Category Archives: Genetic medicine

BOSTON--(BUSINESS WIRE)--Akouos, a precision genetic medicine company developing gene therapies to potentially improve and preserve hearing, announced today that data from its inner ear gene therapy platform will be presented during the 43rd Annual Midwinter Meeting of the Association for Research in Otolaryngology (ARO), being held January 25 to January 29, 2020 in San Jose, CA.

Akouos continues to advance our platform for inner ear disorders, and we are excited to share our progress with the scientific community, said Greg Robinson, Ph.D., chief scientific officer of Akouos. The data presented at ARO further substantiates Akouoss use of AAVAnc80 vector technology and its potential to address many forms of hearing loss.

SYMPOSIUM

Title: The Adeno-associated Viral Anc80 (AAVAnc80) Vector - Precision Genetic Medicines to Address Hearing LossPresenter: Michelle Valero, Ph.D., Director, Anatomy & Physiology, AkouosSession: Symposium 11Date and Time: Saturday, January 25, 3 p.m. (PST)

POSTER PRESENTATIONS

Title: The Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Olive Baboons (Papio anubis)Day and Time: Monday, January 27, 1 p.m. (PST)

Title: The Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Cynomolgus Macaques (Macaca fascicularis)Day and Time: Monday, January 27, 1 p.m. (PST)

Title: Dual Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Non-human PrimatesDay and Time: Monday, January 27, 1 p.m. (PST)

About Akouos

Akouos is a precision genetic medicine company dedicated to developing gene therapies with the potential to improve and preserve hearing. Leveraging its adeno-associated viral (AAV) vector-based gene therapy platform, Akouos is focused on developing precision therapies for forms of sensorineural hearing loss. Headquartered in Boston, the Company was founded in 2016 by world leaders in the fields of neurotology, genetics, inner ear drug delivery, and AAV gene therapy. Akouos has strategic partnerships with Massachusetts Eye and Ear and Lonza, Inc. For more information, please visit http://www.akouos.com.

About AAVAnc Technology

Ancestral AAV (AAVAnc) technology was developed in the laboratory of Luk Vandenberghe, Ph.D., Director of the Grousbeck Gene Therapy Center at Harvard Medical School. AAVAnc technology uses computational and evolutionary methods to predict novel conformations of the adeno-associated viral particle. AAVAnc80, one of 40,000 AAVAnc vectors, has demonstrated preliminary safety and effective gene delivery in both mice and non-human primates in numerous preclinical studies.

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Akouos Announces New Data at the Association for Research in Otolaryngology Midwinter Meeting - Business Wire

A new analysis of available data has convinced a panel genomic experts that nine genes previously believed to be associated with a rare, genetic heart conditionlong QT syndromewere an erroneously linked to the condition, as revealed in a new study funded by the National Human Genome Research Institute (NHGRI), a division of the National Institutes of Health (NIH).

Geneticists and heart specialists around the world had previously reported 17 genes to cause long QT syndrome. However, the Clinical Genome Resources (ClinGen) expert panel has critically reevaluated the scientific evidence for all 17 reported genes, and has concluded at least nine of the genes cannot be linked to the disease, and only three of the genes can be definitively associated with the most common form of the disease.

Long QT syndrome is caused by mutations in genes that regulate the hearts electrical activity. These mutations can cause the heart to have sudden, irregular heart rhythms, or arrhythmias. People with long QT syndrome can have arrythmias that are both unprovoked or as a result of stress and exercise. These arrythmias can be fatal.

Many people with long QT syndrome may be unaware they have the condition, unless they get an unrelated electrocardiogram, know their family history, and have undergone genetic testing.

Ever since the syndrome was described in 1957, researchers have engaged in a genetic race to identify the genes associated with it, which currently includes the 17 genes. By using such a standardized, evidence-based framework, the international ClinGen panel experts on long QT syndrome were able to classify the 17 genes into specific groups.

Three genes, KCNQ1, KCNH2 and SCN5A, had sufficient evidence to be implicated as definitive genetic causes for typical long QT syndrome. Four other genes had strong or definitive evidence supporting their role in causing atypical forms of long QT syndrome, particularly if they presented in the newborn period with associated heart block, seizures or delays in development.

The remaining ten genes were deemed to not have sufficient evidence to support a causal role in the syndrome. In fact, nine of these 10 remaining genes were placed in the limited or disputed category. The study authors suggest that these genes not be routinely tested in clinical settings when evaluating patients and families with long QT syndrome, because they lack sufficient scientific evidence as a cause for the condition.

This removal of genes from the testing list impacts genetic testing providers, who use research papers to determine which genes to include in their testing panels for diagnostic reporting to physicians. Published papers reporting gene-disease associations vary widely in their study design and strength of evidence to support their conclusions. Until recently, standard guidelines that can differentiate between genes found with strong and valid scientific approaches versus those with insufficient evidence did not exist. Clearly, this is a problematic approach, and led to several studies drawing early conclusions.

ClinGens expert panels include researchers, clinicians, and genetic counselors who apply an evidence-based framework in evaluating the available data from research papers to place gene-disease relationships into definitive, strong, moderate, limited, disputed, or refuted categories.

ClinGen is an impressive community effort. With over 1,000 researchers and clinicians from 30 countries volunteering their time and expertise, ClinGen is providing much needed clarity for the clinical genomics community regarding which gene-disease pairs have sufficient evidence to be used clinically, said Erin Ramos, Ph.D., project scientist for ClinGen and program director in the Division of Genomic Medicine at NHGRI.

Our study highlights the need to take a step back and to critically evaluate the level of evidence for all reported gene-disease associations, especially when applying genetic testing for diagnostic purposes in our patients. Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm, says Michael Gollob, M.D., senior author of the paper and researcher at the Toronto General Hospital Research Institute.

Moreover, testing for genes not definitively associated with long QT syndrome can result in inappropriate and costly medical interventions such as implanting of a cardioverter-defibrillator.

This is not the first time a team at ClinGen has clarified published research for clinicians. The same team of researchers published a similar study in 2018, covering another heart condition called Brugada syndrome. In 2019, the American Society of Human Genetics considered the paper as one of the top 10 advances in genomic medicine.

ClinGen is an NHGRI-funded resource created to define the clinical relevance and validity of genes associated with various genetic disorders. It comprises more than 20 expert panels working on a variety of genetically influenced diseases, ensuring the reliability of gene-disease linkage. This work is also instrumental in determining which specific genes should be targeted for further study in precision medicine and research.

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Genes Previously Linked to Heart Condition Disputed - Clinical OMICs News

Eisai and Personal Genome Diagnostics (PGDx) will use liquid biopsy to accelerate Next-Generation drug discovery and development

Japanese firm Eisai Co., Ltd., has entered into a joint research and development agreement with Personal Genome Diagnostics Inc., Maryland, for cancer genetics panel test, and it has initiated the research.

In this joint research and development, Eisai and PGDx will create a kitted cancer gene panel test that enables comprehensive analysis of mutation in more than 500 cancer gene using liquid biopsy with blood samples. Additionally, the kit will be used in our drug discovery and development.

In Eisai's medium term business plan EWAY2025, Eisai is pursuing creating innovation focused in neurology area and oncology area aimed at realizing prediction / prevention and cure. Aiming to acquire next-generation sequencing technology for realizing personalized cancer medicine, Eisai has concluded a joint research and development agreement with PGDx, a US bio-venture with liquid biopsy genomic expertise.

By analyzing the circulating tumor DNA (ctDNA) in the blood using its own created gene panel testing technology, Eisai will investigate the Cancer Evolution, which is a series of process such as developments of cancer cells, recurrence / metastasis and the appearance of acquired drug resistance. Eisai will also identify genetic abnormalities of drug resistance to existing anti-cancer agents that will be the targets of a new drug discovery and use a kitted cancer gene panel test for clinical trials to develop new anticancer drugs. Eisai will continue to work on cancer genome medicine for realizing early detection of cancer, and providing personalized cancer medicine and cures for cancer patients in the future.

In addition to accelerating cancer genome medicine based on the latest liquid biopsy technology, Eisai aims to build an oncology ecosystem, in which a longitudinal trajectory of cancer patients will be monitored, to lead to the creation of cures for cancer patients as well as diagnosis for prediction and prevention of cancer. Eisai will make continuous efforts to meet diversified needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare professionals.

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Eisai and PGDx jointly start R&D of cancer genetics panel test - BSA bureau

The rate of new mutations in the human genome appear to be consistent across diverse populations, except onethe Old Order Amish of Lancaster, Pennsylvania. This group has a lower rate of developing new mutations, according to a study published January 21 in PNAS.The lower mutation rate does not appear to have a genetic component, pointing to a possible role for environmental factors in modifying how fast human genomes accrue new mutations.

It really looks like environmental differences might actually [have] the most significant effect on the number of mutations that you pass on to your offspring, rather than . . . there being some sort of gene causing mutations, says Aylwyn Scally, a geneticist at the University of Cambridge who was not involved in the work. In a larger study than this one, researchers might be better able to detect a genetic contribution if there is one, he says. But still its surprising that it hasnt jumped out, and instead theres this curious effect thats bolstered by their finding about the Amish. Maybe different environments are actually the biggest factor.

Mutation rates are a source of genetic variation within populations. Knowing more about these rates in humans can help researchers better understand disease and evolution. Before this study, mutation rates had really only been looked at in Europeans, and so we wanted to be able to look in a much broader, diverse population, evolutionary geneticist Timothy OConnor of the University of Maryland, a coauthor on the new paper, tells The Scientist.

To this end, he and his colleagues leveraged a dataset of whole genomes from more than 1,400 parent-child trios from the National Heart, Lung, and Blood Institutes TOPMed (Trans-Omics for Precision Medicine) program. The team found that the rate of de novo mutations was similar across populations of African, Latino, and European ancestry. That finding was intriguing because previous work had suggested that populations with high levels of genetic diversity, such as those of African descent, would have higher mutation rates.

Even more unexpected was the mutation rate detected in the 59 Amish families in the cohort. These Amish families are of European descent but have been genetically isolated from other populations since the 1700s and all descended from about 700 individual founders. They had a seven-percent-lower mutation rate compared with the other populations.

We were pretty surprised, says OConnor. Initially the team thought the lower mutation rate had to be an artifact of the sequencing or analysis. We did basically everything we could to try and figure out what kind of artifact would be causing it, and we couldnt find one.

The research team next tried to pinpoint what caused the Amish to have a lower incidence of new mutations. OConnor and his colleagues determined that the lower mutation rates were not heritable, which led the team to speculate that environmental factorssuch as the typical Amish diet and limits on technologymay contribute.

The findings are novel in that the reduced mutation rate hasnt been previously shown with so much sequencing data, says Heather Wheeler, a geneticist at Loyola University Chicago who was not involved in the study. The caveat is that it was still just in one group, and there were only 59 families in the Amish population, she notes. If this is a real effectthe clean-living hypothesis they proposewe definitely want to see it validated in other populations that have similar environments to the Amish.

M.D. Kessler et al., De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population,PNAS,doi:10.1073/pnas.1902766117, 2020.

Abby Olena is a freelance journalist based in Alabama. Find her on Twitter@abbyolena.

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Human Mutation Rates Steady Across GroupsExcept in the Amish - The Scientist

Image: Professor Chris Lord andDr Stephen Pettitt next to the olaparib display in the Science Museum's medicine galleries

The Science Museum's new 24 millionmedicine galleriesshowcases pioneering research from The Institute of Cancer Research, London, as part of its story of modern medicine.

The new galleries, which have transformed the first floor of the world-famous museum, explore humanity's relationship with medicine and health through more than 500 years of history.

Included in the exhibition are extraordinary medical artefacts from the collections of Henry Wellcome and the Science Museum Group, including the world's first MRI scanner, Fleming's penicillin mould, a professional pianist's prosthetic arm and robotic surgery equipment.

Science MuseumLatesare adults-only, after-hours theme nights that take place in the museum on the last Wednesday of every month. Tonight's (Wednesday 29 January) Lates event isMedicine Lates.

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The museum chose to showcase the ICR's pioneering research underpinning the development of targeted drug olaparib, which has transformed the lives of tens of thousands of women with breastand ovariancancers.

Olaparib's origins lie in ICR research into the BRCA genes in the 1990s, when our scientists tracked down the BRCA2 gene.

A decade after the identification of BRCA2, ICR researchers found that targeting a DNA repair protein called PARP was a potential way to kill cancer cells with a faulty BRCA gene. This helped lead to the development of olaparib, and other so-called PARP inhibitors.

The gallery features plates which replicate the original ICR experiment to successfully show that olaparib specifically kills cancer cells with defects in their BRCA genes, while leaving healthy cells unaffected.

You can see these in the Medicine and Bodies gallery, which explores how the search to understand more about the human body has transformed medicine.

Displayed alongside Crick and Watson's molecular DNA model, the plates represent how understanding the genetic basis of cancer has transformed our ability to treat it through the creation of targeted therapies.

Professor Chris Lord,Deputy Head of the Breast Cancer Now Toby Robins Research CentreandDivision of Breast Cancer Researchat the ICR (pictured above), said:

"The fact that the Science Museum have chosen to highlight PARP inhibitors in their new gallery is a real testament to how cancer research can genuinely lead to improvements in the treatment of the disease. We are immensely proud of this, as are the other labs across the world who also contributed to these discoveries."

"Despite PARP inhibitors now being highlighted in Science Museum, this is not the end for us we are still working very hard at the ICR to think about how we can improve the effectiveness of these drugs and to make sure that each patient receives the best possible treatment approach."

Daisy Henesy, the ICRs Public Engagement Officer, said:

"It's a thrill to see the ICR's research showcased alongside other huge advances in modern medicine, and richly deserved.

"I urge everyone to visit the new Science Museum galleries and have a look for yourself and don't forget to tweet us with any pictures @ICR_Londonand let us know what you think!"

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ICR research showcased in major new Science Museum gallery documenting history of medicine - The Institute of Cancer Research

BOSTON--(BUSINESS WIRE)-- Decibel Therapeutics, a development-stage biotechnology company developing novel therapeutics for hearing loss and balance disorders, today announced a new strategic research focus on regenerative medicine approaches for the inner ear. The company is also announcing a collaboration and option agreement that gives Decibel exclusive access to novel compounds targeting proteins in a critical regenerative pathway.

Decibels research focus on regeneration will be powered by the companys research and translation platform. The company has built one of the most sophisticated single cell genomics and bioinformatics platforms in the industry to identify and validate targets. Decibel has also developed unique insights into regulatory pathways and inner ear delivery mechanisms that together enable precise control over gene expression in the inner ear and differentiate its AAV-based gene therapy programs.

Our deep understanding of the biology of the inner ear and our advanced technological capabilities come together to create a powerful platform for regenerative medicine therapies for hearing and balance disorders, said Laurence Reid, Ph.D., acting CEO of Decibel. We see an exciting opportunity to leverage this platform to address a broad range of hearing and balance disorders that severely compromise quality of life for hundreds of millions of people around the world.

The first program in Decibels regeneration portfolio aims to restore balance function using an AAV-based gene therapy (DB-201), which utilizes a cell-specific promoter to selectively deliver a regeneration-promoting gene to target cells. In collaboration with Regeneron Pharmaceuticals, Decibel will initially evaluate DB-201 as a treatment for bilateral vestibulopathy, a debilitating condition that significantly impairs balance, mobility, and stability of vision. Ultimately, this program may have applicability in a broad range of age-related balance disorders. There are currently no approved medicines to restore balance. Decibel expects to initiate IND-enabling experiments for this program in the first half of 2020.

Decibel is also pursuing novel targets for the regeneration of critical cells in both the vestibule and cochlea of the inner ear; these targets may be addressable by gene therapy or other therapeutic modalities. As a key component of that program, Decibel today announced an exclusive worldwide option agreement with The Rockefeller University, which has discovered a novel series of small-molecule LATS inhibitors. LATS kinases are a core component of the Hippo signaling pathway, which plays a key role in regulating both tissue regeneration and the proliferation of cells in the inner ear that are crucial to hearing and balance. The agreement gives Decibel an exclusive option to license this series of compounds across all therapeutic areas.

The agreement also establishes a research collaboration between Decibel and A. James Hudspeth, M.D., Ph.D., the F.M. Kirby Professor at The Rockefeller University and the director of the F.M. Kirby Center for Sensory Neuroscience. Dr. Hudspeth is a world-renowned neuroscientist, a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and a Howard Hughes Medical Institute investigator. Dr. Hudspeth has been the recipient of numerous prestigious awards, including the 2018 Kavli Prize in Neuroscience.

Rockefeller scientists are at the leading edge of discovery, and we are excited to see the work of Dr. Hudspeth move forward in partnership with Decibel, said Jeanne Farrell, Ph.D., associate vice president for technology advancement at The Rockefeller University. The ambitious pursuit of harnessing the power of regenerative medicine to create a new option for patients with hearing loss could transform how we address this unmet medical need in the future.

In parallel with its new research focus on regenerative strategies, Decibel will continue to advance key priority preclinical and clinical programs. DB-020, the companys clinical-stage candidate designed to prevent hearing damage in people receiving cisplatin chemotherapy, is in an ongoing Phase 1b trial. Decibel will also continue to progress DB-OTO, a gene therapy for the treatment of genetic congenital deafness, which is being developed in partnership with Regeneron Pharmaceuticals. The DB-OTO program aims to restore hearing to people born with profound hearing loss due to a mutation in the otoferlin gene and is expected to progress to clinical trials in 2021.

To support the new research focus, Decibel is restructuring its employee base and discontinuing some early-stage discovery programs.

About Decibel Therapeutics, Inc. Decibel Therapeutics, a development-stage biotechnology company, has established the worlds first comprehensive drug discovery, development, and translational research platform for hearing loss and balance disorders. Decibel is advancing a portfolio of discovery-stage programs aimed at restoring hearing and balance function to further our vision of a world in which the benefits and joys of hearing are available to all. Decibels lead therapeutic candidate, DB-020, is being investigated for the prevention of ototoxicity associated with cisplatin chemotherapy. For more information about Decibel Therapeutics, please visit decibeltx.com or follow @DecibelTx.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200129005162/en/

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Decibel Therapeutics Announces Strategic Research Focus on Regenerative Medicine for the Inner Ear - BioSpace

A cruel twist of genetic fate brought Alzheimers disease to a sprawling Colombian family. But thanks to a second twist, one member of the clan, a woman, managed to evade the symptoms for decades. Her escape may hold the key to halting, or even preventing, Alzheimers.

The inherited version of Alzheimers disease erodes peoples memories early, starting around age 40. In this family and others, a mutation in a gene called presenilin 1 eventually leaves its carriers profoundly confused and unable to care for themselves. Locals around the Colombian city of Medelln have a name for the condition: la bobera, or the foolishness.

The woman in the afflicted family who somehow fended off the disease carried the same mutation that usually guarantees dementia. And her brain was filled with plaques formed by a sticky protein called amyloid. Many scientists view that accumulation as one of the earliest signs of the disease. Yet she stayed sharp until her 70s.

Researchers were stumped, until they discovered that the woman also carried another, extremely rare genetic mutation that seemed to be protecting her from the effects of the first one. This second mutation, in a different Alzheimers-related gene called APOE, seemed to slow the disease down by decades, says Joseph Arboleda-Velasquez, a cell biologist at Harvard Medical School.

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There was this idea of inevitability, he says. But the womans circumstances bring a different perspective one in which amyloid buildup no longer guarantees problems. Arboleda-Velasquez and colleagues reported the details of the womans exceptional case November 4 in Nature Medicine, omitting the womans name and precise age to protect her privacy.

Although the discovery is based on one person, it points to a biological weak spot in the degenerative disease that affects an estimated 5.8 million people in the United States alone. So far, nearly every clinical trial designed to slow or stop the disease has failed. Those heartbreaking disappointments have prompted scientists to expand their search for treatments.

Perhaps this unusually resilient woman in Colombia shows a way to halt the disease, or at least slow it down. Can we come up with a drug that does this to people who dont have a mutation? asks Arboleda-Velasquez. The potential for that is tremendous.

The vast majority of people with Alzheimers have a sporadic form of the disease with no clear genetic culprit. These people often reach their 70s or 80s before signs of dementia appear. Mutations that cause trouble much earlier, such as the Paisa mutation found in the Colombian family, are unusual. But despite their different origins and different timelines, these two versions of Alzheimers are thought to progress in somewhat similar ways.

Normally, presenilin 1 makes a protein that helps chop up the long, sticky amyloid precursor protein. One of the resulting small bits is called amyloid-beta. Those smaller pieces are harmlessly washed out of the brain. The mutated presenilin 1 gene found in the Colombian family, however, creates a kink in the chopping process that leads to an abundance of a version of amyloid that knits itself into plaques between brain cells.

This pileup is already visible in brain scans of people in their 20s who carry the mutation. By their mid-40s, many of these people have trouble remembering; they typically develop full-blown dementia by age 50.

Inheriting just one copy of the mutation is enough to lead to excess amyloid, and ultimately dementia. The mutations powerful effect in this family is one of the strongest arguments for the fact that amyloid plays a critical role in Alzheimers, says immunologist and aging expert Richard J. Hodes, director of the National Institute on Aging in Bethesda, Md. Since taking on the role in 1993, Hodes has helped set the course for U.S.-funded Alzheimers research, allocating support for promising projects, including studies happening in Colombia.

The Colombian family, 5,000 members strong, includes an estimated 1,000 or so people who carry the Paisa mutation in the presenilin 1 gene. Their involvement in the research has been invaluable. Access to hundreds of people known to be at high risk for the disease allows scientists to study how Alzheimers unfolds, particularly at its earliest stages, and has led to reports of early signs of Alzheimers, both in the brain and the blood. Family members have gone to great lengths to help, walking or taking a bicycle to the nearest bus stop, and then taking a bus to a train, for many hours, to come to the clinic, Hodes says.

During Hodes recent visit to the Medelln area, a resident told him how the disease is just a part of their lives: If I have the disease, I know that my family, my brother and my sister, will take care of me. And if I dont, I will take care of them.

When Colombian researchers learned of the woman who stayed sharp until her 70s, they arranged for her to travel to Boston in the summer of 2016, accompanied by family members and a research assistant. There, neuroimaging researcher Yakeel T. Quiroz and her colleagues used brain scans to measure levels of amyloid and other markers of brain health, including another Alzheimers-related protein called tau, which can tangle up inside nerve cells.

Those scans revealed a brain loaded with amyloid, says Quiroz, of Harvard Medical School. This woman had most likely been accumulating amyloid for decades. On a scale commonly used to quantify amyloid in the brain, she scored 1.96, well above the threshold of 1.2 that signifies extensive amyloid buildup. Her score was, pretty much the highest that we have seen in anybody we have scanned so far, Quiroz says.

Genetic analyses revealed that the woman had whats called the Christchurch mutation in both copies of her APOE gene. Further tests suggested that this mutation, named for the New Zealand city where it was first found, was shielding her from the disease. The fact that the woman had huge amounts of amyloid in her brain, yet didnt seem impaired until her 70s, is extremely surprising, interesting, provocative and potentially very, very informative, Hodes says.

Scientists need to do more work to confirm that the APOE Christchurch mutation protected her brain. Still, the results reveal a simple truth, Hodes says. Amyloid itself is not necessarily sufficient to cause dementia.

Studies outside of the Colombian family also make clear that amyloid isnt the whole story. Other cellular actors contribute to the death of nerve cells and memory loss that Alzheimers brings. Nerve cellclogging tangles of tau and other signs of brain illness are tightly linked to brain decline, research from many studies has shown. Thats reflected in observations from a study of 480 people age 60 and older who live around Rochester, Minn.

These people, none of whom showed signs of dementia, were randomly chosen to be invited into the study, an unbiased selection that offered researchers a glimpse of brain health in the wider population.

To find out which brain changes best predict future memory loss, neuroradiologist Clifford R. Jack Jr. of the Mayo Clinic in Rochester and colleagues tested volunteers memory performance while measuring their amyloid levels and other brain signals. Amyloid seemed to be closely involved in memory decline over about five years but only in the right context, the team reported in June 2019 in JAMA.

Without either of two other troublesome markers tau tangles or brain shrinkage amyloid didnt predict memory loss. In other words, amyloid might be setting up the shot, but then it passes the ball.

Amyloid in the head is the first stage of what will ultimately lead to full-blown Alzheimers disease, Jack says. But there can be a lot of time between that early stage of amyloid accumulation and the development of symptoms.

Among the Colombian family members, that interval lasts around 10 to 15 years. The same is roughly true for people with the sporadic form of Alzheimers. But for the woman described in the report in Nature Medicine, that lag seemed twice as long.

That suggests that at least its possible to live with amyloid not just for 15 years, but for many decades, says Paul Aisen, director of the University of Southern Californias Alzheimers Therapeutic Research Institute in San Diego. Living healthy longer: Thats very exciting.

The protective effect of the womans mutation seems to come from an extremely specific change. In the Christchurch variant, a single spot in the APOE gene is tweaked. The resulting protein has a serine amino acid swapped in for the standard arginine.

The swap prevents the APOE protein from binding to some sugar-dotted proteins called heparan sulfate proteoglycans, or HSPGs, experiments on the isolated proteins revealed. Earlier studies showed that HSPGs may promote amyloid accumulation and nudge nerve cells to slurp up more toxic tau.

But to misbehave, HSPGs might need to partner with the APOE protein. The Christchurch mutation could have protected the womans brain by scrambling that nefarious relationship, the researchers suspect. Without that specific connection between APOE and HSPGs, the disease process gets stalled, Arboleda-Velasquez says. This really puts a block on the cascade of events.

Fleshing out the APOE proteins normal biological cascade, and how that changes with the Christchurch mutation, is going to allow for much more finely targeted drug development, says Aisen, who also works as a consultant for Biogen, a biotechnology company in Cambridge, Mass. The company is developing an amyloid-targeting drug called aducanumab and is expected to apply for approval from the U.S. Food and Drug Administration this year (SN: 1/18/20, p. 8).

As one of the strongest genetic risk factors for dementia, the APOE gene has long been scrutinized as a possible target for Alzheimers drugs. People who carry a version of the gene called APOE4 have a higher risk of Alzheimers.

The APOE2 version dramatically lowers the risk, Quiroz, Arboleda-Velasquez and colleagues report in preliminary research posted online November 2 at medRxiv.org. APOE3 usually brings an average risk of Alzheimers, with the notable exception of the version with the Christchurch mutation carried by the Colombian woman.

In the general population, old age is the biggest risk factor for Alzheimers. As the number of older people balloons, so too will the number of people with dementia. By 2050, an estimated 13.8 million people in the United States will have Alzheimers. Worldwide, an estimated 50 million people have dementia; Alzheimers accounts for the bulk of those cases.

The family in Colombia continues to help. A clinical trial testing a drug that is designed to lower amyloid is under way in Colombia. People who have the Paisa mutation but have not shown Alzheimers symptoms, as well as people without the mutation, are receiving the drug. The drug, crenezumab, is an antibody thats thought to mark amyloid for destruction by immune cells. Its being developed by Roche/Genentech.

Quiroz and her colleagues also plan to follow the Colombian woman and other members of the family over time, as part of a research exchange between Fundacin Universidad de Antioquia in Medelln, which has led the studies on this family, and Massachusetts General Hospital in Boston.

Each month, the project, called COLBOS, for Colombia-Boston, flies a new group of about five adult participants to Boston for extensive evaluation, including thinking and memory tests, brain scans and measurements of smelling ability, fitness and music perception. Participants being studied in Colombia are as young as 9 years old.

The project may yield insights about how Alzheimers takes hold early on. But in a way, the initial trigger might not even matter. It could be that the cause or more likely, causes of Alzheimers might ultimately be poor targets for drugs, Arboleda-Velasquez says.

People with loved ones suffering from Alzheimers, including the Colombian family, dont necessarily care what causes the disease, Quiroz says. They are more interested in seeing if there is anything that can help them to get better. Thats what the patients and families are waiting for.

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How one woman became the exception to her familys Alzheimers history - Science News

More than 100 genes appear to be involved in autism spectrum disorders (ASD), according to the largest genetic study of the condition to date.

The study, involving over 50 centres around the globe, identified 102 genes associated with ASD including a few dozen that had not been recognised before.

Some of the genes are also associated with intellectual disabilities and developmental delays, the researchers said. But others are unique to ASD, and appear related to the social difficulties that mark the disorder.

Knowing the genes involved in ASD will help researchers better understand the causes and possibly develop new drug therapies for children with severe impairments, said senior researcher Joseph Buxbaum.

"Autism exists on a spectrum, and many people wouldn't need any new, targeted drug therapies because they're doing fine," said Buxbaum, who directs the Seaver Autism Center for Research and Treatment at Mount Sinai, in New York City.

But for children who are profoundly affected, he said, there could be promise in the "precision medicine" approach treatments that are tailored to individuals based on their characteristics, like the genes they carry.

ASD is a brain disorder that affects social skills, communication and behaviour control. In the United States, it affects one in 59 children, according to the US Centers for Disease Control and Prevention.

The disorder is complex and varies widely from one person to the next. Some children have milder problems with socialising and communicating, while others are profoundly affected speaking little, if at all, and getting wrapped up in repetitive, obsessive behaviours, for example. Some children with ASD have intellectual disabilities, while others have average or above-average IQs.

Experts have long believed that a combination of genetic susceptibility and environmental exposures conspire to cause ASD but genes are the bigger factor. A recent study, of about two million people, estimated that genes account for 80% of the risk of ASD.

But the precise genes will vary among individuals, experts say.

"We realise that large studies like this as well as even larger ones will be needed to truly understand why we say, 'If you have seen one person with autism, you have seen one person with autism,'" said Dean Hartley.

Hartley, who was not involved in the new study, is senior director of genomic discovery and translational science at the non-profit Autism Speaks.

Previously, researchers had identified 65 genes associated with ASD. Buxbaum said his team was able to find more, in part, because of the study size: It involved over 35 000 people, including nearly 12 000 with ASD; the rest were their parents, unaffected siblings or other individuals without ASD.

Using newer analytic techniques, Buxbaum said, the researchers were able to zero in on 102 genes associated with ASD.

Some genes, he explained, are "high risk" and carry outright mutations. Most people with ASD possibly 80% would not harbor those, according to Buxbaum. Instead, they would carry "tiny, tiny changes across multiple genes," he said.

More research is needed to understand precisely what all these genes do. But most risk genes are active early in brain development, and have roles in regulating the activity of other genes or communication among brain cells, the investigators found.

The risk genes are also active in both "excitatory" and "inhibitory" neurons (nerve cells). That, Buxbaum said, shows that autism is not only related to one major type of brain cell but involves "many disruptions" in brain cell function.

The findings were published online in the journal Cell.

New targets for treatments

Dr Andrew Adesman is chief of developmental and behavioural paediatrics at Cohen Children's Medical Center, in New Hyde Park, New York. He said, "This study represents yet another major advance in our understanding of some of the underlying genetic causes for ASD."

At this point, though, he noted, it's not possible to root out the genetic cause in most children diagnosed with ASD.

Hartley agreed that the latest findings could eventually lead to new therapies. "This study importantly confirms previous biological pathways in autism, but has identified new biological processes possibly involved," he added. "These pathways are important for finding new targets for treatment and more personalised health care."

The hunt for ASD-related genes is not over, however. Buxbaum said he expects a "couple hundred more" will be found.

Image credit: iStock

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Largest-ever study ties over 100 genes to autism - Health24

Data further supports Akouoss use of AAVAnc80 technology delivered via intracochlear administration to potentially improve hearing

Akouos, a precision genetic medicine company developing gene therapies to potentially improve and preserve hearing, announced today that data from its inner ear gene therapy platform will be presented during the 43rd Annual Midwinter Meeting of the Association for Research in Otolaryngology (ARO), being held January 25 to January 29, 2020 in San Jose, CA.

"Akouos continues to advance our platform for inner ear disorders, and we are excited to share our progress with the scientific community," said Greg Robinson, Ph.D., chief scientific officer of Akouos. "The data presented at ARO further substantiates Akouoss use of AAVAnc80 vector technology and its potential to address many forms of hearing loss."

SYMPOSIUM

Title: The Adeno-associated Viral Anc80 (AAVAnc80) Vector - Precision Genetic Medicines to Address Hearing LossPresenter: Michelle Valero, Ph.D., Director, Anatomy & Physiology, AkouosSession: Symposium 11Date and Time: Saturday, January 25, 3 p.m. (PST)

POSTER PRESENTATIONS

Title: The Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Olive Baboons (Papio anubis)Day and Time: Monday, January 27, 1 p.m. (PST)

Title: The Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Cynomolgus Macaques (Macaca fascicularis)Day and Time: Monday, January 27, 1 p.m. (PST)

Title: Dual Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Non-human PrimatesDay and Time: Monday, January 27, 1 p.m. (PST)

About Akouos

Akouos is a precision genetic medicine company dedicated to developing gene therapies with the potential to improve and preserve hearing. Leveraging its adeno-associated viral (AAV) vector-based gene therapy platform, Akouos is focused on developing precision therapies for forms of sensorineural hearing loss. Headquartered in Boston, the Company was founded in 2016 by world leaders in the fields of neurotology, genetics, inner ear drug delivery, and AAV gene therapy. Akouos has strategic partnerships with Massachusetts Eye and Ear and Lonza, Inc. For more information, please visit http://www.akouos.com.

About AAVAnc Technology

Ancestral AAV (AAVAnc) technology was developed in the laboratory of Luk Vandenberghe, Ph.D., Director of the Grousbeck Gene Therapy Center at Harvard Medical School. AAVAnc technology uses computational and evolutionary methods to predict novel conformations of the adeno-associated viral particle. AAVAnc80, one of 40,000 AAVAnc vectors, has demonstrated preliminary safety and effective gene delivery in both mice and non-human primates in numerous preclinical studies.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200124005380/en/

Contacts

Katie Engleman, 1ABkatie@1abmedia.com

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Akouos Announces New Data at the Association for Research in Otolaryngology Midwinter Meeting - Yahoo Finance

As infectious disease specialists and epidemiologists race to contain the outbreak of the novel coronavirus centered on Wuhan, China, theyre getting backup thats been possible only since the explosion in genetic technologies: a deep-dive into the DNA of the virus known as 2019-nCoV.

Analyses of the viral genome are already providing clues to the origins of the outbreak and even possible ways to treat the infection, a need that is becoming more urgent by the day: Early on Saturday in China, health officials reported 15 new fatalities in a single day, bringing the death toll to 41. There are now nearly 1,100 confirmed cases there.

Reading the DNA also allows researchers to monitor how 2019-nCoV is changing and provides a roadmap for developing a diagnostic test and a vaccine.

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The genetics can tell us the true timing of the first cases and whether they occurred earlier than officials realized, said molecular biologist Kristian Andersen of Scripps Research, an expert on viral genomes. It can also tell us how the outbreak started from a single event of a virus jumping from an infected animal to a person or from a lot of animals being infected. And the genetics can tell us whats sustaining the outbreak new introductions from animals or human-to-human transmission.

Scientists in China sequenced the viruss genome and made it available on Jan. 10, just a month after the Dec. 8 report of the first case of pneumonia from an unknown virus in Wuhan. In contrast, after the SARS outbreak began in late 2002, it took scientists much longer to sequence that coronavirus. It peaked in February 2003 and the complete genome of 29,727 nucleotides wasnt sequenced until that April.

Since the sequencing of the first 2019-nCoV sample, from an early patient, scientists have completed nearly two dozen more, said Andrew Rambaut of the University of Edinburgh, an expert on viral evolution. That pace is unprecedented and completely unbelievable, said Andersen, who worked on sequencing the Ebola genome during the 2014 outbreak. Its just insane.

The genome of the Wuhan virus is 29,903 bases long, one of many clues that have led scientists to believe it is very similar to SARS.

By comparing the two dozen genomes, scientists can address the when did this start question. The 24 available samples, including from Thailand and Shenzhen as well as Wuhan, show very limited genetic variation, Rambaut concluded on an online discussion forum where virologists have been sharing data and analyses. This is indicative of a relatively recent common ancestor for all these viruses.

Given whats known about the pace at which viral genomes mutate, if nCoV had been circulating in humans since significantly before the first case was reported on Dec. 8, the 24 genomes would differ more. Applying ballpark rates of viral evolution, Rambaut estimates that the Adam (or Eve) virus from which all others are descended first appeared no earlier than Oct. 30, 2019, and no later than Nov. 29.

The progenitor virus itself was almost certainly one that circulates harmlessly in bats (as SARS does) but has an intermediate reservoir in one or more animals that come into contact with people, Andersen said. Presumably, that reservoir is one of the species of animals at the Wuhan market thought to be ground zero for the outbreak. The ancestor of 2019-nCoV existed in that species for some unknown time, never infecting people, until by chance a single virus acquired a mutation that made it capable of jumping into and infecting humans.

The genome sequences suggest that was a one-time-only jump. The genomes [from the 24 samples] are very uniform, Andersen said. If there had been multiple introductions, including from many different animals, there would be more genomic diversity. This was a single introduction.

That means that whats sustaining the spread is human-to-human transmission (suggesting that closing Wuhans animal market is very much an after-the-horse-has-fled-the-barn reaction).

Unfortunately, genetic analysis cant identify what animal species the coronavirus jumped from into humans. But an analysis by a team from the Wuhan Institute of Virology, posted to the preprint server bioRxiv, determined that the genome of this coronavirus (the seventh known to infect humans) is 96% identical to that of a bat coronavirus, suggesting that species is the original source. (Writing in the New England Journal of Medicine on Friday, another team of scientists in China reported that the new coronavirus is 86.9% identical to the bat SARS-like coronavirus.)

Virologists differ on whether its possible to read out viral properties from just the genome sequence, such as whether the microbe is spread by coughing, sneezing, touching,or merely breathing. But the analysis by the Wuhan Institute team found that it enters human cells using the same doorway that SARS did. Called angiotensin converting enzyme 2 (ACE2), the door is a receptor to which a spike protein on the viruss surface first attaches and then enables the virus to fuse with the host cell.

If ACE2 is druggable, blocking it could conceivably treat 2019-nCoV. It should be expected and worth to test if ACE2 targeting drugs can be used for nCoV-2019 patients, the scientists wrote.

The genome sequences have more to give. They will be crucially important for development of diagnostics [and] vaccines, said biologist Richard Ebright of Rutgers University.

For instance, the genome-editing technology CRISPR is the basis for Cambridge, Mass.-based startup Sherlock Biosciences diagnostics, which promise to slash how long it takes to make a definitive identification. In the U.S, thats now done only by sending samples to the Centers for Disease Control and Prevention, which uses a technology invented in the 1980s, polymerase chain reaction or PCR, to identify the presence of coronavirus.

Our vision is that our [CRISPR-based] SHERLOCK and INSPECTR platforms are tailor-made for outbreaks like coronavirus, said Sherlock CEO Rahul Dhanda, who declined to discuss specific plans related to coronavirus.

And as scientists keep adding 2019-nCoV genome sequences to their collection, they could get an early glimpse of whether the virus is mutating in a way that could make it more dangerous or more transmissible. You need continuous sequencing, Andersen said.

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DNA sleuths read the coronavirus genome, tracing its origins - STAT