Category Archives: Gene Medicine

Amid concerns over gene mutations going undetected due to the variety of medical devices and test reagents in use, a Japanese organization has drawn up guidelines for standard procedures and frameworks to ensure that genetic tests are reliable.

The Japanese Committee for Clinical Laboratory Standards published the guidelines after studying international standards as well as guidelines and articles at home and abroad. The guidelines stipulate what staff are required, the records that need to be kept and the correct way to check instruments and reagents.

JCCLS consists of representatives from companies and academic societies with a focus on disease diagnosis and treatment.

The guidelines also call for hospitals and other medical facilities analyzing test results to compare the results with those from other institutions to ensure precision.

The move comes as an increasing number of people are opting to have their genes checked on being diagnosed with an intractable disease or in order to select an appropriate cancer treatment.

In collaboration with the committee, the Japan Accreditation Board, which evaluates abidance to international standards across various fields, has launched work to recognize institutions that carry out genetic testing in line with the new guidelines.

Accreditation is subject to passing on-site investigations and practical exams.

"Producing a correct result is key to safe, secure medicine," said Hayato Miyachi, a Tokai University professor who is involved in crafting the guidelines. "I believe the guideline will play a major role."

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Organization crafts genetic testing guidelines to ensure reliability - Japan Today

A landmark study has identified 102 genes associated with autism spectrum disorder (ASD) in what researchers say may not only lend to understanding the causes and mechanisms behind the condition but may one day pave the way to developing precision treatments for those affected.

An international cohort of researchers from more than 50 research facilities around the world conducted the genetic sequencing study to identify associated genes as part of the Autism Sequencing Consortium (ASC), publishing their findings in Cell. In what is the largest autism sequencing study to date, scientists collected and analyzed more than 35,000 genetic samples, including nearly 12,000 from those with severe forms of ASD, looking for both inherited genetic mutations and those that may occur spontaneously when the egg or sperm is formed, or de novo mutations.

The take-home message is that there are probably many different paths to autism, Joseph Buxbaum, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai, told IFLScience. That is the nature of complex disorders many of the things that have been studied now and patient-based research is complicated now because the easy stuff has been figured out.

With more than 20,000 genes in the human genome, Buxbaum says that it is not just one major class of cells that are involved in autism but rather a variety of many disruptions in brain development and neuronal function.

As we look more and more into autism, we are discovering that it is much more complex than we thought, he said. The first shock was that it was going to be a large number of genes that could be indicators for autism, somewhere between 500 and 1,000 is our estimate.

Genes break down into two main classes, the first being a critically important component of turning genes on and off and the other being involved in nerve function. When mutated, certain genes may alter nerve function, which can be linked to autism.

Were finding that about half of the genes that we discover are involved in regulating gene expression, and that is both temporal and spatial. As you develop, different genes have to be turned on and off and as each cell develops in different parts of the brain, explained Buxbaum, adding that there is not one process in the brain that causes autism but rather a likely combination of the two.

Of the 102 genes found to be associated with ASD, 49 are also associated with other developmental delays. Genes associated with ASD and other intellectual disabilities and developmental delays often overlap, but this work begins to tease apart the specificity. The findings help to inform what brain changes underlie ASD and present a beginning for understanding new treatment approaches. Researchers hope to next test new methodologies to understanding whether specific genes are linked with ASD and if so, how. Someday, the work may lead to precision treatment whereby specific genes are targeted, manipulated, and changed in order to determine whether and what characteristics of ASD change.

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More Than 100 Identified Genes Found To Be Associated With Autism - IFLScience

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

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 University of Texas at Dallas scientist recently received two federal grants totaling $2.7 million to support research aimed at better understanding and perhaps exploiting the role of protein evolution and interactions in human health and disease.

Dr. Faruck Morcos

Dr. Faruck Morcos, assistant professor of biological sciences in the School of Natural Sciences and Mathematics, received a Maximizing Investigators Research Award for Early Stage Investigators (ESI-MIRA) from the National Institute of General Medical Sciences, a component of the National Institutes of Health (NIH). The grant (R35GM133631) provides about $1.9 million over five years.

Unlike a traditional research grant, MIRA grants offer investigators the flexibility to pursue a broader scientific question as it evolves, rather than being tied to one specific project. The grant program is part of the NIHs strategy to bring innovation and risk-taking back to basic medical research.

The larger questions we are asking often guide us on winding courses of research, Morcos said. This support from the National Institutes of Health is special because we can explore a spectrum of areas and go where the work takes us, which I really value.

Morcos also received a National Science Foundation(NSF) Faculty Early Career Development (CAREER) Award, which provides him with more than $855,000 infunding over five years.

Both grants support his research on how proteins and RNA can change due to mutations and yet still maintain functional roles. The NIH support facilitates investigations of a variety of model systems and their potential biomedical applications. The NSF grant, which also has an educational outreach component, is aimed at building models of protein evolution.

The Faculty Early Career Development Program supports early-career faculty who exemplify the role of teacher-scholars through outstanding research and excellent education. The highly selective program is the National Science Foundations most prestigious award for junior faculty who are considered likely to become leaders in their fields.

When we hear about a mutated gene or protein, we typically think that means something goes wrong and that it suddenly does not work anymore, he said. Thats the case in the majority of mutations. However, my group is interested in mutated proteins that still perform their function, but maybe in a different way.

Morcos said a mutation might allow a protein to interact with other proteins that it previously was incompatible with which could have positive or negative effects.

For example, in antibiotic resistance, sometimes there is a single change in a protein that allows a bacterium to be resistant to treatment with antibiotics, Morcos said. But this might not be because the protein has changed its function; rather, it might be that it has changed its partners the other molecules it can interact with. We are studying these kinds of examples.

Our work is novel because it is hard to predict such network-level effects that involve more than just a single molecule.

Morcos has developed a computational framework and statistical models to predict how changes to a proteins structure both changes that are allowed by nature and those that are not affect the proteins function.

We look at hundreds of thousands of possibilities. But the models we are building will help us make predictions about how changes to a protein will affect its function, which might enable us to design proteins that can fight disease.

Dr. Faruck Morcos, assistant professor of biological sciences in the School of Natural Sciences and Mathematics

We look at hundreds of thousands of possibilities the space is enormous; its astronomical, Morcos said. But the models we are building will help us make predictions about how changes to a protein will affect its function, which might enable us to design proteins that can fight disease. To tackle those problems, my lab has established important collaborations with other labs at UTDallas and nationwide. I feel very fortunate to work in such a collaborative environment.

The CAREER award will support undergraduate and graduate student research aimed at creating new tools to promote the understanding of biomolecules and their evolution. Morcos group will develop 3D printing technologies and interactive software to engage general audiences in building and manipulating models of real biological molecules.

This kind of interactive, hands-on strategy is expected to serve as an effective mechanism for teaching the fundamental principles of biomolecular interactions, Morcos said. I am also excited about how this funding will help us reach underrepresented students in science by creating links with local community colleges and supporting student engagement in solving scientific questions.

More than a dozen undergraduates, graduate students and postdoctoral researchers are part of Dr. Faruck Morcos lab in the Department of Biological Sciences.

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NIH, NSF Grants Help Advance Scientist's Protein Research - University of Texas at Dallas

Scientists strive to have a better understanding of the complex biological processes involved in health and disease, and what they can learn usually goes hand-in-hand with the number, quality and type of measurements techniques provide.

Cancer, for instance, usually originates through changes on many different genes and pathways, not just one, but currently most cell-based screening assays conduct single measurements, said Dr. Koen Venken, assistant professor of biochemistry and molecular biology, and pharmacology and chemical biology at Baylor. We thought that if we could see what happens to more than one cellular pathway at once, we could have a more complete picture of what goes on inside a cancer cell.

To get a more detailed picture of the cellular processes that differentiate normal versus cancer cells, researchers resort to conduct several independent screening assays at the expense of time and additional cost.

In his lab at Baylor College of Medicine, Venken and his colleagues apply state-of-the-art synthetic biology, cell biology, genetics, genome engineering and transgenic technologies to have a better understanding of the processes involved in cancer.

Our goal in this study was to measure multiple cellular pathways at once in a single biological sample, which would also minimize experimental errors resulting from conducting multiple separate assays using different samples, said Venken, a McNair Scholar and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

Dr. Alejandro Sarrion-Perdigones, first author of the paper, wanted to develop an experimental assay that would expand the number of molecular pathways that can be studied simultaneously in a cell sample.

He focused on developing a multiplexed method a method for simultaneously detecting many signals from complex systems, such as living cells. He developed a sensitive assay using luciferases, enzymes that produce bioluminescence. The assay includes six luciferases, each one emitting bioluminescence that can be distinguished from the others. Each luciferase was engineered to reveal the activity of a particular pathway by emitting bioluminescence.

To engineer and deliver the luciferase system to cells, we used a molecular Lego approach, said co-author Dr. Lyra Chang, post-doctoral researchers at the Center for Drug Discovery at Baylor. This consists of connecting the DNA fragments encoding all the biological and technological information necessary to express each luciferase gene together sequentially forming a single DNA chain called vector. This single vector enters the cells where each luciferase enzyme is produced separately.

Treating the cells with a single multi-luciferase gene vector instead of using six individual vectors, decreased variability between biological replicates and provided an additional level of experimental control, Chang explained. This approach allowed for simultaneous readout of the activity of five different pathways (a control makes number six), compared to just one using traditional approaches, providing a much deeper understanding of cellular pathways of interest.

The new assay is sensitive, saves time and expense when compared to traditional approaches, reduces experimental error and can be adapted to any research field where the dual luciferase assay is already implemented, and beyond.

In addition to applications in cancer research, as we have shown in this work, our multiplex luciferase assay can be used to study other cellular pathways or complex diseases across different research fields, Venken said. For instance, the assay can be adapted to study the effect of drugs on insulin sensitivity in different cell types, the immune response to viral infections or any other combinations of pathways.

Interested in this new technology? Find all the details in the journal Nature Communications.

Other contributors to this work include Yezabel Gonzalez, Tatiana Gallego-Flores and Damian W. Young, all at Baylor.

This work was supported by start-up funds provided by Baylor College of Medicine, the Albert and Margaret Alkek Foundation and the McNair Medical Institute at The Robert and Janice McNair Foundation. Additional support was provided by March of Dimes Foundation grant #1-FY14-315, the Foundation For Angelman Syndrome Therapeutics grant FT2016-002, the Cancer Prevention and Research Institute of Texas grants R1313 and R1314 and the National Institutes of Health grants 1R21GM110190, 1R21OD022981 and R01GM109938.

The authors dedicate this work to the memory of Dr. Alejandro Sarrion-Perdigones, who passed away before the paper was published.

By Ana Mara Rodrguez, Ph.D.

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Six is better than two: assay assesses multiple cellular pathways at once - Baylor College of Medicine News