Category Archives: Genetic Medicine

CAMBRIDGE, Mass., Nov. 05, 2019 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (SRPT), the leader in precision genetic medicine for rare diseases, today announced that senior management will present at the Credit Suisse 28th Annual Healthcare Conference on Tuesday, Nov. 12, 2019 at 11:10 a.m. E.T. / 9:10 a.m. M.T. The fireside chat will be held at the at The Phoenician in Scottsdale, Ariz.

The presentation will be webcast live under the investor relations section of Sareptas website at http://www.sarepta.com and will be archived there following the presentation for 90 days. Please connect to Sarepta's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

AboutSarepta TherapeuticsSarepta is at the forefront of precision genetic medicine, having built an impressive and competitive position in Duchenne muscular dystrophy (DMD) and more recently in gene therapies for Limb-girdle muscular dystrophy diseases (LGMD), MPS IIIA, Pompe and other CNS-related disorders, totaling over 20 therapies in various stages of development. The Companys programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. Sarepta is fueled by an audacious but important mission: to profoundly improve and extend the lives of patients with rare genetic-based diseases. For more information, please visit http://www.sarepta.com.

Internet Posting of InformationWe routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Source: Sarepta Therapeutics, Inc.

Sarepta Therapeutics, Inc.Investors:Ian Estepan, 617-274-4052iestepan@sarepta.com

Media:Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

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Sarepta Therapeutics to Present at the Credit Suisse 28th Annual Healthcare Conference - Yahoo Finance

Call it The Case of the Dueling Genes. A woman at high risk for early-onset Alzheimers disease because of an inherited genetic mutation unexpectedly stayed dementia-free for decades, and investigators believe a different genetic mutation may have protected herproviding potential clues for an Alzheimers treatment.

The womans family carries a genetic mutation known to cause early-onset Alzheimers. However, she did not develop signs of the disease until her 70s, nearly 30 years after the expected onset. Researchers suspect she may have been protected because she also had two copies of the APOE3 Christchurch (APOE3ch) gene variant. Findings of a case study published in Nature Medicine suggest that two copies of the APOE3ch variant may protect against Alzheimers.

Early-onset Alzheimers is rare, representing less than 10% of all people who have the disease. Risk for both early- and late-onset Alzheimers disease is affected by genetic factors.

For the study, investigators at Massachusetts General Hospital, in collaboration with other researchers from Colombia, Boston, and Phoenix, looked at genetic data from a Colombian family with more than 6,000 living members. Family members who carry a rare gene mutation called Presenilin 1 (PSEN1) E280A have a 99.9% risk of developing early-onset Alzheimers disease.

This woman carried the PSEN1 E280A mutation. However, she also had two copies of the APOE3ch gene variant, unlike any other affected relative. Imaging tests showed that she had large amounts of amyloid protein deposits, a hallmark of Alzheimers disease, in her brain. But the amount of tau tangles, another hallmark of the diseaseand the one more correlated with how thinking and memory are affectedwas relatively low.

Experiments as part of the study showed that the APOE3ch variant may reduce the ability of APOE to bind to certain sugars called heparan sulphate proteoglycans (HSPG). APOE binding to HSPG has been implicated as one mechanism that may contribute to the amyloid and tau protein deposits that destroy the brain. The research suggests that a drug or gene therapy that could reduce APOE and HSPG binding has the potential to be a new way to treat or prevent Alzheimers disease.

The study was funded in part by the National Institute on Aging.

Source: NIH, November 4, 2019

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Her Genes Cause Early Alzheimer'sSo How Did She Avoid It? - Managed Care magazine

PTC Therapeutics announced a strategic partnership with Aldevronto ensure the production of high-quality plasmid DNA to be used with PTCs investigational gene therapies, including AGIL-AS for the treatment of Angelman syndrome (AS).

PTCs growing gene therapy pipeline for genetic disorders of the central nervous system (CNS) also includes an investigational gene therapy for AADC deficiencythats nearing submission to the U.S. Food and Drug Administration (FDA), as well as candidates for Friedreichs ataxiaand Angelman syndrome that are at earlier development stages. Other candidates for cognitive disorders and inherited retinal disorders are in preclinical research.

Our strategic collaboration with Aldevron represents our continued commitment to produce and provide the highest quality product to patients, Neil Almstead, PhD, PTCs chief technical operations officer, said in a press release.

Our gene therapy pipeline is addressing the unmet needs of multiple patient populations, and we feel an urgent need to develop safe products with the utmost speed. The development of relationships with top-tier companies like Aldevron aligns with our goal of partnering with the best collaborators as we drive meaningful improvements in the lives of patients, Almstead said.

PTCs gene therapy candidate for Angelmans syndrome is called AGIL-AS. It uses a modified virus that does not cause infection called an adeno-associated virus (AAV) to deliver a working copy of the UBE3Agene, the faulty gene in Angelman syndrome, to the brain and spinal cord of patients. The process is designed to restore production of the E6-AP protein produced by the UBE3A gene, this way improving cell function and rescuing neurological defects in Angelman syndrome.

Preclinical studieshave shown that AGIL-AS targets nerve cells in the brain, increases levels of E6-AP, and eases AS-like cognitive deficits in animal models of the disease.

AGIL-AS was granted orphan drug designationfrom the U.S. Food and Drug Administration in 2015, followed by a similar designation from theEuropean Commission in 2016.

Under the agreement, Aldevron will manufacture the plasmid DNA (circular molecules of DNA) where the functional version of UBE3A gene will be enclosed for delivery. The company ensures the materials are produced under Good Manufacturing Practice (GMP), a set of guidelines allowing products to be consistently made and controlled according to quality standards.

It is truly an honor to work with PTCs motivated team of experts. They are making enormous contributions to the future of genetic medicine, saidMichael Chambers, founder and CEO of Aldevron.

This is Aldevrons mission to serve scientists and researchers who are relentlessly pursuing cures for people who need them, he added.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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PTC, Aldevron Partner to Advance Angelman and Other Gene Therapy Candidates - Angelman Syndrome News

ALISO VIEJO, Calif., Nov. 5, 2019 /PRNewswire/ --Ambry Genetics(Ambry), a leading clinical genetic testing company, will present at this week's National Society of Genetic Counselors Annual Conference in Salt Lake City, Utah, data from the first 2,500 patients that received +RNAinsight, paired RNA and DNA genetic testing for hereditary cancer risk. Data revealed that +RNAinsight resulted in a substantial increase in diagnostic yield, identifying more patients with genetic mutations (disease-causing errors in our DNA) compared to DNA testing alone. This is the first major increase in diagnostic yield for hereditary cancer risk in over 10 years, since the adoption of deletion/duplication testing. Through +RNAinsight,Ambry is the first and only lab to offer paired RNA and DNA genetic testing for hereditary cancer as a commercially available clinical test.

Standard DNA testing for hereditary cancer risk excludes large portions of DNA, thereby missing some mutations. In addition, DNA testing can produce inconclusive results and fail to determine that an error in our DNA increases cancer risk. These limitations impact patients and their families because doctors may not have the information needed to recommend appropriate preventive, early detection, or therapeutic steps. Additionally, relatives may not be referred for genetic testing and obtain the care they would otherwise have gotten if they had learned they had mutations.

Adding RNA to DNA testing overcomes these limitations for a substantial number of patients as it provides considerably more evidence than DNA testing alone about whether our DNA has mutations. Ambry will present data showing that paired testing with +RNAinsight both (1) identified new mutations that would have been missed with DNA testing alone, and (2) clarified inconclusive results as disease-causing. DNA testing alone would have found these latter results as inconclusive and left doctors without this crucial information.

"These findings further demonstrate that hereditary cancer panels should include both RNA and DNA genetic testing," said Rachid Karam, MD, PhD, lead study author and Director of the Translational Genomics Lab at Ambry Genetics. "By looking at regions of the gene that other tests don't,+RNAinsight reduces false negatives, maximizing the number of patients who learn they have higher risks for hereditary cancer."

The data show an overall relative increase in diagnostic yield of 6.7 percent compared to DNA testing alone, increasing by as much as 19 percent for specific genes.For example, for BRCA1, 14 percent more patients learned they had a mutation that increased their cancer risks than would have if they had only received DNA testing. Moreover, by analyzing regions of DNA known as introns that standard DNA testing alone does not assess, paired RNA and DNA testing found completely new mutations that DNA-only testing would not have found or identified as disease-causing. Thus, patients who learn they have mutations from paired testing can get the appropriate medical treatment while those who undergo standard DNA testing alone might not because they may never learn they have those mutations.

RNA genetic testing also resulted in an overall 4.5 percent relative decrease in the number of patients that would have received inconclusive results with DNA testing alone, reducing inconclusive results by as much as 9 percent in specific genes. As with identifying entirely new mutations, clarifying results can let more patients with mutations learn they have them.

+RNAinsight is now available through doctors and genetic counselors around the country. For more information on RNA genetic testing, please go to http://www.ambrygen.com/RNAinsight.

In addition to this paired RNA and DNA testing data, Holly LaDuca, Senior Manager, Clinical Affairs Research at Ambry, will present data from a survey sent to clinicians assessing how genetic testing results inform patient care.

SinceJanuary 2018, Ambry Genetics has provided surveys to all clinicians ordering hereditary cancer testing through Ambry both before and after they receive their patients' genetic test results. In the first few months of offering the survey, 131 providers completed pre-and post-test surveys for 469 patients who received genetic testing. When genetic testing found mutations, changes to preventive screening recommendations were made for 62.1 percent of patients and surgical recommendations were made for 37.9 percent of patients. In addition, 40.9 percent of clinicians recommended genetic counseling changes, such as the testing of family members and discussions of reproductive risks.

"Management guidelines have been developed for numerous cancer-predisposition genes. However, data is limited on how these guidelines and genetic testing results impact patient care in the real world," said Ms. LaDuca. "Preliminary data from this ongoing survey demonstrate that positive genetic test results frequently lead to changes in medical management."

For the full list of studies that will be presented at NSGC, please see below:

Featured Oral Presentations at 2019 NSGC

Date & Time

Presentation

Presenter

Session

Tues., Nov. 5,2019

8:30 AM 2:30PM

Clarity in Chaos: Using somaticgenetic testing to inform germlineinterpretation

PiaSummerour

Session #A03:Pre-ConferenceSymposium

Wed., Nov. 6,2019

12:30 PM

Unparalleled Clarity and Mutations:Clinical RNA Testing ProvidesAnswers Beyond DNA

Rachid Karam

Level 2,

Room 250

Lunch Presentation

Thurs., Nov. 7,2019

3:10 PM- 4:40PM

The New GC in Town: Demystifyingthe Role of Gene Curation in VariantInterpretation, Clinical Reporting andCase Reanalysis

Kelly Radtke

Session #C16:Educational BreakoutSession

Featured Poster Presentations at 2019 NSGC

Date & Time

Presentation

Lead Author

Poster

Wed., Nov. 6,2019

6:15 PM 7:30PM

A Nationwide Multi-Center Study Provides Insightinto the Increase in Clinically Actionable Resultsfrom Concurrent DNA and RNA Genetic Testing

Rachid Karam

B-131

Investigating Variants of Uncertain Significance:Reclassification Triggers and Drivers in BreastCancer Predisposition Genes

Kirsten Kelly

B-233

Thurs., Nov. 7,2019

1:20 PM 2:35PM

Better than Guidelines? Pre & Post Genetic TestingData Suggests Change in Management Trends

Ze Powis

C-132

What Should I Order? Genetic Testing OrderingTrends for Autism Spectrum Disorder

CatherineSchultz

C-294

ABOUT AMBRY GENETICSAmbry Genetics, as part of Konica Minolta Precision Medicine, excels at translating scientific research into clinically actionable test results based upon a deep understanding of the human genome and the biology behind genetic disease. Our unparalleled track record of discoveries over 20 years, and growing database that continues to expand in collaboration with academic, corporate and pharmaceutical partners, means we are first to market with innovative products and comprehensive analysis that enable clinicians to confidently inform patient health decisions. We care about what happens to real people, their families, and the people they love, and remain dedicated to providing them and their clinicians with deeper knowledge and fresh insights, so together they can make informed, potentially life-altering healthcare decisions. For more information, please visitambrygen.com.

For more information on risk factors for hereditary cancer, please visit cancer.gov's fact sheet on hereditary cancer and genetic testing.

Press Contact:Liz Squirepress@ambrygen.com (202) 617-4662

View original content:http://www.prnewswire.com/news-releases/new-data-from-ambry-genetics-show-substantial-increase-in-diagnostic-yield-further-supporting-the-routine-use-of-rna-genetic-testing-for-hereditary-cancer-panels-300952288.html

SOURCE Ambry Genetics

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New Data from Ambry Genetics Show Substantial Increase in Diagnostic Yield, Further Supporting the Routine Use of RNA Genetic Testing for Hereditary...

These Five Life Science Organizations are Striving to Cure HIV

For those that lived through the devastation and horror of the HIV/AIDS epidemic of the early 1980s, effective treatment, let alone a cure for Human Immunodeficiency Virus (HIV), seemed unimaginable.

Some three decades later, a host of Maryland life science companies and research organizations are getting closer to making what was once unthinkable, real.

So little was known about this devastating immune disorder in the early phases of the HIV/AIDS epidemic.

In the early days of the HIV/AIDS crisis, the BioHealth Capital Region was the epicenter of HIV/AIDS research, with much of this groundbreaking research occurring within the lab of the now famed NIH researcher, Dr. Robert Gallo. In 1983 and 1984 Gallo and his collaborators co-discovered and confirmed that the virus responsible for the killer disease known as AIDS was human T lymphotropic virus type III (HTLV-III). Gallo and the company went on to develop the first test that identified the virus in humansthe HIV-antibody blood test.

By 1983 the disease had started to spread globally. By 1999, approximately 33 million people across the globe were living with HIV and an estimated 14,000,000 million people had died from AIDS since the epidemic began.

The 1995 approval of Highly Active Antiretroviral Treatment (HAART), which was the result of the remarkable, collaborative efforts of the scientific community, led to the reduction of AIDS-related deaths and hospitalizations by 60-80%. A short time later what was once a three-drug cocktail had been transformed into a pill taken once daily by HIV sufferers.

As of 2017, 19.5 million people are estimated to be receiving antiretroviral treatment globally. While one of the greatest achievements in medical history, HAART and subsequent treatment forms do not cure HIV. Within just weeks of stopping treatment, the virus returns to full strength and chronic inflammation caused by suppressed HIV can lead to adverse health effects over the long term. Current HIV treatments control it but do not cure it; in fact, research shows that those being treated for HIV are more susceptible to other diseases and health risks at an earlier age.

Despite the amazing advancements in HIV/AIDS treatments, HIV/AIDS continues to be a major global health threat.

It would be a fitting conclusion for an HIV cure to emerge from the state where the virus was first linked to AIDS and where the first human diagnostic was developed.

Multiple Maryland companies and research institutions are on the leading-age of HIV research and development, making the state a hotbed of potential next-generation HIV therapies and, possibly, the source of a cure for this devastating global health issue. Some of the most promising cure candidates are coming out of Marylands thriving cell and gene therapy cluster.

Lets take a look at some of the amazing progress thats happening right now across Maryland and take a deeper dive into five of the leading organizations that are on a mission to develop the first HIV cure.

AGT is a gene and cell therapy company with a proprietary gene-delivery platform to rapidly develop gene and cell therapies to cure infectious diseases, cancers and monogenic disorders.

One of its lead gene therapy products is a potential functional cure for HIV. AGT just announced that it has submitted the IND to the FDA for a Phase I trial of its autologous cell therapy for HIV.

While HIV has become a manageable chronic virus for many, in less developed countries HIV/AIDS is still a devastating illness. Developing an HIV cure would relieve millions from the side effects of antiretrovirals used to suppress HIV and prevent AIDS, avoid the serious quality-of-life issues of long-term treatment, and potentially save the lives of countless others.

AGT is currently developing a highly innovative HIV treatment strategy that uses the tools of genetic medicine for immunotherapy to potentially create a functional cure for HIV.

If we are successful, patients will be able to throw away their medication, will not progress to AIDS, and will be immune to future HIV exposures.

The potential single-dose treatment would be delivered as a genetically-modified cell product made from a patients own cells. AGTs strategy is unique because it focuses on the key immune cells responsible for catalyzing strong immunity against a virus. AGTs treatment strategy seeks to protect these cells; one of the first cell subsets to be disabled by HIV. This subset of cells is understood to be critical to building an immune response to any virus. If achieved, the cells natural process of immunity is restored and any future rise of HIV in the body will be attacked by an individuals own immune system.

AGTs treatment includes the production of an autologous cell product that is highly enriched for HIV-specific CD4+ T cells that are then transduced with a lentivirus vector known as AGT103 to protect against HIV-mediated T cell depletion. The combination of these enriched cells and the lentiviral vector forms a cell product AGT has dubbed AGT103-T. This cell product is delivered intravenously to HIV patients. AGT103-T should control viremia and work to remove infected cells from the body, thus eliminating the need for lifelong antiretroviral treatment.

AGT is currently collaborating with the Institute of Human Virology, University of Maryland Baltimore to collect leukapheresis specimens from HIV positive individuals for an ongoing observational study performing and qualifying the cell process, which is explained in greater detail here. The company expects its potential HIV cure to move into clinical trials in the next six months.

IHV is part of the University of Maryland School of Medicine and is a recognized leader in the virology field. IHV was founded by Dr. Robert C. Gallo who co-discovered HIV and developed the first HIV blood test.

IHV is heavily focused on HIV/AIDS research and the organization is currently progressing a promising HIV/AIDS vaccine through its pipeline. IHV01 (FLSC-001) has completed a Phase I trial and was supported, in part, from funding provided by the Bill and Melinda Gates Foundation.

This potential HIV/AIDS treatment seeks to neutralize the different strains of HIV found across the globe from the moment of infection. IHVs HIV/AIDS research is focused on the CCR5 chemokine receptor that plays a crucial role in HIV-1 infection and as such offers an important potential therapeutic target. (IHV Website). IHV is striving to develop biological HIV/AIDS treatments that are less expensive, have fewer adverse impacts and are more accessible to patients around the globe.

Lentigen is a leading provider of custom lentiviral vectors used in cell and gene therapy research and development. For HIV, Lentigen is at the forefront of efforts to use Chimeric Antigen Receptors (CAR) T-Cell therapy to improve the treatment of HIV and possibly cure it.

Lentigen, along with researchers at the University of Pittsburgh in Pennsylvania and the Albert Einstein School of Medicine, has been conducting a promising study of the use of CAR T in the treatment of HIV. The researchers developed duoCAR T cells that were able to kill white blood cells infected with a range of HIV variants. Testing in mice also produced promising results. Mice with humanized immune systems were simultaneously injected with CAR T cell and HIV-infected human cells into their spleens. When the spleens were examined a week later, five of the six mice had no identifiable HIV DNA and their viral levels had decreased by 97.5% (source: Science).

The study hopes to test the duoCAR T approach in HIV-infected people in the near future.

IBBR is a joint research enterprise of the University of Maryland, College Park and the National Institute of Standards and Technology (NIST). Last year IBBR received $3.9M from the National Institutes of Health (NIH) to develop a multi-specific, single-agent antibody therapeutic against HIV-1 to block virus infection and to clear the reservoir of HIV-infected cells from the body, according to an IBBR press release from November 2018.

The project is led by Dr. Yuxing Li, Associate Professor, Department of Microbiology and Immunology, University of Maryland School of Medicine, and Fellow at the Institute for Bioscience and Biotechnology Research (IBBR), in collaboration with Dr. Qingsheng Li, University of Nebraska-Lincoln, and Dr. Keith Reeves, Harvard Medical School/Beth Israel Deaconess Medical Center.

IBBRs research has focused on overcoming some of the limitations of existing antiretroviral (ARV) HIV treatments, including adverse side effects, ARV treatment drug resistance and how HIV integrates into the human genome, creating pockets of HIV that ARV cannot eliminate. Dr. Li and his group have produced bi and tri-specific antibodies that demonstrated neutralization of 95% of circulating HIV-1 viruses. These bi and tri-specific antibodies can also bind to multiple locations on the HIV-1 surface glycoprotein Env, which could potentially thwart treatment resistance via mutation. The team is now working to optimize their multivalent antibody constructs to recognize Env proteins on the surface of latently infected host cells, and to signal other immune system components to destroy those cells that contain the hard-to-reach viral pockets, or as the team calls them, a viral reservoir. (IBBR press release)

NIAID has been at the forefront of HIV research for decades and continues to be a major player in the research and development of possible HIV treatments and potential cures. NIAIDs research into HIV played a critical role in developing ARV drugs that transformed HIV into a chronic condition rather than a fatal infection.

NIAID-supported research has led to many ARV drug improvements, including reducing the number of pills required, diminishing adverse impacts and identifying the best drug combinations. The organization works with many leading global HIV/AIDS research organizations to identify and develop better HIV treatments.

NIAID is focused on both developing new HIV treatments as well as supporting other researchers and research organizations investigating new therapies. The ultimate goal is to potentially make HIV treatment a single dose, lifetime treatment, and, eventually, the complete eradication of HIV. NIAID is involved in many research and development projects focused on HIV and there are too many to dig into in a single article. Some of their current HIV research and development efforts are focused on investigational long-acting HIV drugs, rilpivirine LA and cabotegravir LA, for patients that have had difficulty following conventional antiretroviral therapy programs. Another NIAID study will test combining monthly injections of cabotegravir LA and infusions of an NIAID-discovered broadly neutralizing antibody called VRC01LS to see if the combination can keep HIV suppressed in people whose infection was previously controlled by antiretroviral therapy.

The organizations support has also helped in the discovery of the experimental drug islatravir (also known as EFdA or MK-8591) and maturation inhibitors. NIAID also has partnered with the Maryland industry, including a research collaboration agreement with AGT for research studies on the companys cell and gene therapy for HIV/AIDS.

A partnership between NIAID, Frederick National Labs for Cancer Research (operated by Leidos Biomedical Research, Inc.) and a team of collaborators recently developed 38 new simian/human immunodeficiency viruses (SHIVs) for prevention and treatment studies. These new SHIVs have closed a gap that previously existed in HIV research. These SHIVs are pathogens engineered in the lab that can help in the investigation of potential new HIV therapies as well as other treatments and vaccines.

These SHIVs target HIV subtype C, which causes approximately half of all HIV infections, and were created using HIV samples from people recently infected, allowing better modeling of more current forms of HIV subtype C circulating globally. The stronger modeling will increase pre-clinical researchs ability to predict effectiveness. Other SHIVs had used samples acquired from patients that had been infected long before the sample was pulled, limiting the SHIVs effectiveness against more current strains of HIV. While improvements are still needed, including challenges with replication, these new tools for HIV research and discovery hold tremendous promise.

In the late 1970s and early 1980s finding a cure for HIV/AIDS wasnt even on the radar. The scientific community was racing to understand the fundamentals of a virus that was rapidly spreading devastation and death across the globe. The speed with which the medical community came to understand the disease and to develop treatments like HAART is one of the truly amazing stories of the 20th century.

One or several of these Maryland companies and research institutions have a real chance to achieve what was once unthinkablefinding a cure for HIV that could help tens of millions of people across the globe live better, healthier and longer lives.

If an HIV cure emerges from Maryland, the BHCR community will have helped write the final chapter of HIV/AIDS terrible yet hopeful story.

Steve has over 20 years experience in copywriting, developing brand messaging and creating marketing strategies across a wide range of industries, including the biopharmaceutical, senior living, commercial real estate, IT and renewable energy sectors, among others. He is currently the Principal/Owner of StoryCore, a Frederick, Maryland-based content creation and execution consultancy focused on telling the unique stories of Maryland organizations.

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Heres Why the First Cure for HIV Could Emerge from Maryland - BioBuzz

By Sonia Fernandez for UCSB | November 6, 2019 | 2:49 p.m.

There is, in Colombia, a family with the tragic legacy of forgetfulness.

People in this large family get Alzheimers like clockwork at age 45-50, said UC Santa Barbara neuroscientist Kenneth S. Kosik, the campuss Harriman professor of Neuroscience and co-director of the Neuroscience Research Institute.

Their aggressive, genetic form of the disease has been passed down from generation to generation, causing rapid cognitive and physical declines in both the men and the women of this family.

For decades, Kosik and colleagues, including Dr. Francisco Lopera of the University of Antioquia; Dr. Eric Reiman of the Banner Alzheimers Institute in Phoenix; clinical neuropsychologist Yakeel Quiroz of Massachusetts General Hospital; and Dr. Joseph Arboleda-Vasquez of Massachusetts Eye and Ear, have been studying this family, from their brains right down to their genes.

They have even traced the specific gene mutation of this disease back as far as the time of the Spanish conquistadors.

During their studies, the researchers also have witnessed the predictable onset of the disease as members of this family enter into their middle years. Sometimes it happens sooner, sometimes later, but all paths have always led to the same destination.

But one woman has defied the odds. Now in her late 70s, she has the mutant gene and the plaques of amyloid protein that are the hallmark of Alzheimers disease yet she has exhibited no signs of cognitive impairment associated with Alzheimers.

When you find an escapee, its extremely interesting, said Kosik, co-author of a study that appears in the journal Nature Medicine.

The woman, and others who are considered outliers in the normal trend of neurodegeneration of this family, may present hints at a new approach for therapy for and even prevention of the disease, he said.

The culprit in this version of Alzheimers is a mutation to the presenilin 1 gene, called E280A, copies of which are found in every member of this family afflicted with the disease. It is implicated in the high production of those sticky amyloid plaques.

The mutation is known to cause the onset of the disease at age 45, and its really flagrant by the time youre in your 50s, Kosik said. The woman, in her late 60s at the time they were conducting their study, was positive for the mutation, but exhibited few symptoms.

It was amazing, Kosik said. In the course of their analysis they found that the woman also had another mutation in another gene that is responsible for making lipoproteins in the central nervous system, a gene called apolipoprotein E or APOE.

A variant of this gene called the Christchurch variant is exceedingly rare, but its presence in the patient hinted at a protective mechanism. The researchers turned to the Kosik Labs extensive collection of genomes to look for other family members with this same variant.

They asked us especially to look at people who were also outliers who got it at a very late age, Kosik said. They found a few others who had the variant, he said. Importantly, however, while there were others who did carry the Christchurch mutation, they all carried one copy, inherited from one parent.

The key thing about this discovery is that this patient is homogyzous for the variant; it came from both the mother and the father, Kosik explained.

The researchers lab studies showed that the APOE gene variant might delay the onset of Alzheimers by binding to sugars (called heparin sulphate proteoglycans, or HSPG) and preventing the uptake and inclusion of tau proteins in neurons that ultimately lead to the tangles that are a pathological hallmark of the disease.

Tau is a common structural protein in the brains of patients with Alzheimers and other neurodegenerative diseases that becomes sticky and insoluble.

More work needs to be done to investigate this single patients resistance to a disease that affects her extended family of 6,000 people, but this promising development could point toward an approach and a therapy for the estimated 44 million people in the world who have Alzheimers, a number that continues to rise.

"This finding suggests that artificially modulating the binding of APOE to HSPG could have potential benefits for the treatment of Alzheimer's disease, even in the context of high levels of amyloid pathology," said the papers co-lead author Joseph F. Arboleda-Velasquez, in a press statement.

For Kosiks part, he and Arboleda-Vasquez (who formerly was Kosiks graduate student at Harvard) continue to probe for other genetic one-offs and outliers that may contribute to Alzheimers resistance.

Sonia Fernandez for UCSB.

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A Woman's Resistance to Genetic, Early-onset Alzheimer's May Hold Key to Future Therapies - Noozhawk