Most significantly, explained first author Dezheng Huo, associate professor of public health sciences at the University of Chicago, we observed a higher genetic contribution to estrogen-receptor negative breast cancer in blacks.

Black women were more likely to get these highly aggressive cancers. This is one of the first studies to connect genetics to this racial difference in tumor subtype frequencies.

The study also revealed 142 genes that showed differences in expression levels according to race. One gene, CRYBB2, was consistently higher in tumors from black patients within each breast cancer subtype, as well as in normal tissues, suggesting it may be a race-specific gene.

The researchers also found somatic mutations in 13 genes or DNA segments that differed in frequency in tumors from black and white women. One of them, a mutated gene called TP53, was more common in black women than white women and was a strong predictor of disease recurrence.

Despite the relatively short follow-up time in the TCGA dataset, we were able to detect a significant racial disparity in patient survival using breast cancer-free interval as the endpoint between patients of African and European ancestries, said co-first author Hai Hu, vice president for research at the Chan Soon-Shiong Institute of Molecular Medicine at Windber. Most of the worst outcomes came from basal-like subtype breast cancer patients of African Ancestry.

Black women in all categories, including the most common breast cancers, were likely to have a worse prognosis, Olopade said.

Understanding the basic, underlying genetic differences between black and white women, the higher risk scores and the increased risk of recurrence should lead us to alternative treatment strategies, said Perou.

The crucial long-term benefit of this study, according to Olopade, is that it is a step toward the development of polygenic biomarkers, tools that can help us better understand each patients prognosis and, as we learn more, play a role in choosing the best treatment.

Genes matter, she added. This is a foot in the door for precision medicine, for scientifically targeted treatment.

This study now outlines a path for us to personalize breast cancer risk assessment and develop better strategies to empower all women, especially black women, to know their genetics and be more proactive in managing their risk, Perou said.

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Understanding genetic variations in black women could improve cancer outcomes - ScienceBlog.com (blog)

Although the odds of developing breast cancer are nearly identical for black and white women, black women are 42 percent more likely to die from the disease. This mortality gapdriven by social and environmental, as well as biological factorscontinues to persist.

A large, multi-institutional study, published May 4 in JAMA Oncology, was designed to understand this gap by beginning to unravel the germline genetic variations and tumor biological differences between black and white women with breast cancer. This is the first ancestry-based comprehensive analysis of multiple platforms of genomic and proteomic data of its kind, the authors note.

Findings from this study could lead to more personalized risk assessment for women of African heritage and hasten the development of novel approaches designed to diagnose specific subtypes of aggressive breast cancers early and treat them effectively.

One new finding is that black women with hormone receptor positive, HER2-negative breast cancer had a higher risk-of-recurrence score than white women. The study also confirmed that black patients were typically diagnosed at a younger age and were more likely to develop aggressive breast-cancer subtypes, including basal-like or triple-negative cancerstumors lacking estrogen receptors, progesterone receptors and HER2as well as other aggressive tumor subtypes.

People have long associated breast cancer mortality in black women with poverty, or stress, or lack of access to care, but our results show that much of the increased risk for black women can be attributed to tumor biological differences, which are probably genetically determined, said study author Olufunmilayo Olopade,the Walter L. Palmer Distinguished Service Professor in Medicine and Human Genetics at the University of Chicago.

The good news, she said, is that as we learn more about these genetic variations, we can combine that information with clinical data to stratify risk and better predict recurrencesespecially for highly treatable cancersand develop interventions to improve treatment outcomes.

This is a great example of how team science and investments in science can accelerate progress in identifying the best therapies for the most aggressive breast cancers, said co-author Charles Perou, a member of the University of North Carolina Lineberger Comprehensive Cancer Center and professor of genetics, and pathology & laboratory medicine at the UNC School of Medicine.

In the largest dataset to date that has good representation of tumors from black women, we did not find much difference between the somatic mutations driving tumors in black and white women, he added. Yet black women were more likely to develop aggressive molecular subtypes of breast cancer. Now we provide data showing that differences in germline genetics may be responsible for up to 40 percent of the likelihood of developing one tumor subtype versus another.

The study used DNA data collected from 930 women154 of predominantly African ancestry and 776 of European ancestryavailable through The Cancer Genome Atlas, established by the National Cancer Institute and the National Human Genome Research Institute. The researchers combed through the data methodically, looking for racial differences in germline variations, somatic mutations, subtypes of breast cancers, survival time, as well as gene expression, protein expression and DNA methylation patterns.

Most significantly, explained first author Dezheng Huo, associate professor of public health sciences at the University of Chicago, we observed a higher genetic contribution to estrogen-receptor negative breast cancer in blacks.

Black women were more likely to get these highly aggressive cancers. This is one of the first studies to connect genetics to this racial difference in tumor subtype frequencies.

The study also revealed 142 genes that showed differences in expression levels according to race. One gene, CRYBB2, was consistently higher in tumors from black patients within each breast cancer subtype, as well as in normal tissues, suggesting it may be a race-specific gene.

The researchers also found somatic mutations in 13 genes or DNA segments that differed in frequency in tumors from black and white women. One of them, a mutated gene called TP53, was more common in black women than white women and was a strong predictor of disease recurrence.

Despite the relatively short follow-up time in the TCGA dataset, we were able to detect a significant racial disparity in patient survival using breast cancer-free interval as the endpoint between patients of African and European ancestries, said co-first author Hai Hu, vice president for research at the Chan Soon-Shiong Institute of Molecular Medicine at Windber. Most of the worst outcomes came from basal-like subtype breast cancer patients of African Ancestry.

Black women in all categories, including the most common breast cancers, were likely to have a worse prognosis, Olopade said.

Understanding the basic, underlying genetic differences between black and white women, the higher risk scores and the increased risk of recurrence should lead us to alternative treatment strategies, said Perou.

The crucial long-term benefit of this study, according to Olopade, is that it is a step toward the development of polygenic biomarkers, tools that can help us better understand each patients prognosis and, as we learn more, play a role in choosing the best treatment.

Genes matter, she added. This is a foot in the door for precision medicine, for scientifically targeted treatment.

This study now outlines a path for us to personalize breast cancer risk assessment and develop better strategies to empower all women, especially black women, to know their genetics and be more proactive in managing their risk, Perou said.

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Understanding genetic variations in black women could improve cancer outcomes - UChicago News

05 May 2017

A paper in the May 3 Science Translational Medicine identifies a potential new risk gene for amyotrophic lateral sclerosis (ALS). Mutations in ANXA11, which encodes the phospholipid binding protein annexin A11, turned up in people with both familial and sporadic forms of the disease, report scientists led by Christopher Shaw of Kings College London, Vincenzo Silani of the University of Milan, and John Landers of the University of Massachusetts Medical School, Worcester. Mutant proteins strayed from their normal binding partner, the calcyclin protein, and instead aggregated in the nucleus and cytoplasm. Annexin A11 appears to aid in vesicletransport.

This falls in line with themes we are seeing in all ALS mutations, which are impairments in proteostasis, autophagy, vesicular trafficking, and aggregation, said Matthew Harms, Columbia University, New York. It adds some genetic firepower to our interest in thosepathways.

Mutant annexin A11 inclusions take varied forms, including an ordered series of parallel tubules seen from the side (left) and top. [Courtesy of Science TranslationalMedicine/AAAS.]

This paper lists a handful of co-first authors: Bradley Smith, Simon Topp, and Han-Jou Chen of Kings College, with Claudia Fallini of UMass Worcester, and Hideki Shibata, Nagoya University, Japan. On their hunt for new ALS-associated genes, they analyzed whole exome sequences from 751 patients with familial disease and from 180 with sporadic ALS. They found six rare mutations in annexin A11 in 13 people, including a p.D40G amino acid substitution that segregated with disease in two families. These mutations were absent from 70,000 healthy controls. They clustered at the N-terminal tip of the protein. Previous studies suggest that annexin A11 aids in vesicular transport between the endoplasmic reticulum and Golgi apparatus (Shibata et al., 2015).

Carriers developed ALS at an average age of 67, with a classic ALS phenotype and primarily bulbar-onset disease, meaning they first had trouble speaking and swallowing. One patient who had the p.D40G mutation donated tissue for postmortem analysis. As is typical in ALS, neuron loss, astrogliosis, and phosphorylated TDP-43 inclusions pervaded their spinal cords; the latter also appeared in the medulla, temporal neocortex, andhippocampus.

The surprise came when the researchers stained for annexin A11. We saw the most extraordinary inclusions, Shaw told Alzforum. The skein-like patterns and tubular structures in motor neurons of the spinal cord were a far cry from the disordered blobs of TDP-43 that are typical of ALS neuropathology. They were unlike anything the scientists had ever seen, Shaw said (see image above). Add to that the torpedo-shaped structures in axons of the motor cortex, temporal neocortex, and hippocampus, and Shaw knew they were onto something. This mutant protein is actually aggregating in our patients, he said. That gave me 100 percent confidence that we had found a real gene causingpathology.

To find out how ANXA11 causes disease, the authors expressed several of the disease-associated variants or the wild-type protein in mouse primary motor neurons. Wild-type annexin A11 appeared in the nucleus, and in large, vesicle-like structures throughout the cytoplasm of the axons, soma, and dendrites. By contrast, the mutant proteins largely stayed out of vesicles; they aggregated instead. Their inclusions trapped functional, wild-type annexin A11 protein, implying they robbed the cell of the function of the normalprotein.

The variants also appeared to disrupt Annexin A11 binding to calcylin. Computer modeling predicted that the N-terminus of annexin A11 forms two helices, one in and the other next to the calcyclin binding site. Two of the six mutations appeared to disrupt formation of one of those helices. Immunoprecipitation assays revealed that while wild-type annexin A11 bound calcyclin, those mutants did not. The authors suggested that when annexin A11 cannot bind calcyclin, annexin A11 builds up in the cytoplasm and accumulates. As controls, the authors expressed non-pathogenic annexin A11 variants that appear in the general population; these variants left calcyclin bindingintact.

That last step was important, and provides a model for how these assays should be done in the future, said Harms, adding, It demonstrated that the ALS-specific functional defect was coming from mutations that they found in the patients. In general, researchers should always compare suspected pathogenic mutations to non-pathogenic ones to avoid assays picking up on nonspecific effects. Harms agreed this paper offers clear evidence that the p.D40G mutationwhich segregates with disease and leads to those unusual inclusionsis causative of ALS. More work needs to be done to see if the other five mutations are pathogenic, hesaid.

Shaw said his collaborators are now making transgenic zebrafish and mouse models with the mutations so they can study them in whole organisms.Gwyneth DickeyZakaib

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Potential New ALS Gene Leads to Extraordinary Aggregates - Alzforum

Welcome to theNational Academies of Sciences, Engineering, and Medicine study that examined a range of questions about gene drive research.The study wasconducted by acommittee of expertsand released June 8, 2016.

Gene drives are systems of biased inheritance that enhance the ability of a genetic element to pass from an organism to its offspring through sexual reproduction. A wide variety of gene drives occur in nature. Researchers have been studying these natural mechanisms throughout the 20th century but, until the advent of CRISPR/Cas9[1] for gene editing, have not been able to develop a gene drive.

Since early 2015, laboratory scientists have published four proofs-of-concept showing that a CRISPR/Cas9-based gene drive could spread a targeted gene through nearly 100% of a population of yeast, fruit flies, or mosquitoes. Biologists have proposed using gene drives to address problems where solutions are limited or entirely lacking, such as the eradication of insect-borne infectious diseases and the conservation of threatened and endangered species. This study provided an independent, objective examination of what has been learned since the development of gene drivesbased on current evidence.

The resulting report, Gene Drives on the Horizon outlines the state of knowledge relative to the science, ethics, public engagement, and risk assessment as they pertain to gene drive research and the governance of the research process. This report offers principles for responsible practices of gene drive research and related applications for use by investigators, their institutions, the research funders, and regulators.

Follow on Twitter:#GeneDriveStudy

Send email to:ksawyer@nas.edu

[1] CRISPR (Clustered regularly-interspaced short palindromic repeats) are segments of bacterial DNA that, when paired with a specific guide protein, such as Cas9 (CRISPR-associated protein 9), can be used to make targeted cuts in an organisms genome

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Gene Drive Research in Non-Human Organisms ...

The Division of Molecular Medicine and Gene Therapy is located at the Biomedical Center (BMC), Lund University, Sweden. Established as a joint venture between the Medical Faculty at Lund University and the Hematology Clinic at Lund University Hospital, our mission is to translate basic science to clinical applications.

Our research focuses on hematopoiesis, the continuous and dynamic process of blood cell formation. The laboratory consists of eight closely collaborating research groups that all share a common interest in investigating the properties of blood stem cellsto eventually understand and treat hematological disorders.

Five of our researchers belong to the Hemato-LinnExcellence Linnaeus Research Environment funded by The Swedish Research Council and Lund University. Several of the groups are engaged in StemTherapy, a Strategic Research Area for Stem Cells and Regenerative Medicine that is also supported by The Swedish Research Council.

Please welcome our new colleague MelissaIlsleyto the Flygare lab. Melissa joins our Division from theMater Research Institute, University of Queensland, Brisbane, Australia, where she's studied the transcriptional control of erythropoiesis.During her postdoc project, Melissa will be screening for therapeutic targets of Diamond Blackfan anemia.

Welcome to the Division of Molecular Medicine and Gene Therapy, Melissa.

Congratulations to Shubhranshu Debnath and all co-authors, whose work "Lentiviral vectors with cellular promoters correct the anemia and lethal bone marrow failure in a mouse model for Diamond-Blackfan anemia" has been accepted in Molecular Therapy.

In this study, the authorsdemonstrate the feasibility of lentiviral-based gene therapy in a mouse model of Diamond-Blackfan anemia (DBA), a rare inherited bone marrow failure disorder. Using lentiviral vectors with cellular promoters, Debnath et al. cured DBA in a mouse model of the disease and improved the safety profile following integration as characterised by a lower risk of insertional oncogenesis.These findings support the potential of clinical gene therapy as treatment option for DBA patients in the future.

Congratulations to all authors!

On May 11, Carolina Guibentifwill defend her thesis entitled"Modelling Human Developmental Hematopoiesis".

May 11 at9 am; Segerfalk Lecture Hall, BMC A10

Professor Nancy A. Speck,Perelman School of Medicine, University of Pennsylvania, USA

Associate Professor Niels-Bjarne Woods

Professor Jonas Larsson

Welcome!

Welcome to this months Stem Cell Talk, which will take place onWednesday April 19th, starting at 14:45 with fika atSegerfalkLecture Hall at A10.

Speaker:Kenichi Miharada

Title: Stressresponse and management in hematopoiesis

Welcome!

Please welcome our new colleaguesEmma Smith, Mayur Jain and MitsuyoshiSuzuki, who recently joined the Division of Molecular Medicine and Gene Therapy.

Emma Smith will be working in Stefan Karlsson's group as a staff scientist, where she will be involved in a collaborative project that aims to develop gene therapy as treatment option for patients suffering from the rare geneticlysosomal storage disorder Gaucher's disease.

Mayur Jain joined Sofie Singbrant Sderberg's group as a postdoctoral fellow. During his postdoc project, Mayur will be elucidating disease contributing factors in myeloproliferative disease, andinvestigatehow chronic anemia affects the ability of hematopoietic stem cells to provide a balanced blood production.

MitsuyoshiSuzuki joined the Miharada lab from Juntendo University in Tokyo, Japan. During his postdoc project, he will be clarifying therole of bile acid in fetal hematopoiesis and liver development.

Welcome to our Divison!

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Molecular Medicine and Gene Therapy | Medicinska ...