Category Archives: Genetic medicine

The most populous boroughs in New York City, Queens and Brooklyn, likely served as the major hub of coronavirus disease (COVID-19) spread in the spring of 2020, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the new investigation analyzed more than 800 coronavirus genetic samples to trace the path of the virus as it traveled across New York City during the pandemics deadly first wave. It identified Queens and, to a lesser extent, Brooklyn as the likely origin point of most cases sampled, with more cases circulating within their borders and spreading from these parts of the city into Manhattan and the outer boroughs than in the other direction.

Our findings appear to confirm Queens role as the early epicenter of coronavirus transmission throughout the rest of the New York metropolitan area, says study co-senior author Ralf Duerr, MD, PhD. Now that we understand how viral outbreaks can spread between neighborhoods, we can better plan for future contagions and prioritize testing in the most vulnerable areas.

Dr. Duerr, a research assistant professor in the Department of Pathology at NYU Langone, notes that if a disease that transmits similarly to the coronavirus strikes New York again, it could likely follow the same basic path through the region.

Although more research is needed to identify the underlying reasons behind the spread, the study researchers suspect that commuting likely played a key role. Dr. Duerr notes that 35 percent of Queens and Brooklyn workers travel daily to Manhattan by car, subway, and bus. In addition, both of the citys main airports, LaGuardia Airport and John F. Kennedy International Airport, are located in Queens. That Black and Hispanic Americans, who were hit particularly hard by the pandemic, disproportionally use public transportation and live in these two boroughs may have been another possible factor, says Dr. Duerr.

Past studies revealed that the coronavirus first took root in New York in late February 2020, with more than a hundred separate outbreak sources bursting into chains of infection rather than from a single patient zero. However, the dynamics of viral spread within and between individual boroughs had remained unclear.

The new study, published May 20 in the journal PLOS Pathogens, was designed to precisely track the dispersal of the coronavirus within the five New York City boroughs and Long Island during the first wave of the pandemic, according to Dr. Duerr.

In gene sequencing, researchers compare small snips of genetic code to identify mutations that are only found in a particular strain of the virus. These flags, researchers say, can then be used to map when and where the strains had spread over time. This is similar to tests used to trace ancestry in people. Experts have previously used this technique to follow outbreaks of influenza, methicillin-resistant Staphylococcus aureus (MRSA), and Ebola, among others.

For the new investigation, the researchers analyzed viral genetic information gathered from hundreds of nasal swabs. Samples were taken from men and women who had tested positive for COVID-19 in New York City and on Long Island from March to May of 2020. Using the different mutation flags, the date the samples were collected, and patient ZIP codes, the study investigators created computer simulations that traced the virus path through the region. The research was carried out in the Genome Technology Center at NYU Langone.

They found that 8 out of 10 simulations pointed to Queens as the major hub of viral spread in the first wave of infection. Meanwhile, the other two simulations identified Brooklyn and the Bronx, respectively, as the pandemic epicenter, which the study authors say suggests that these two boroughs played important, albeit smaller, roles in viral transmission throughout the city.

Past research has relied on hospitalization data to infer how the outbreak traveled. The new findings, the study authors say, provide a more direct map of the infections movement.

These gene sequencing and computer modeling techniques can be used by any community looking to track how a virus might spread when mass testing and contact tracing are in limited supply, says study co-senior author Adriana Heguy, PhD. Dr. Heguy, a professor in the Department of Pathology at NYU Langone, encourages other public health officials in the United States and abroad to use these methods to map how the pandemic spread in their cities as well.

She says the research team next plans to apply the methods used in the investigation to study coronavirus spread during the second wave of the pandemic in New York City.

Funding for the study was provided by National Institutes of Health grants U01 Al152151 and R01 AI122953. Additional research support came from the Fonds National de la Recherche Scientifique the Research FoundationFlanders, and the Internal Funds KU Leuven in Belgium. The South African Medical Research Council provided further support.

In addition to Dr. Duerr and Dr. Heguy, other NYU Langone researchers were Matthew T. Maurano, PhD; Sitharam Ramaswami, PhD; Paul Zappile, MS; and Christian Marier, BSc. Other study co-investigators were Simon Dellicour, PhD; Samuel Hong, BA; Bram Vrancken, PhD; Guy Baele, PhD; and Mandev Gill, PhD, at the University of Leuven in Belgium; Antoine Chaillon, MD, PhD, at the University of California San Diego; and Gordon Harkins, PhD, at the University of the Western Cape in South Africa.

Shira PolanPhone: 212-404-4279shira.polan@nyulangone.org

More here:
Coronavirus Transmission in Queens Drove the First Wave of New York City's COVID-19 Pandemic - NYU Langone Health

A blind man who could only perceive the faintest bit of light can now perceive fuzzy shapes, thanks to gene therapy and a pair of specially engineered goggles.

The man was diagnosed with a condition called retinitis pigmentosa 40 years ago, at the age of 18, according to a new report, published Monday (May 24) in the journal Nature Medicine. People with retinitis pigmentosa carry faulty genes that, due to many mutations, cause the light-sensitive cells in the retina at the back of the eye to break down, according to the National Eye Institute (NEI).

These genes would usually code for functional proteins in the retina, but instead fail to build those proteins, or make abnormal proteins that malfunction or produce substances that directly damage the retinal tissue. The condition affects roughly 1 in 4,000 people worldwide, according to the NEI, and can sometimes lead to complete blindness, as occurred in the 58-year-old patient in the new study, BBC News reported.

Related: 12 amazing images in medicine

In an attempt to treat the man's vision loss, scientists inserted genes that code for a light-sensing protein into a modified virus, then injected those genetically tweaked viral vectors into one of his eyes, the researchers reported. The protein, called ChrimsonR, is a engineered version of a light-sensitive protein found in unicellular algae, which allows the single-celled organism to detect and move toward sunlight, MIT Technology Review reported.

ChrimsonR belongs to a family of light-sensitive proteins called channelrhodopsins, hence the added "H" in crimson, and has been modified to react to colors within the reddish end of the color spectrum, namely amber light. By injecting genes for ChrimsonR into the retina specifically into retinal ganglion cells, a kind of nerve cell that sends visual signals to the brain the team hoped to make these cells sensitive to yellow-orange light, MIT Technology Review reported.

Here's where the special goggles came in. The goggles pick up changes in light intensity from the environment and then translate that signal into an intense, amber image that gets projected straight onto the patient's retina, with the aim of activating ChrimsonR. Months passed before a significant quantity of ChrimsonR accumulated in the man's eye and began to alter his vision, but eventually, he began to perceive patterns of light with help from the goggles, BBC News reported.

"The patient perceived, located, counted and touched" different objects using his treated eye, alone, and while wearing the goggles, the researchers wrote in the study. For instance, the patient could perceive a notebook and cups placed on a table in front of him, although when asked to count the cups he did not always give the correct number, according to MIT Technology Review.

Prior to receiving the therapy, the man could not detect any objects, with or without the goggles on, and following the injection, he could only see while wearing the goggles, since they convert all light into an amber hue, the researchers reported.

In addition to the notebook and cups, the patient reported being able to see the painted white lines at a pedestrian crossing, the BBC reported. "This patient initially was a bit frustrated because it took a long time between the injection and the time he started to see something," first author Dr. Jos-Alain Sahel, an ophthalmologist and scientist at the University of Pittsburgh and Institute of Vision in Paris, told the BBC. The patient began training with the goggles about 4.5 months after his injection and only started reporting improvements in his vision about 7 months after that, the team reported.

"But when he started to report spontaneously he was able to see the white stripes to come across the street you can imagine he was very excited. We were all excited," Sahel told the BBC.

Even now, the man's vision still remains fairly limited, in that he can only see monochromatic images and at a fairly low resolution. But "the findings provide proof-of-concept that using optogenetic therapy to partially restore vision is possible," senior author Dr. Botond Roska, founding director of the Institute of Molecular and Clinical Ophthalmology Basel at the University of Basel, told BBC News. ("Optogenetics" broadly describes the technique of using light and genetic modification to control the activity of neurons.)

Of course, although these initial results are exciting, the study is limited in that only one patient has received the treatment so far, James Bainbridge, a professor of retinal studies at the University College London who was not involved in the study, told the BBC.

Read more about the research in BBC News and MIT Technology Review.

Originally published on Live Science.

Read more:
Genes from algae helped a blind man recover some of his vision - Livescience.com

Welcome to this week's Chutes & Ladders, our roundup of hirings, firings and retirings throughout the industry. Please send the good wordor the badfrom your shop to Fraiser Kansteiner, and we will feature it here at the end of each week.

TevardBiosciencesGopi Shanker, Ph.D., lands at the startup as chief scientific officer.

Shanker's departure marks something of a trend for Novartis. In late April,Jeff Engelman, M.D., Ph.D.,left the Novartis Institutes for Biomedical Research (NIBR) to stand up the new oncology biotechTreelineBiosciences. Just a few days later, fellow Novartis cancer R&D execPeter Hammerman, M.D., Ph.D., leftto start as chief scientific officer of molecular machines biotech MOMA Therapeutics.Shanker, for his part, will take up the post ofchief scientific officer at gene therapy startup TevardBiosciences. After heading upneuroscience atNIBR, Shanker will nowlead the preclinical scientific programs at the transfer RNA-based gene therapystartup.A few months back, Tevard forged a pact withZogenix to seek out and work on gene therapies for Dravet syndrome, a rare form of epilepsy, and other genetic epilepsies.Fierce Biotech

Blueprint MedicinesPercy Carter, Ph.D., takes up the helm of chief scientific officer.

Carter is in good company at Blueprint, where he joins former Bristol Myers Squibb compatriotFouad Namouni, M.D., who became president of R&D last fall. Carter, who joinedBristol Myers Squibb in 2001and eventually rose through the ranks tosenior vice president and head of discovery, willspearhead research and preclinical development as the new chief scientific officer at Blueprint. More recently, Carter held posts atJohnson & Johnson, where he was global head of discovery sciences in the healthcare giant's Janssen unit, andFibroGen, where he was in the CSO seat for less than a year. He joins Blueprint a little over a year after the company's first approval. In January 2020,Ayvakit,kinase inhibitor, became the first targeted treatmentfor patients with a type of stomach cancer called gastrointestinal stromal tumor who carry a (PDGFR) exon 18 mutation.Fierce Biotech

IovanceBiotherapeuticsMariaFardis, Ph.D.,is hitting the exit.

Fardis, who's also Iovance's president and a director, alertedthe company on Tuesday that she wasresigning topursue other opportunities," Iovance quietly revealed in a Wednesday securities filing. Her exit coincides withadditional data requests on potency assays for Iovance'slead candidate lifileucelfrom the FDA.Iovancewill continue validating the potency assays and expects to submit further data and meet with the FDA in the second half of 2021.The setback pushesIovancesbiologics license application submission into the first half of 2022,the company said. The "optics" of Fardis departure are "challenging" and raise "questions about whether something else is behind the change or whether the Board chose to make the change, Jefferies analysts wrote to clients this week. Long term,we think the drug works [] and it will eventually get to market," the Jefferies team added.IovancesBoard will appoint general counsel Frederick Vogt, Ph.D., as interim president and CEO. The company will immediately kick off the huntfor a successor.Fierce Biotech

>Passage Bio has bidadieu to chief medical officer Gary Romano, M.D., Ph.D. The gene therapy startup and Romanomutually agreed they should part waysTuesday, and Romano hit the exit that same day.Chief Financial Officer Richard Morris is also leaving the company on May 30, but Passage Bio described the situation differently: It said Morris' departure was not the result of any disagreement regarding any matter relating to the Companys operations, financial statements, internal controls, auditors, policies, or practices. Passage didn't say whether Romano's departure was the resultof a disagreement.Fierce Biotech

>Merck KGaA has slottedChris Round into the role ofpresident at its North America healthcare unit, replacing Andrew Patterson, who'll step into the newly minted role of chief marketing officer.EMD Serono is hoping to cash in with three promising drugsits Pfizer-partnered immuno-oncology medBavencio, multiple sclerosis treatment Mavenclad and Tepmetko for non-small cell lung cancer.Round will be based in Rockland, Massachusetts. He served for 20 years at Merck & Co. before arriving at Merck KGaA in 2017 to spearheadcommercial operations in Asia, the Middle East and Africa.Fierce Pharma

>Clinical Ink, a global clinical trial technology firm, has summoned Janette Morgan as EVP, general manager, Europe, the Middle East and Africa. Morgan joins after a 13-year run at Medidata, where she most recently served as vice president, global partner initiatives & partner business management. In that role, she was in charge ofglobal leadership and management of Medidatas Partner Study-by-Study business.Release

>Xenter, hot on the heels of last week's $12 million series A, has enlistedScott Heuler as senior vice president of global sales and marketing, whileGary Baldwin signs onas chief technology officer in Xenter'shospital technologies business unit.Baldwin previously led R&D, engineering and product teams for multiple organizations. Heuler, for his part, has held seniorsales and marketing leadership roles with NeuroOne Medical Technologies, Guidant Corporation and U.S. Surgical Corporation, Xenter said.Release

> Clinical-stage immuno-oncology companyMedicenna has tapped Mann Muhsin, M.D., as chief medical officer. With more than 20 years experience in medical practice and drug development, Muhsin signs on with "an outstanding track record of innovation in oncology and immuno-oncology trial design," Medicenna said in a release. Muhsin kicked off his clinical research career atPICR phase I unit, where he conducted more than 17 clinical trials for international sponsors likeAstraZeneca,Hoffmann La Roche, Merck, Novartis, Eli Lilly, Johnson & Johnsonand Bayer. He then went on to lead early clinical development programs at Johnson & Johnson's Janssen unit.Release

>CDMO and clinical supply services company Experic is putting David Wood in charge as chairman and chief executive officer. Over a 30-year run in the industry, Wood has lead organizations and teams atCaptek Softgel International, Catalent Pharma Solutions, Cardinal Health PTS and Becton Dickinson. He's taking the reins from Jeffrey McMullen, one of Experic's founders and its former chairman and CEO. McMullen took on aninterim CEOrole in 2019 after the untimely passing of the executive previously managing the company.Release

>NeuBase Therapeutics, looking to push its first drug candidate into the clinic next year, will welcomeSandra Rojas-Caro, M.D., as chief medical officer onMay 24. At NeuBase, she'll be in charge of thepreclinical and clinical development, medical, and regulatory strategy of NeuBases pipeline. She most recently worked at Gemini Therapeutics, where she held the same post. Before that, she was CMO atAeglea BioTherapeutics.Release

>Rain Therapeutics, working on precision oncology therapeutics, has lifted co-founderRobert Doebele, M.D., Ph.D., into the role ofpresident and chief scientific officer. Doebele co-founded Rain with chairman and CEOAvanish Vellanki in 2017. Before he joined the company full-time in October 2020, Doebele served asassociate professor of medicine in the division of medical oncology at the University of Colorado School of Medicine, director of the Thoracic Oncology Research Initiative at the University of Colorado Cancer Center and as principal investigator for the University of Colorado Lung Cancer Specialized Program of Research Excellence.Release

> Precision oncology firm Fore Biotherapeutics is building out its leadership team with the addition ofStacie Peacock Shepherd, M.D., Ph.D., as chief medical officer and Nora Brennan as chief financial officer. Shepherd will oversee clinical strategy and operational advancement of Fore's lead precision oncology program, FORE8394, and she will also helpexpand the company's clinical pipeline in the coming months. Brennan, for her part, previously served as CFO atTELA Bio, and held the same role at Xeris Pharmaceuticals before that.Release

>Cybrexa Therapeutics has summonedStephen Basso as its chief financial officer. Before joining the Cybrexa team, Basso served as senior vice president of finance atInozyme Pharma. He also served as vice president, North America commercial finance, global G&A at Alexion Pharmaceuticals, and as director, financial planning and analysis at Pfizer.Release

>Celularity, developing off-the-shelf cell therapiesderived from the postpartum human placenta, has signed onBradley Glover, Ph.D., as EVP and chief technology officer. At Celularity, Glover will oversee all aspects of the company's technical operations, includingprocess development, quality, manufacturing, supply chain, IT, facilities and engineering, and more. He joins the team from Kite Pharma, where he wore a number of executive hats in corporate development and technical operations.He rose through the ranks at Genentech and Roche before that.Release

> Early-stage allogeneic cell therapy company Appia Bio has enlisted Qi Wei, Ph.D. as senior vice president and head of technical operations. Wei is bringingsome serious cell and gene therapy know-how to the fold. He's had stints atNovartis, Gilead's Kite, Eli Lilly, TCR2 Therapeutics and Geneception.He had a hand in the development of several CAR-Ts, including Novartis' Kymriah and Kite and Gilead's Tecartus.Release

>Aerovate Therapeutics, working on meds for patients with rare cardiopulmonary disease, has handed the CEO torch toTimothy Noyes. Noyes was also elected to the company's board of directors in April. He previously served as president and chief executive ofProteon Therapeutics. He previously served aschief operating officer of Trine Pharmaceuticals and held the position of president of Genzymes renal division following its acquisition of GelTex Pharmaceuticals. Noyes started his industry run at Merck & Co.Release

> Biopharma product and portfolio strategy planner Prescient has appointed John Crowley as director of the company's intelligence and insight business, whileSugandh Sharma enters the role of senior director in the same business unit. Before joining the fold at Prescient, Crowleyled analyst teams at Decision Resources Group, covering rare diseases in neurology, immunology and hematology, as well as infectious diseases.Release

>Cognito Therapeutics, developing a new class ofdisease-modifying digital therapeutics to treat neurodegenerative disorders likeAlzheimers disease,tapped Everett Crosland as its chief commercial officer. He recently held the same role at AppliedVR, where he was in charge ofnational launch sales, marketingand payer strategy on the first breakthrough designated virtual reality therapeutic. Prior to that, he was VP of market access & reimbursement atPear Therapeutics.Release

>Umoja Biopharma, developing an integrated, in vivo immunotherapy platform, has signed onIrena Melnikova, Ph.D., as chief financial officer. She comes over from SVB Leerink, where she was a managing director in investment banking. Before that, shewas a managing director at Burrill & Company and, prior to that, director of strategy and external innovation at Sanofi.Release

>ONI has enlistedTyler Ralston, Ph.D., as its chief technology officer. In his role, Ralston willprovide leadership, strategic vision and oversee the research and development of ONI's technology. He signs on from the 4Catalyzer incubator, where he most recently served as CTO for Tesseract. Release

> Quanterix, working ondigital protein biomarker technology to enableprecision health, tappedMasoud Toloueas president of Quanterix and Diagnostics. He'll enter the role on June 9. He joins the team fromPerkinElmer, where he most recently served as senior vice president, diagnostics. He alsofounded and led Bioo Scientifics next generation sequencing business, which was acquired by PerkinElmer in 2016.Release

> Gene therapy firm AavantiBio has named Jessie Hanrahan, Ph.D., as Chief Regulatory Officer. She's the fifth senior executive to joins AavantiBio's leadership team in recent months and will be in charge ofglobal regulatory affairs for AavantiBios diversified pipeline of gene therapy programs targeting rare diseases with significant unmet medical need.Most recently, she was vice president of regulatory science at bluebird bio.Release

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Chutes & LaddersAnother Novartis exec answers the biotech call, this time for gene therapy startup Tevard - FierceBiotech

UT Dallas research scientist Dr. Zhenghong Gao is leading a multidisciplinary team to develop a minimally invasive technology that delivers CRISPR to edit a genetic mutation that causes the familial form of amyotrophic lateral sclerosis.

University of Texas at Dallas researchers are working on a method that uses the gene-editing tool CRISPR to delete a genetic mutation that causes the familial form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease.

Dr. Zhenghong Gao, amechanical engineeringresearch scientist in theErik Jonsson School of Engineering and Computer Science, recently received a $648,389, two-year award from the U.S. Army Medical Research Acquisition Activity to support this preclinical research.

ALS is a rare, fatal neurodegenerative disease. Individuals with ALS lose the ability to speak and eat, and the disease can lead to paralysis of the muscles that control breathing,with many patients dying from respiratory failure, according to the National Institute of Neurological Disorders and Stroke. Some studies suggest that people who have served in the military are at greater risk of developing ALS and dying from the disease than those with no history of military service, according to the institute. Currently, no effective treatment is available for slowing the progression of the disease.

The UT Dallas research focuses on ALS associated with inherited mutations, which account for approximately 5% to 10% of ALS cases.

Our goal is to test in a small animal model the idea of using CRISPR to delete mutations as a one-time treatment for inherited ALS. In this project, we focus on deleting one of the most common and well-characterized mutations. If successful, we may be able to apply this novel approach to deleting or editing other mutations, said Gao, the studys principal investigator.

Nanotechnology Leads to Novel Method

The central challenge in ALS gene therapy is delivering the genome editing agents through the blood-brain barrier/blood-spinal cord barrier, a layer of densely packed cells in blood vessels that prevents therapeutics from entering the brain and spinal cord.

The proposed approach involves packaging the gene-editing components in a virus called an AAV, or adeno-associated virus. However, this commonly used gene carrier has very limited capability of crossing the barriers in the brain and spinal cord.

To address the central problem of delivering AAV-based CRISPR gene therapy across the barriers, the researchers turned to nanotechnology.Dr. Zhenpeng Qin, assistant professor ofmechanical engineeringat UTDallas, is an expert in the use of nanotechnologies to improve the treatment of brain diseases, and he is a co-investigator on the project.

Our expertise in nanomaterials has provided a novel method to target and remotely modulate this barrier, Qin said.

The UT Dallas team will use a light-sensitive gold nanoparticle for targeting the barriers. After attaching nanoparticles to the barriers, the researchers will apply short laser pulses from an external source, which causes the gold nanoparticles to generate gentle mechanical energy that is fine-tuned to open the barrier temporarily, allowing the AAV to pass through.

Ideally, without the mutated gene, cells cannot make the toxic proteins anymore, and the disease cant develop. We hope that by enhancing the delivery of CRISPR-based therapy using our novel barrier-opening technology we can significantly slow down or even stop the disease progression.

Dr. Zhenghong Gao, a mechanical engineering research scientist in the Erik Jonsson School of Engineering and Computer Science

Once the AAV is taken up by cells containing the target mutation, the AAV releases the CRISPR gene-editing components to delete the mutation in the DNA of these cells.

Ideally, without the mutated gene, cells cannot make the toxic proteins anymore, and the disease cant develop, Gao said. We hope that by enhancing the delivery of CRISPR-based therapy using our novel barrier-opening technology we can significantly slow down or even stop the disease progression.

The team of researchers also includes co-principal investigatorDr. Leonidas Bleris, UTDallas associate professor ofbioengineering and Fellow, Cecil H. and Ida Green Professor in Systems Biology Science, a pioneer in genome editing.

CRISPR is an incredibly powerful tool, Bleris said. We are optimistic that in the near future we will be able to perform surgical modifications in the brain with single-cell precision. The possibilities are endless.

The multidisciplinary team also includes two experts in ALS pathology and biology, Dr. Han-Xiang Deng and Dr. Evangelos Kiskinis at the Northwestern University Feinberg School of Medicine.

Gao cautioned that the research is in the beginning stages and could take years before it becomes available to humans. Once developed, the technique could be adapted for similar treatments for ALS associated with other inherited genetic mutations. It might also be used to treat other neurodegenerative diseases, such as Parkinsons, Alzheimers and Huntingtons, Gao said. Gao, who joined UTDallas last year, said he became interested in developing a treatment for ALS through his research on nanotechnology applications for advancing the diagnosis and treatment of neurological diseases.

Originally posted here:
Army Grant Assists Researchers' Mission Against ALS - University of Texas at Dallas

Introduction

Lynch syndrome, caused by germline pathogenic variants in the mismatch repair (MMR) genes, MLH1, PMS2, MSH2, and MSH6, is the most common type of hereditary colorectal cancer. The syndrome is, however, also associated with a series of other cancer types, including endometrial cancer, ovarian cancer, urothelial tract cancer, small bowel cancer, gastric cancer, brain tumor, and sebaceous skin tumor.13 Lynch syndrome-associated tumors develop through inactivation of the second MMR allele leading to biallelic loss of MMR protein expression and hence deficient MMR (dMMR). Tumors with d-MMR have lost the ability to repair DNA errors introduced during replication and these tumors often present with high levels of mutation, reflected as microsatellite instability (MSI).4 The increased number of mutations are often presented as neoantigens that recruit and activate the host immune cells.5 Further tumor progression can be facilitated through immunoediting like T cell exhaustion, eg, by targeting immune checkpoints like the programmed death 1 (PD-1) or cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors.6 Inhibiting these checkpoint blockades may reactivate the anti-tumorigenic T cells.

In 2017, MSI or dMMR were approved as pan-cancer biomarkers for the anti-PD-1 checkpoint therapy pembrolizumab by the American Food and Drug Administration (FDA).7 The approval was based on multicenter, multicohort, single-arm trials, some of which included Lynch syndrome data.4,8 Shortly after, nivolumab was approved by the FDA in 2017 for MSI colorectal cancer and in 2018 in combination with ipilimumab based on the CheckMate-142 study.7,8 Pembrolizumab has not received a tissue-agnostic indication by the European Medicines Agency (EMA) and despite comparable mechanism of action, the other immune checkpoint inhibitors, like atezolizumab, durvalumab, and avelumab, have neither been approved by the FDA nor the EMA in an MSI/dMMR pan-cancer setting.

Based on the expected tumor-agnostic effects, many Lynch syndrome MSI tumors may have been enrolled in clinical trials using these drugs. However, Lynch syndrome may only be the causative reason for tumor development in a smaller subset of all MSI tumors (35%),912 hence, their specific response rate may be masked by the responses of sporadic MSI cancers, that may differ molecularly from Lynch syndrome tumors.1316 Here, we review large clinical trials that have presented data separately for Lynch syndrome and sporadic MSI cancer patients to elucidate the clinical benefit from immune checkpoint-based therapy in Lynch syndrome. Furthermore, we summarize current data on Lynch syndrome case reports, although these may be publication biased.

A systematic literature search was performed to identify studies with Lynch syndrome specific treatment data to evaluate the clinical benefit of immune checkpoint-based therapies in this cohort. All published studies including patients with Lynch syndrome-associated cancer, who had been treated with one or more of the FDA- and EMA-approved checkpoint-based immunotherapies targeting CTLA-4 (ipilimumab), PD-1 (pembrolizumab and nivolumab), or PD-L1 (atezolizumab, avelumab, and durvalumab) and where data was available on clinical outcomes, were considered eligible for this review.

The search strategy was developed in collaboration with a research librarian at the Medical Library, Aalborg University Hospital, Denmark. The search string was assembled from MeSH and non-MeSH terms included in the two categories: a cancer subtype specific domain [Lynch syndrome OR hereditary MSI OR hereditary MMR-deficiency OR colorectal neoplasm, hereditary nonpolyposis] and a treatment domain [Ipilimumab OR Nivolumab OR Atezolizumab OR Durvalumab OR Pembrolizumab OR Avelumab] combined with a Boolean logical AND. In PubMed, all search terms were coined as MESH terms, as SUPPLEMENTARY CONCEPT, or as TEXT WORD (combined with OR) securing capture of yet unindexed articles. In Embase, the search terms were used as EMTREE terms and TEXT WORDS. In Web of Science, the search terms were used as TOPIC. In the Cochrane Library, the search terms were used as MeSH terms and as Title, abstract, and keywords terms. No constraints related to language or publication type were appliedexcept for exclusion of conference abstracts on Embase. Detailed search terms are available from the authors upon request.

The final search in the four databases was conducted on November 3, 2020. The combined results of the analog searches in PubMed, Embase, Web of Science, and Cochrane Library were imported into the Rayyan QCRI application (Qatar Computing Research Institute, https://libraryguides.mcgill.ca/rayyan, last updated on October 7, 2020).17 Herein, all the items identified from the four databases were imported and the software identified 196 duplicates, which were manually checked before removal (N=195). Studies identified through reference lists from the included studies (N=3)8,18,19 were included if they were scored as relevant (Figure 1).

Figure 1 Flowchart showing the systematic literature search and screening procedure following the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Data extraction was performed using modified criteria based on the guidelines given by the Cochrane Collaboration for the 31 studies included.

All studies identified were independently reviewed by four authors (IB, LHJ, MR, or CT) with at least two reviewers per item analyzing inclusion/exclusion criteria defining the study population. Whenever discrepancy was met, consensus was reached involving a third reviewer.

Study eligibility was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA), while data extraction was performed using modified criteria based on the guidelines given by the Cochrane Collaboration.20 Data were extracted regarding study population (eg, age, sex, race, and MMR germline mutation), tumor type (eg, location, organ, dMMR/MSI status, and stage), treatment regimen (eg, pharmaceutical drug used, line of treatment, combinational treatment, and period), and outcome (eg, objective response rate, overall survival, progression-free survival, and alternative endpoints).

Since this was a scoping review, quality assessment was not conducted. Publication bias was considered, as case reports may only be reported when interesting results are available. Likewise, funding sources were extracted to assess any conflicts of interest. All studies were requested to be on Homo sapiens and written in English and published as original articles unless sufficient data could be extracted from an English abstract (N=1).21 Redundant data, which was published in overlapping studies, motivated exclusion (N=2) or merging of the studies (N=4) (Figure 1).18,2224 When information on overlapping data was missing, data from the two studies was presented separately according to the outcome in focus.19,25 One study included two cases with two different tumor types and responses and was for clarity depicted as two separate case reports in Table 2.26

Table 1 Study Characteristics and Response Data from Included Cohort Studies

As this review included all types of MSI or dMMR Lynch syndrome-associated cancers (irrespective of organ or tumor stage) with all lines of therapy, and primarily case reports, meta-analysis was not considered appropriate. Instead, data was grouped by study design with clinical trials in unselected MSI/dMMR cancer cohorts scored as a high level of evidence, while case reports were considered to have a lower level of evidence and a higher level of bias.

Lynch syndrome diagnostics were based on individuals with pathogenic or likely pathogenic variants in one of the four MMR genes: MLH1, PMS2, MSH2/EPCAM, and MSH6 found by germline DNA sequencing (18 case studies and three cohort studies). Since some of the cohort studies included few variants of unknown significance (VUS) as causative for Lynch syndrome25 or included Lynch syndrome families based on individuals with dMMR/MSI tumors in families with a cancer history,8,21 we chose to include two case studies with VUS26,27 and two case studies with clinical Lynch syndrome diagnostics, but with unknown germline MMR gene variant.28,29 Lynch syndrome individuals with biallelic MMR variants (also referred to as constitutional MMR deficiency (CMMR-D) syndrome) were also included in this study, since these tumors show the same molecular phenotype as monoallelic Lynch syndrome tumors (N=1). There were no selection criteria regarding tumor type and no restrictions in period.

The primary endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ORR was measured as the best response during treatment or alternating immune checkpoint-based therapies using the response evaluation criteria in solid tumors (RECIST) guidelines, with partial response (PR) and complete response (CR) categorized as response. In cases where the RECIST criteria were not used, pathological complete response was classified as CR, while nonqualified tumor decrease was categorized as stable disease (SD). Disease control rates were calculated as all CR, PR and SD divided by the total number of treated and evaluable patients. PFS was measured in months from first dose of immune checkpoint-based therapy to tumor progression or end of follow-up. In case of alternating immunotherapeutic regimens, PFS were defined as the time from first dose of immunotherapy to end of the last regimen of immunotherapy caused by disease progression. OS was measured in months from the first dose of immune checkpoint-based therapy to death or end of follow-up. Inclusion of alternative endpoints was motivated when ORR data was not available, as these may translate into a clinically meaningful benefit in PFS and OS. Decreasing prostate specific antigen (PSA) level was categorized as disease control for one case according to the prostate cancer clinical trial working group (PCWG3) guideline.30 Whenever possible, the analyses were based on original raw data and Lynch syndrome cases were sought and extracted from larger studies with separate endpoint data from the sporadic cancers.

In total, 492 studies were identified (two from Cochrane Library, 167 from Embase, 130 from PubMed, and 193 from Web of Science) (Figure 1). After removal of 195 duplicates, 297 studies were reviewed on title and abstract level following the PRISMA guidelines. Hereafter, 47 studies were screened on full text level and three additional studies were added to the search based on the references of the reviewed publications.8,18,19 In total, 31 articles were included for this review, six of which included overlapping cases: two cases were described in two case reports18,2224 and one clinical trial was updated with different data presented in two papers.19,25

Large cohort studies of consecutive unselected patients were considered to be less biased by publication and were initially investigated for specific data on Lynch syndrome cases. Seven studies were identified and presented in Table 1. Three studies investigated the response rates in colorectal cancer and found that Lynch syndrome patients had an ORR between 46 and 71% after immune checkpoint-based therapy.8,19 Two of the articles presented data from the MK-3475 study covering three to six centers in the US (NCT01876511), in which Lynch syndrome-associated ORR were calculated in the study from Le et al,25 while individual Lynch syndrome cases could be extracted in the study from Le et al.19,25 In Le et al,19 eight Lynch syndrome patients with colorectal cancer were treated with pembrolizumab, of which two showed PR giving an ORR of 25% and six showed SD reaching disease control in 100% of the patients. In the updated paper from 2017, the Lynch syndrome-associated ORR had increased to 46%.25 The percentage of Lynch syndrome cases presenting with disease control was not specified in here, but 23% of the entire cohort (covering 86 patients) showed SD reaching disease control in 77% of the unselected MSI/dMMR cohort. Furthermore, mean time to response was 21 weeks and mean time for complete response was 42 weeks.25 Corresponding data from the sporadic MSI/dMMR cohort were only specified in the paper from 2015 with two colorectal cancer patients both showing PR (ORR=100%).19 Though similar data was missing in the updated paper from 201725 statistical analyses did not identify significant difference in ORR between Lynch syndrome and sporadic MSI/dMMR colorectal cancers (ORR of the entire study cohort was 52%). The CheckMate-142 study presented by Overman et al, which is a multicenter study covering 28 centers in eight countries, included 35 Lynch syndrome patients of which 25 patients showed objective response (ORR=71%).8 In comparison, sporadic (non-Lynch syndrome) MSI/dMMR colorectal cancers showed an ORR of 48%. No comparison was made between the two groups and lack of individual data restrained further analyses. For both clinical trials, sufficient follow-up to calculate PFS and OS was not reached, and not specified for Lynch syndrome and sporadic MSI cancers individually.

Investigating noncolorectal cancers, we found four studies with specified Lynch syndrome response data, three of which published from the Memorial Sloan Kettering Cancer Center, New York, USA.21,3133 Hu et al identified five Lynch syndrome patients in a retrospective cohort of 833 consecutively collected patients with pancreatic ductal carcinomas, of which three responded (ORR=60%) to anti-PD1/anti-PD-L1 drugsone with a mixed response involving a complete response followed by metastasis eight months later.33 The mean PFS of four cases with available data was 12.5 months, although the responses appeared after 22 and 24 months. No sporadic cases with an MSI phenotype were identified nor treated with immunotherapy. Abida et al, 2019 identified two Lynch syndrome patients among a prospectively collected cohort of 1033 patients with prostate cancer, of which one showed PR and the other had PD after anti-PD-1/anti-PD-L1 therapy.31 Likewise, Raj et al found two Lynch syndrome patients in a prospective phase II study of 39 patients with adrenocortical carcinomas; both showed PR and a mean PFS of 27.5 months when treated with pembrolizumab.32 In 2015, the MK-3475 study from Johns Hopkins University presented three Lynch syndrome-associated noncolorectal cancer patients with an ORR of 33%.19 In the updated cohort from 2017, this increased to 59%.25

At the American Society of Clinical Oncology (ASCO) in May 2020, Bari et al, presented a large retrospective study design, in which they aimed to describe the response rates in a Lynch syndrome cohort irrespective of tumor type.21 They identified 194 Lynch syndrome patients with different types of solid tumors, of which 22 had received treatment with immune checkpoint-based therapies. Of the 22 patients, two showed CR, one had PR, 13 had SD, and six showed PD giving an ORR of 14% and a disease control rate of 73%. In contrast to the other studies, treatment responses were measured irrespective of MSI status and showed continued response after nine months of treatment in one (out of three) microsatellite stable (MSS) Lynch syndrome tumors.21 Detailed PFS and OS were not calculated but 15 out of 22 patients showed continuous disease control or complete remission at 48 months of follow-up.

In summary, these studies identified 107 Lynch syndrome cancer patients and individual response data could be collected from 77 cases (excluding Le et al).25 Thirty-six of these cases responded to treatment, giving a summarized ORR of 47% (63% for CRC and 29% for noncolorectal cancer). In comparison, summarized ORR for sporadic MSI colorectal cancer patients were 55% (17 out of 33) and 42% for sporadic MSI noncolorectal cancer patients (five out of 12). PFS was only reported in three studies (all regarding noncolorectal cancers) and summarized to 15.2 months for Lynch syndrome cancer patients.

Next, we reviewed the Lynch syndrome cancer case reports. Twenty-four case reports covering 26 patients (three with multiple cancers) presented treatment response. Two cases were presented in two papers each, but since data was overlapping the studies were merged to two case reports.18,2224 In contrast, one study presented to cases with two different types of MSI cancers and was for simplicity presented as two separate cases (Table 2).26 Cancer center, country, MMR gene affected, immune checkpoint-based treatment, therapeutic setting, and outcome results for the 26 unique cases are presented in Table 2. Two of the studies did not present data on the MMR gene test analyses nor the MMR variant identified in the patients, and it remains uncertain how Lynch syndrome was diagnosed in these individuals.28,29 The cases were identified in USA (N=13), Canada (N=3), China (N=3), Japan (N=2), France (N=1), Chile (N=1), UK (N=1), Brazil (N=1), and Australia (N=1). The responses were evaluated using the RECIST criteria (N=13), pathologic complete response with no viable tumor cells after surgery (N=2), tumor decrease with unknown percentage of decrease (N=7), clinical response with proceeded treatment due to no or little tumor progression (N=2), and as a decrease in prostate specific antigen (PSA) (N=2).

The case reports either presented cases with clinical responses/disease control (N=21), or disease progression (N=4), or cases with two primary tumors, of which one progressed and the other responded (N=1). The majority of studies presenting positive treatment responses may indicate publication bias as these cases are more likely to be published.

In summary, 10 cases were included with a colorectal cancer (three with multiple cancers in other organs as well) and one patient with liver metastases from a previously removed colorectal cancer.18,24,26,28,29,3438 Two cases obtained CR, two showed PR, three had SD, and three showed PD giving an ORR of 40% and disease control rate of 70%. All the patients, who showed positive response, were given immunotherapy as first (N=3) or second (N=1) line treatment. The mean PFS was 14.9 months with a mean time to response of 13.3 months. As only one patient died one month after treatment end,18,24 PFS was equal to OS in these cases.

Investigating noncolorectal cancers, 21 MSI/dMMR Lynch syndrome-associated solid tumors developed (three glioblastoma multiforme, four pancreatic cancers, three ureteral cancers, two lung cancers, two prostate cancers, two adrenocortical carcinomas, two bladder cancers, one endometrial cancer, one rhabdomyosarcoma, and one intrahepatic cholangiocarcinoma).18,2224,26,34,3849 Although it was not stated, it was considered highly likely that the pancreatic cancer showing PD at 22 months by Hu et al,49 was included in the large pancreatic cancer cohort study.33,49 However, in order to reduce publication bias, this case was included in the following summary. Among the 21 noncolorectal cancers, three showed CR, eight showed PR, eight had SD (two of which had decreased PSA levels as the only response data), and two experienced PD resulting in a summarized ORR of 53% and disease control in 90%. Mean PFS was 14.1 months with a mean time to positive response of 18.3 months. Again, OS was not reported for the majority of the studies as follow-up was ended at tumor progression or with PFS.

Irrespective of the cancer type, treatment lines of which the immune checkpoint-based therapy was introduced varied across the included studies with seven tumors receiving immunotherapy in first line, 14 in second line, seven in third line, and three in fourth line. Two cases received different regimens of immunotherapy due to local progression or adverse events with the selected treatment. A male 64-year-old Lynch syndrome carrier presenting with three urothelial cancers (bladder and bilateral ureter) and a liver metastasis 10 years after previously removed colorectal cancer was treated with pembrolizumab at the indication of dMMR in one of the urothelial tumors. At nine months, the patient was treated with atezolizumab based on progression of the urothelial cancers. The patient obtained eight months of disease control before progression of the liver metastasis. Pembrolizumab was reintroduced for three months until progression and the patient switched to combination therapy with nivolumab and ipilimumab resulting in tumor decrease after two months. The patient continued therapy with nivolumab alone with disease control for seven months. At this time, his bilirubin levels increased probably attributed to immunotherapy-related adverse events and the patient declined continued therapy and passed away one month later.18,24

The second case report presented a boy at 3.5 years with homozygous biallelic PMS2 pathogenic variants with a glioblastoma multiforme tumor in the frontal cortex that was surgically removed. Ten months later multinodular recurrence was observed, and he was treated with nivolumab with initial response. Six months later, a new nodal glioblastoma reoccurred at the primary surgical site and ipilimumab was added to the nivolumab treatment for four doses. Significant response was observed after three months (nine months from first immunotherapy dose) and complete response was reached after one year. The patient continued on nivolumab for maintenance and magnetic resonance imaging confirmed CR 30 months from first glioblastoma recurrence and first immunotherapeutic dose.

Herein, we summarized the clinical responses among Lynch syndrome cancer patients treated with FDA- and EMA-approved checkpoint-based immune therapies. We identified 31 studies including 133 unique Lynch syndrome cancer patients. For Lynch syndrome, the large cohort studies showed ORRs between 4671% for MSI/dMMR colorectal cancers and 14100% for noncolorectal MSI/dMMR cancers. The corresponding ORRs for sporadic MSI/dMMR cancers were 48100% and 50100%, respectively. Summarizing the Lynch syndrome case reports, the ORRs were 40% and 53%, respectively. In addition, the only study investigating a systematic difference between Lynch syndrome and sporadic MSI cancers did not reach any significance. Together the data indicates that Lynch syndrome cancer patients may benefit from immune checkpoint-based therapy to the same extend as sporadic MSI/dMMR tumors, though the sample size is limited and confidence intervals large.

Since the approval of pembrolizumab as a tissue-agnostic drug against MSI/dMMR solid tumors, more than 100 clinical trials have been registered at ClinicalTrial.gov and are still ongoing, testing immunotherapy in a wide range of solid tumors. Many of these studies select tumors based on MSI or dMMR status, but only a few studies choose to investigate hereditary germline MMR variants and even fewer to report the outcome data according to germline MMR status. One of the pioneering studies within this field is Le et al, who showed that Lynch syndrome cancer patients had an ORR of 27% compared to an ORR of 100% for sporadic MSI tumors.19 The reduced response rate observed in these preliminary results is hypothetically supported by molecular differences between the sporadic and hereditary MSI tumors, including different immune evasion mechanism affecting, eg, the antigen processing and presentation pathway.1416 However, the updated study from Le et al,25 reported no significant difference in response rates between the two subsets though separate ORRs for sporadic or Lynch syndrome MSI/dMMR tumors are not reported. The PFS and OS measures are still not complete and separate data for these groups is awaited.

Although many of the immune-checkpoint-based drugs are not approved for MSI/dMMR noncolorectal solid tumors, the case reports and cohort studies presented in here show that Lynch syndrome cancer patients may be potential candidates for such treatments. Complete responses (five out of 26 cases) were reported in advanced rectal cancer, glioblastoma, muscle invasive bladder cancer, and cases with lung metastases, albeit these stories may be more likely to get published than negative findings.22,43,45 It remains very important to publish Lynch syndrome cancer cases with resistance or tumor progression in response to immune checkpoint-based therapy as these tumors may evade the immune system through alternative routes. One such case was presented by Hu et al,49 in which mutation analyses was conducted on the primary pancreatic cancer and the ovarian metastasis. IImmunoediting was suspected to be the cause of acquired resistance, but no mutations were found in the antigen processing and presentation genes, eg the HLA genes, B2M, JAK1, JAK2, PTEN, or TAP1.49 Future molecular studies revealing the genetic makeup of resistant tumors are needed to elucidate why some Lynch syndrome tumors may not respond to immunotherapy.

The majority of the cases presented here were offered immunotherapy due to an MSI phenotype. It is important to note that while dMMR is largely associated with MSI in Lynch syndrome colorectal (98%)50 and endometrial (94%)51 cancers, the concordance is much lower for other Lynch syndrome cancer types such as urothelial cancer (23%)52 and brain tumors (0%).53 In accordance with this, an MSS phenotype has been found in 36% of Lynch syndrome tumors, with associations to noncolorectal, nonendometrial tumors and MSH6 and PMS2 gene variants.54 Abida et al, presented one case with prostate cancer and an MSH6 germline pathogenic variant, but due to an MSS phenotype this patient was not treated.31 In contrast, Bari et al, reported one MSS Lynch syndrome tumor that had continued response at nine months, but immunohistochemical dMMR was not reported in this abstract.21 Though data is still scarce, it is possible that thorough molecular diagnostics, eg, both dMMR and MSI in addition to deeper analyses such as tumor mutation burden, may help guide treatment decision.21,25,31

Tumor mutation burden may add valuable knowledge in the selection of Lynch syndrome patients to immunotherapy, although this has only been investigated and associated with positive responses in some of the included case reports.29,31,32,49 Two cases with locally advanced rectal cancer showed high tumor mutation burden and experienced complete pathological response,29 while two of the cohort studies only associated high tumor mutation burden with MSI status and did not use it as an independent indicator for treatment response.29,31,32 In contrast, a recent case study reported discrepancies between MSI and tumor mutation burden.55 Two Lynch syndrome cancer patients: one with a dMMR and MSI hepatic cholangiocarcinoma and one with a dMMR but MSS neuroendocrine carcinoma were treated with nivolumab in combination with ipilimumab and pembrolizumab, respectively, and both progressed after three cycles of treatment. The authors suspected that the resistance was caused by lack of neoantigen presentation as these tumors showed low tumor mutation burden.55 Yet, the nonresponsive pancreatic cancer reported by Hu et al, presented with a high tumor mutation burden with massive tumor-infiltrating lymphocytes.49 These data emphasize the tumor heterogeneity and lack of solid molecular markers to select responsive cases. To this end, we may add that it is possible that MSS tumors appearing in Lynch syndrome cancer patients may simply not arise from the pathogenic germline MMR variants, and that the specific MMR gene mutated as well as the mutation type may affect cancer risk and survival.56,57 It is possible that the type of mutation may affect the tumor mutation burden and the number of neoantigens presented, hypothetically triggering the immune system differently and affect responses to treatment with immune checkpoint inhibitors.

Owing to scarce Lynch syndrome specific response data, we included case reports in our review. The majority of these cases presented with positive treatment responses indicating publication bias. Hence, these results should be interpreted with caution. However, the summarized ORR from all the cases was 40% for colorectal cancer and 53% for noncolorectal cancers, which is in alignment with the Lynch syndrome-specific ORR presented in the larger cohort studies (ORRs between 46 and 71% for colorectal cancers and between 14 and 100% noncolorectal cancers). Another limitation to this study is the inclusion of eight individuals with VUS alterations. These individuals have previously been categorized as Lynch-like or unexplained MMR deficiency, as they may be caused by biallelic somatic MMR mutations within the tumor.58,59 Though these tumors may mimic Lynch syndrome tumors with an MSI phenotype, the colorectal cancer risk is somewhat lower compared to Lynch syndrome carriers of pathogenic variants.59 Specific response data were not reported according to MMR variants in the unselected cohort described by Le et al,25 but focusing on the case reports with VUS individuals, we observed ORRs of 0% and 50% for colorectal and noncolorectal cancer, respectively. The corresponding numbers were 17% and 53% for verified pathogenic MMR gene variant carriers.

Despite the fact that data is still scarce, we have found that Lynch syndrome cancer patients may benefit from immune checkpoint-based therapies and that no difference in the response rates has been reported to date between Lynch syndrome and sporadic MSI cancer patients. It remains unknown, however, why some Lynch syndrome cancer patients do not respond to immune checkpoint-based therapies and thorough molecular profiling including dMMR, MSI, tumor mutation burden, and immunoediting driver mutations may aid in the selection of patients, who are more likely to respond. Until the routes of resistance are clarified, it is encouraged to report Lynch syndrome-specific outcome data from the large clinical trials.

The authors would like to acknowledge the medical librarian Jette Frost, Aalborg University Hospital, for assisting in the different database searches.

Dr Lars Henrik Jensen reports he is an investigator for clinical trials run by MSD, BMS and INCYTE. All payments are to institution for the work performed, outside the submitted work. The authors report no other conflicts of interest in this work.

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53. Gylling AHS, Nieminen TT, Abdel-Rahman WM, et al. Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis. 2008;29:13511359. doi:10.1093/carcin/bgn133

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56. Dominguez-Valentin M, Sampson JR, Seppl TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med off J Am Coll Med Genet. 2020;22:1525.

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Immune checkpoint therapy for treatment of Lynch syndrome | CEG - Dove Medical Press

High school students planning their careers in the nascent and already booming longevity ... [+] biotechnology industry. Promoting women in longevity at AgingPharma.org, the world's largest non-profit conference on aging research in the pharmaceutical industry.

Have you ever wondered why all of us age? Is aging really just a natural process of life or can it be delayed? Are we predestined to live a certain number of years or do we just wear out over time? According to data provided by the World Health Organization, the global life expectancy increased by over 6 years between 2000 and 2019 from 66.8 years in 2000 to 73.4 years in 2019. Is this the best we can do? Or can we use science and research to extend our lifespan?

Aging research is becoming a trend and is rapidly being commercialized. The field is also gaining scientific and investor credibility. Just like in physics or math, some students are planning a career in aging research from a very early age. Some of these students dream about a bright future without aging and disease, while others take a more pragmatic view and see it as the hottest area in biomedical research with infinite possibilities.

Today, I interviewed participants of the 8th Aging Research & Drug Discovery (ARDD) Inspire Longevity program; the high-school seniors who are planning a career in aging and longevity, and the program leaders who are graduate students at the University of Copenhagen.

I was pleasantly surprised that all of the students in the program were female who knew the material and already did some research in this area.

Harsehaj Dhami, a 16-year-old student in Toronto, told me she is interested to learn how aging can be used to tackle diseases. She said she wants to use artificial intelligence in order to improve the access to education for children with hearing impairment. Andrea Olsen, another 16-year-old, is considering taking a neuroscience approach to longevity in order to advance her research on tackling neurodegeneration for a healthy longevity.

A further high-schooler, Nina Khera, wants to look at longevity through the lens of machine learning and computer programming-based approaches.

I was also pleasantly surprised that all of them are planning to do academic research and then go into industry.

Harsehaj wants to run her own company some day and develop medicine and technology that help in slowing the aging process.

Meanwhile, Andrea collects data and information through her various internships. Nina, on the other hand, likes to create puzzles around her research ideas.

All three high-schoolers want to transfer into the industry and perpetuate science from that platform in order to help commercialize aging research and bring it closer to the patients.

I was happy to interview them and get inspired by how enthusiastic they are in joining aging research. I think now is a great time to join aging research. 20 years ago, was too early. 10 years ago, was a good time. But there isnt a better time to join aging research other than right now.

Aging research is likely to result in a very rewarding, vibrant, stimulating and impactful career that can start in academia and branch into the industry.

Simply put, it is a great time to enter the field!

At the ARDD meeting, the participants will be able to meet prolific academics, pharmaceutical company executives, longevity physicians, entrepreneurs, or government officials, and ask these questions directly, either in person or virtually.

The ARDD is also a great opportunity to present yourself and show initiative, ambition, and skill. And you can also meet your fellow students who have similar ambitions and questions to form long-lasting friendships and support groups.

To help me with this interview and provide a clinicians perspective, I invited Dr. Evelyne Yehudit Bischoff, a longevity physician. Dr. Bischoff is co-chairing the Longevity Medicine workshop at the ARDD.

Interview with the members of Inspire Longevity program - high school students planning their ... [+] careers in longevity biotechnology

Alex Zhavoronkov: As participants of the 8th Aging Research & Drug Discovery (ARDD) Student Ambassador Program, we are all interested in longevity. Maria and Esther will supervise the program while I will advise and navigate the program. Let's start with a round of introductions to get to know each other better.

Maria Thaysen: Im studying for a masters degree in molecular biomedicine at the University of Copenhagen. Im currently conducting research for my thesis in the Morten Scheibye-Knudsen lab. The goal of my thesis is to investigate an in vivo model of a premature aging disorder. Esther and I are coordinating the ARDD program.

Esther Meron: I'm also a master's student at the Morten Scheibye-Knudsen lab. I'm currently conducting research for a master's in Pharmaceutical Science. My research is focused on drugs that modulate DNA repair.

Harsehaj Dhami: I'm a 16-year-old student in Toronto and Im interested in how aging can be used to tackle diseases. Im also interested in how health span can be extended along with lifespan. Aside from longevity and science, I'm interested in the field of artificial intelligence as well as how we can use AI to improve the access to education for hard of hearing children.

Andrea Olsen: I'm a 16-year-old as well and I go to school in England. I'm interested in longevity as well as neurobiology. I'm considering taking a neuroscience approach to longevity in order to further my research.

Nina Khera: I'm also very interested in aging and longevity. My research is centered on mapping cells and their features with machine learning in order to find different features in their mitochondria. I'm also interested in neuroscience and looking at aging when it ceases. I love AI and different computer programming-based approaches.

Alex: Evelyne, since you are organizing the longevity medicine workshop at the 8th ARDD, perhaps you can provide an introduction as well.

Evelyne: I'm based in Shanghai right now but Im from Germany. I made my way through several continents as a medical student and medical resident fellow and I now work as an academic and clinical medical doctor. I have a strong interest in longevity medicine and in bringing our innovative and scientific backgrounds into clinical medicine.

Alex: Great! Lets start the discussion on why you decided to go into aging research and longevity? And how do you plan on pursuing your research?

Maria: I came into longevity or aging research because it allows me to combine my interest in neurology and DNA repair in a way I haven't seen in other areas of science. After completing my master's this summer, I'm thinking about doing a PhD in aging research. I want to continue with the aspects of in vivo modelling because it makes it more approachable and is relatable to human diseases. I hope Ill join the industry in the future because the industry has more resources to conduct clinical trials and research interventions.

Alex: How do you see the industry 15 years from now?

Maria: I think there will be some drugs in the market that can slow down the aging process to an extent. I don't think the drugs will stop the aging process; but it's probable that we will be able to extend our lifespan by a couple of years. I think we see glimpse of this now with drugs like Metformin.

Esther: I got into aging research after having researched different age-related diseases, such as Alzheimer's disease and cardiovascular disorders. I think it is interesting to look at aging as an underlying factor. In the future, Id like to gain more experience in basic laboratory research. Ill likely also join the industry eventually.

Alex: Esther and Maria are both planning to go into the industry. How do you see the future in aging research?

Esther: I think we will understand aging more and that will enable us to understand age related disorders. Hopefully we will be able to create new drugs against various age-related disorders by understanding aging itself.

Alex: Thats very interesting. Okay high schoolers, who wants to take a shot at answering the question?

Harsehaj: I never really liked science until I took a webinar on gene editing during March break. It was like a light bulb went off in my head because I thought Whoa! Science is cool.I then looked at where we can actually apply gene editing. So, I started looking at aging with a genetic engineering approach. From there, I moved to solving diseases related to aging with the gene editing approach. And that's where I plan to pursue my research. In the future, I want to go into engineering with medicine and technology. I'm also interested in AI so I want to go somewhere where I can create things with technology and science.

Alex: And how do you see your career path? Are there any possible alternatives?

Harsehaj: There are a few alternatives. The ideal for me is to run my own company and develop either medicine or technology that helps in slowing the aging process. Another possibility is to take the research route and dive deep into understanding the different hallmarks of aging. These are the two paths I'm thinking about.

Andrea: My interest in longevity sparked when I noticed that a common fear that people have is loosing time and approaching the end of their life. As a natural problem solver, I though about the possibility of making some molecule, some elixir of youth that you could drink to stay young, and I started looking at different diseases that contribute to shorter lifespans. Most of these are cancer. I realized that aging is different than cancer and that it's a natural process of cellular life, which we have managed to slow down through treating diseases and changing our lifestyle. I'm deeply interested in understanding exactly this and what can be done to slow down the physical process of not only full organism aging, but single cell aging.

At the moment, I'm trying to gather as much information from sources as possible and interning with some places, for example, with the Atlas Biomedicine Genetics and Oncology Department. I think that longevity is going to be a topic on the rise in the future. I would like to understand longevity from the point of view of neuroscience because these fields are really important at the moment. More specifically, I want to understand how the brain, mind and consciousness have different effects on longevity.

Nina: I got into longevity because my relatives went through some aging related diseases when I was younger and I didn't know what exactly had happened. I realized then that I want to do something about it. So, when I was 12, I started thinking about longevity and the aging process. I began by looking into whatever material I came across regarding longevity and aging. Once I started looking deeper, I noticed that aging is a central cause of many diseases. I had some research ideas as my interest progressed and I began to create puzzles around them. I want to further my interest in this field. I really like start-ups and entrepreneurship, so I think I want to go into the industry in the future. My goal is to stop brain aging.

Alex: I think its phenomenal that everybody here wants to go into the industry. Evelyne, it would great if you can tell us a little bit about your career path. Because in addition to the industry, there is also medicine and some of you might want to consider a career in medicine as well.

Evelyne: I remember myself when I was 16 and I was at the same crossroads as some of you. I faced the same questions as you. Where do you want to go? Where do you want to be? I was really fascinated by gene engineering at that time so I also looked at gene editing back when it was extremely preliminary. I used to have Craig Venter hanging on my wall as I didn't have a lot of mentors at that time. But one person told me that if you would like to one day really drive changes in people, then open your doors a little bit more and go and study medicine.

Being an MD doesn't necessarily mean that you are always bound to the clinic or that you have no access to whatever the industry is offering, especially in the longevity field. Its the opposite. In my opinion, physicians are crucial for this field to develop and to evolve. The industry will need the support and leadership of the physicians to translate what the industry will offer to the patients, in the right way. Being a physician in the short term now will also require working closely with AI.

I find it fascinating and fantastic what you are doing in high school in addition to all of the obligations that you have. So please continue to pursue it. At your age, being curious and hungry for knowledge is the best thing you can do.

Alex: By the way, Nina, kudos on the blogs that you write. I think its very important to disseminate the information you collect. Are you still writing them?

Nina: I have been writing articles for Lifespan IO. Many of these have been focused on recent research in the longevity area.

Alex: What do you like most about ARDD and how do you think this program will help advance your career? In addition, who would you like to interview on ARDD and why?

Harsehaj: I like ARDDs mission of spreading information to people and of addressing public opinion of longevity. I would like to interview David Sinclair because I watched his TED talk about aging when I was first introduced to the subject. Ive read his book as well and have been following up on whatever he's been up to. He's a big role model for me.

Nina: I completely agree. David Sinclairs TED talk was one of my first exposures too. I think ARDD is cool because I believe longevity needs more people since there are many Venture Capital funds willing to fund longevity. It is only a matter of how we get people into this industry; and how we get people to think of ideas to fund. I think this is an amazing mission that I'd be happy to support.

In terms of how it will advance my career, I'm just really excited to learn from all the speakers. I'd love to interview Dr. Judith Campisi. Her paper on Senescence cells caught my interest.

Andrea: I think it's important to learn from people who are really proud of this field and are specialists in it. I also think it's important to listen to a range of people since everyone has their own ideas and approaches to things. In terms of people who Im interested in interviewing, I would say Laura Deming. She is a young researcher and may have some tips or suggestions for young people like us.

Alex: Alright, so we need to invite Laura Deming as a highlight of the program! Maria, Esther and Evelyne, if you were to wind back the clock, five or ten years ago, what would you do better to formulate your career?

Maria: I would not have changed anything because I've been involved within aging research throughout my university career.

Alex: Esther, would you have changed anything?

Esther: I agree with Maria. No, I don't think I would change anything. I come from a pharmaceutical background and only recently got into aging during the last year of my master's for my thesis. I think that brought a different perspective for me.

Alex: That's great to hear! Kudos to Morten because it means that if people go into his lab, they do not have any regrets. What I regret is that I did not go into longevity science right away.

Evelyne: I would change several things in my career path after looking from a different perspective. I would have intensified my learning of Chinese language since the future is in China. China is the center of innovation.

Coming from the medical field, I believe that in the past, there were some restrictions in academia that might have hindered physicians from learning about other fields. We were also far away from the industry, which is now a disadvantage because at some point you see many radical changes that are out there that you can implement to your patients. I would have thus started to look into the field of longevity much earlier.

Alex: So, any questions for the program managers?

Nina: Im curious to know at what stage should you understand that youre ready and able to create your own business or your own company? What sort of things help you and what things set you back in that process?

Alex: I think theres never a right time to start, so any time is the right time. I think that the right time to start a business in this industry would be after youve completed your doctoral studies and have worked in a research capacity for some years.

Evelyne: Were there some things that were really helpful for you?

Alex: I think my previous career in IT helped a lot. A knowledge of computer science and experience with algorithms and writing code helped later when I got into AI for drug discovery.

It also helped to have some business education and working in teams, learning leadership, learning operations, and accounting helps too. I recommend taking courses in project management, operations and consulting so youll know how to find optimal supply and demand as well as to find new solutions to problems. One of the major downsides of my career path is that I did not go into biomedicine right away and had to hack my way in. The absence of this academic credibility and knowledge of the many basics of biomedicine really hurt at the very beginning. So, you really need to be in this industry, know a lot of people, know who is who. Any other questions?

Evelyne: How do you know if you want to go into academia or business or the industry?

Alex: Maybe Maria or Esther might want to take a shot at this question?

Esther: I think for a lot of people, whether you go into academia or the industry, you get to do very similar things. There's so much of it in both places. For me, it's knowing that either way it'll be research and I'll be contributing to the medical field, whether that's at a university or at the industry.

Evelyne: What was helpful for me, was that I was very certain that my goal is my path. There are many opportunities to experience the industry for a little while. And at the end of the day, I think you swing between industry and academia if you pursue both on some level.

Alex: I think it's important to have the industry perspective at all times because regardless of whether you decide to take the academic path, it's important to know how your research is going to be used later on. So even when you're talking about target sciences, target discovery, formulating the disease hypothesis, formulating the hypothesis for a basic biological aging process, you need to keep in mind about what will happen with your research after it is published.

Thank you for starting your journey in this exciting field. What excites me the most is that most of you see this field as the high potential industry in the future!

The ARDD meeting will take place from August 30 to September 3rd in Copenhagen and Online. The meeting is non-profit and is organized by the University of Copenhagen in partnership with the Columbia University, and Insilico Medicine http://www.AgingPharma.org.

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High School Students Preparing To Join The Fight Against Aging - Forbes

PITTSBURGH, May 12, 2021 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc. (Nasdaq: NBSE) ("NeuBase" or the "Company"), a biotechnology company accelerating the genetic revolution with a new class of precision genetic medicines, announced today the appointment of Gerald (Gerry) J. McDougall to the Company's Board of Directors. For more than 25 years, Mr. McDougall has been the driving force behind large-scale strategic alliances, joint ventures, and industry partnerships across the healthcare industry to advance innovations in precision medicine and cancer.

"Gerry's deep expertise, passionate commitment to improve the human condition, and vast network have been the foundation for numerous transformational alliances in life sciences and healthcare, and his ability to create synergistic combinations of people, ideas, and resources is exceptional," said Dietrich A. Stephan, Ph.D., Founder, CEO and Chairman of NeuBase. "The Board and I look forward to working closely with Gerry as we advance NeuBase's comprehensive approach to precision genetic medicine to address previously untreatable diseases."

"Genetics are the foundation for understanding and treating rare and common diseases including cancers, and the ability to precisely modulate gene function is key to developing new medicines for the many diseases that still have no treatment options," said Mr. McDougall. "I have dedicated my career to coalescing divergent approaches to achieve precision care, and I believe NeuBase can unify the field of precision genetic medicine with its PATrOL technology platform."

Mr. McDougall spent almost his entire career as a senior partner at PwC where he built and led the firm's Global Health Science consulting practice before retiring. He has worked across the entire ecosystem of the healthcare industry and advised an array of Fortune 500 companies, including leading global pharmaceutical companies. Mr. McDougall has been instrumental around the globe in building public-private partnerships to address human health imperatives. These include the creation and maturation of the Translational Genomics Research Institute (TGen), Arizona's renowned bio-cluster; the design and launch of the Multiple Myeloma Research Consortium (MMRC); the strategic plan for the California Institute of Regenerative Medicine (CIRM) and the Country of Luxemburg's biotechnology commercialization ecosystem.

About NeuBase Therapeutics, Inc.NeuBase is accelerating the genetic revolution by developing a new class of precision genetic medicines which can be designed to increase, decrease, or change gene function, as appropriate, to resolve genetic defects that drive disease. NeuBase's targeted PATrOL therapies are centered around its proprietary drug scaffold to address genetic diseases at the DNA or RNA level by combining the highly targeted approach of traditional genetic therapies with the broad organ distribution capabilities of small molecules. With an initial focus on silencing disease-causing mutations in debilitating neurological, neuromuscular, and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions. To learn more, visit http://www.neubasetherapeutics.com.

Use of Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements are distinguished by use of words such as "will," "would," "anticipate," "expect," "believe," "designed," "plan," or "intend," the negative of these terms, and similar references to future periods. Forward-looking statements include, among others, those related to the anticipated strategic guidance and assistance that the Company's new director will provide to support the Company's comprehensive approach to precision genetic medicine to address previously untreatable diseases. These views involve risks and uncertainties that are difficult to predict and, accordingly, our actual results may differ materially from the results discussed in our forward-looking statements. Our forward-looking statements contained herein speak only as of the date of this press release. Factors or events that we cannot predict, including those risk factors contained in our filings with the U.S. Securities and Exchange Commission (the SEC), may cause our actual results to differ from those expressed in forward-looking statements. The Company may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Because such statements deal with future events and are based on the Company's current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of the Company could differ materially from those described in or implied by the statements in this press release, including: the Company's plans to develop and commercialize its product candidates; the timing of initiation of the Company's planned clinical trials; the timing of the availability of data from the Company's clinical trials; the timing of any planned investigational new drug application or new drug application; the Company's plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of the Company's product candidates; the Company's commercialization, marketing and manufacturing capabilities and strategy; global health conditions, including the impact of COVID-19; the Company's ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all, as well as those risk factors contained in our filings with the SEC. Except as otherwise required by law, the Company disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

NeuBase Investor Contact:Dan FerryManaging DirectorLifeSci Advisors, LLCdaniel@lifesciadvisors.comOP: (617) 430-7576

NeuBase Media Contact:Jessica Yingling, Ph.D.Little Dog Communications Inc.jessica@litldog.com+1 (858) 344-8091

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NeuBase Therapeutics Appoints Gerald J. McDougall to Board of Directors - BioSpace

- Intracochlear delivery of a dual AAVAnc80 vector encoding human otoferlin results in full-length protein expression in inner hair cells of non-human primates and in durable protein expression sufficient for sustained restoration of auditory function in Otof knockout mice

- Multiple analyses demonstrate in vitro transduction with dual AK-OTOF vector results in full-length otoferlin expression, with no detection of truncated proteins

- Long-term, local expression of anti-VEGF protein is robust and well tolerated following intracochlear administration of AK-antiVEGF in non-human primates

- Akouos continues to progress towards planned IND submissions for AK-OTOF in the first half of 2022 and for AK-antiVEGF in 2022

BOSTON, May 11, 2021 (GLOBE NEWSWIRE) -- Akouos, Inc. (NASDAQ: AKUS), a precision genetic medicine company dedicated to developing potential gene therapies for individuals living with disabling hearing loss worldwide, today presented nonclinical data supporting the future clinical development of both AK-OTOF, a gene therapy intended for the treatment of otoferlin gene (OTOF)-mediated hearing loss, and AK-antiVEGF, a gene therapy intended for the treatment of vestibular schwannoma, in three digital presentation sessions at the virtual American Society of Gene and Cell Therapy (ASGCT) 24th Annual Meeting.

We are excited to share new data that highlight the potential of genetic medicines for inner ear conditions with the broader gene therapy community, said Manny Simons, Ph.D., M.B.A., co-founder, president, and chief executive officer of Akouos. Inner ear conditions represent one of the largest areas of unmet need in medicine today, and one of the challenges in this area is the ability to efficiently address the broad range of conditions that collectively affect hundreds of millions of individuals worldwide. The nonclinical data presented today for the AK-OTOF and AK-antiVEGF programs demonstrate how we are leveraging our genetic medicines platform and multiple AAV-mediated modalities, including gene transfer and therapeutic protein expression, to begin to address that challenge.

Nonclinical data presented at ASGCT for AK-OTOF continue to support the potential to restore physiologic hearing and provide long-lasting benefit to individuals with OTOF-mediated hearing loss. In Otof knockout mice, AK-OTOF administration results in durable expression of human otoferlin protein sufficient for sustained restoration of auditory function. In addition, data presented indicate that expression of exogenous secreted protein at or above reported biologically active levels, driven by a ubiquitous promoter, is well tolerated in non-human primates following administration of AK-antiVEGF. These IND-enabling nonclinical studies are promising and support future clinical development. Our team continues to work towards submission of INDs for AK-OTOF and AK-antiVEGF expected in 2022, said Greg Robinson, Ph.D., chief scientific officer of Akouos.

In Vitro and In Vivo Analyses of Dual Vector Otoferlin Expression to Support the Clinical Development of AK-OTOF (AAVAnc80-hOTOF Vector)

Presenting Author: Eva Andres-Mateos

Abstract Number: 355

Otoferlin plays a critical role in exocytosis of synaptic vesicles at the inner hair cell synapse, and mutations inOTOF, the gene encoding otoferlin, are associated with autosomal recessive sensorineural hearing loss. AK-OTOF is designed to deliver normal OTOF by utilizing a dual vector approach,which encodes the 5 and the 3 components of OTOF. Multiple analyses demonstrate in vitro transduction with dual AK-OTOF vector results in full-length human otoferlin (RNA and protein), with no detection of truncated proteins from either AK-OTOF or its component vectors (5hOTOF and 3hOTOF). A one-to-one ratio of the AK-OTOF component vectors appears to be optimal for efficient reconstitution of full-length human otoferlin. In cynomolgus macaques, full-length human otoferlin protein expression is detected in inner hair cells of non-human primate (NHP) cochleae by both immunohistochemistry and immunodetection one month following intracochlear administration of AAVAnc80-FLAG.hOTOF.

The digital presentation is located at https://akouos.com/gene-therapy-resources/.

Durable Recovery of Auditory Function Following Intracochlear Delivery of AK-OTOF (AAVAnc80-hOTOF Vector) in a Translationally Relevant Mouse Model of Otoferlin Gene (OTOF)-Mediated Hearing Loss

Presenting Author: Ann Hickox

Abstract Number: 569

Otoferlin gene (OTOF)-mediated hearing loss is caused by mutations in the OTOF gene and is typically characterized by a congenital, Severe to Profound sensorineural hearing loss. The physiologic deficiency resulting from OTOF mutations is localized; specifically, synaptic transmission between the inner hair cell and the auditory nerve is affected, as measured by an absent or abnormal auditory brain stem response (ABR). Gene therapy for OTOF-mediated hearing loss is expected to confer the greatest benefit when cochlear integrity is preserved, as represented by present otoacoustic emissions (OAEs). Individuals with OTOF-mediated hearing loss typically experience a decline in cochlear integrity within the first decade of life, indicated by initially present, then absent, OAEs. In an Otof knockout mouse model that recapitulates the human phenotype, administration of AK-OTOF, an adeno-associated viral gene therapy vector encoding human otoferlin under the control of a ubiquitous promoter, results in durable restoration of auditory function, as measured by ABRs, and may preserve OAEs.

The digital presentation is located at https://akouos.com/gene-therapy-resources/.

Demonstration of Tolerability of a Novel Delivery Approach and Secreted Protein Expression Following Intracochlear Delivery of AK-antiVEGF (AAVAnc80-antiVEGF Vector) in Non-Human Primates

Presenting Author: John Connelly

Abstract Number: 358

Data published from previous clinical trialsshow that systemic VEGF inhibitor therapy can reduce vestibular schwannoma (VS) tumor volume and improve hearing in some participants with mutations in the NF2 gene. However, toxicity limits the potential of this systemic delivery approach from being a viable treatment option for vestibular schwannoma. The exposure and tolerability of local expression of anti-VEGF protein following bilateral, intracochlear administration of AK-antiVEGF was evaluated through analyses of protein levels, as well as physiologic and histologic evaluations, in NHPs. Long-term, local expression of anti-VEGF protein, driven by a ubiquitous promoter, is robust and well tolerated in NHPs following intracochlear administration of AK-antiVEGF. Computational modelling supports the potential for diffusion of anti-VEGF protein at or above reported biologically active levels to the site of the VS tumor.

The digital presentation is located at https://akouos.com/gene-therapy-resources/.

About Akouos

Akouos is a precision genetic medicine company dedicated to developing gene therapies with the potential to restore, improve, and preserve high-acuity physiologic hearing for individuals living with disabling hearing loss worldwide. Leveraging its precision genetic medicine platform that incorporates a proprietary adeno-associated viral (AAV) vector library and a novel delivery approach, Akouos is focused on developing precision therapies for forms of sensorineural hearing loss. Headquartered in Boston, Akouos was founded in 2016 by leaders in the fields of neurotology, genetics, inner ear drug delivery, and AAV gene therapy.

Cautionary Note Regarding Forward-Looking Statements

Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to the initiation, plans, and timing of our future clinical trials and our research and development programs, the timing of our IND submissions for AK-OTOF and AK-antiVEGF, our expectations regarding our manufacturing capabilities and timelines, and the period over which we believe that our existing cash, cash equivalents and marketable securities will be sufficient to fund our operating expenses. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, should, target, will, would, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: our limited operating history; uncertainties inherent in the development of product candidates, including the initiation and completion of nonclinical studies and clinical trials; whether results from nonclinical studies will be predictive of results or success of clinical trials; the timing of and our ability to submit applications for, and obtain and maintain regulatory approvals for, our product candidates; our expectations regarding our regulatory strategy; our ability to fund our operating expenses and capital expenditure requirements with our cash, cash equivalents, and marketable securities; the potential advantages of our product candidates; the rate and degree of market acceptance and clinical utility of our product candidates; our estimates regarding the potential addressable patient population for our product candidates; our commercialization, marketing, and manufacturing capabilities and strategy; our ability to obtain and maintain intellectual property protection for our product candidates; our ability to identify additional products, product candidates, or technologies with significant commercial potential that are consistent with our commercial objectives; the impact of government laws and regulations; risks related to competitive programs; the potential that our internal manufacturing capabilities and/or external manufacturing supply may experience delays; the impact of the COVID-19 pandemic on our business, results of operations, and financial condition; our ability to maintain and establish collaborations or obtain additional funding; and other factors discussed in the Risk Factors included in the Companys Annual Report on Form 10-K for the year ended December 31, 2020 filed with the Securities and Exchange Commission, and in other filings that the Company makes with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contacts

Media:Katie Engleman, 1ABkatie@1abmedia.com

Investors:Courtney Turiano, Stern Investor RelationsCourtney.Turiano@sternir.com

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Akouos Presents Nonclinical Data Supporting Future Clinical Development of AK-OTOF and AK-antiVEGF at the American Society of Gene and Cell Therapy...

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Study to look for genetic pathways that lead to formation of plaques, tangles

A $10.7 million, five-year grant will support a comprehensive study in which whole genome sequencing will be used to address critical gaps in knowledge about Alzheimer's disease. The project is led by researchers at Washington University School of Medicine in St. Louis and the University of Pittsburgh Graduate School of Public Health.

Despite decades of research and investment, the genetic underpinnings of Alzheimers disease are still largely unknown, stymieing efforts at drug development and early diagnosis. To change that, a new grant will support the first comprehensive study to use whole genome sequencing to address critical gaps in knowledge about the disease. The $10.7 million, five-year project is led by researchers at Washington University School of Medicine in St. Louis and the University of Pittsburgh Graduate School of Public Health.

Funded by the National Institute on Aging of the National Institutes of Health (NIH), the research team plans to identify the genetic variants, genes and pathways that lead to formation of plaques and tangles, two specific signs of disease called biomarkers that begin appearing in the brains of people with Alzheimers 15 to 25 years before they show symptoms.

Cruchaga

Genetic studies of measurable traits such as plaques and tangles provide advantages over other classic case-control studies, because these traits appear earlier and are more closely related to the biology behind the disease, said Carlos Cruchaga, PhD, a co-principal investigator of the study and the Reuben Morriss III Professor of Neurology at Washington University School of Medicine. In addition, studying these traits is more likely to lead to the identification of druggable targets along the genetic pathways that lead to disease. This genetic information can help us better predict disease risk at the individual patient level.

Cruchaga, also a professor of psychiatry, is working with co-principal investigator Ilyas Kamboh, PhD, a professor of human genetics and epidemiology at Pitt Public Health. Together, they plan to study as many as 5,000 participants at high risk for Alzheimers. The researchers will gather biomarker data to identify genetic variants that appear decades before clinical symptoms of the disease.

All of the clinical trials to find a drug to stop Alzheimers disease have failed because theyve focused on patients who already have developed the disease, so they already had high levels of plaques and tangles, said Kamboh. Once you have the plaques and tangles, it seems to be an irreversible process, so were focused on the preclinical stage of the disease.

According to the World Health Organization, Alzheimers disease is the most common form of dementia, with about 50 million cases worldwide and 6 million new cases each year. It is one of the major causes of disability and dependency among older people.

The plaques and tangles in the brain associated with Alzheimers can be thought of like cholesterol in the arteries of the heart and its association with heart disease, Kamboh explained. Cholesterol can quietly accumulate over years along the walls of the coronary arteries without causing symptoms until it causes a heart attack and does irreversible damage to the heart. Some genes predispose people to accumulate more cholesterol, and understanding that can allow people to take medication and make lifestyle changes that reduce the risk of heart disease. It also can prompt pharmaceutical companies to develop drugs that target the genetic pathways that lead to the formation of cholesterol deposits.

The new project will look for the genetic underpinnings of the plaques and tangles known to define Alzheimers disease and that formed due to abnormal accumulation of amyloid beta and tau proteins, respectively. Both can be detected early in the brains of living people through neuroimaging and the testing of cerebrospinal fluid.

In the past, we could detect these plaques and tangles only after death, through a brain autopsy, Kamboh said. Now we can identify them while people are living.

But those imaging and fluid-collection techniques are expensive and can be invasive.

New methods are now being developed to detect the presence of abnormal amyloid beta and tau proteins in less expensive blood tests, Cruchaga said. We hope that by learning more about the genes associated with the plaques and tangles, we might uncover underlying pathways that lead to Alzheimers disease and discover potential drug targets.

This study is supported by the National Institute on Aging of the National Institutes of Health (NIH). Grant number R01 AG064877.

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

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WashU, Pitt awarded $10.7 million for Alzheimer's disease research Washington University School of Medicine in St. Louis - Washington University...

BETHESDA, Md., May 11, 2021 /PRNewswire/ -- The American College of Medical Genetics and Genomics (ACMG) has released an important new clinical practice resource from a global team of specialists in cancer genetics that will help inform the clinical management of patients who are at increased risk of breast cancer, pancreatic cancer and likely ovarian cancer.

"Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)"was published in ACMG's official journal, Genetics in Medicine.

PALB2(Partner and Localizer of BRCA2) germline pathogenic variants are associated with substantially increased breast cancer risk and smaller increased risk for pancreatic and ovarian cancer. Germline pathogenic/likely pathogenic (P/LP) variants in PALB2 were first associated with increased cancer risk in 2007 and clinical testing has been available since then. It has come to be considered as the third most important breast cancer gene after BRCA1 and BRCA2. Despite the emerging importance of this gene, there has been a dearth of resources to guide clinical management of women and men with PALB2 germline P/LP variants.

"PALB2 is sometimes referred to as 'BRCA3,' given its importance in risk of breast cancer. People who harbor a germline pathogenic or likely pathogenic variant in PALB2 face challenging questions, especially about their personal risk to develop cancers of the breast, ovaries and pancreas, and how to manage that risk. In developing this clinical practice resource, we sought to help guide patients and their treating providers to make the best possible decisions based on current high-quality peer-reviewed evidence and a worldwide network of practicing physicians with expertise in cancer genetics," said Douglas R. Stewart, MD, FACMG, co-author and past chair of the ACMG Professional Practice and Guidelines Committee.

Key recommendations include the following:

This Clinical Practice Resource concludes that this guidance is similar to those for patients with BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, it is lower in PALB2, so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine, as yet, unanswered questions, such as the risk of contralateral breast cancer and survival after cancer diagnosis.

"This new document is landmark for the ACMG in a couple of ways," said Marc S. Williams, MD, FAAP, FACMG, FACMI, president of the American College of Medical Genetics and Genomics. "First, it reflects a commitment of the ACMG to develop guidance for use of germline genetic information for the treatment of patients with cancer. Second, this represents the first of what we hope will be many guidance documents that reflect a diverse, global perspective. The working group included experts on PALB2 from around the world so that the guidance will have relevance for patients from diverse backgrounds receiving care in a variety of settings," he said.

The global team of authors for this new Clinical Practice Resource includes Marc Tischkowitz, MD, PhD, Judith Balmana, MD, PhD, William D. Foulkes, MBBS, PhD, Paul James, MD, PhD, Joanne Ngeow, MBBS, MPH, Rita Schmutzler, MD, Nicoleta Voian, MD, MPH, Myra J. Wick, MD, PhD, Douglas R. Stewart, MD and Tuya Pal, MD and the ACMG Professional Practice and Guidelines Committee. They are experts in clinical cancer genetics, breast and gynecologic surgery and medical oncology and practice in Australia, Asia, the United States, Canada, the United Kingdom and Europe.

About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical professional organization solely dedicated to improving health through the practice of medical genetics and genomics, and the only medical specialty society in the US that represents the full spectrum of medical genetics disciplines in a single organization. The ACMG is the largest membership organization specifically for medical geneticists, providing education, resources and a voice for more than 2,500 clinical and laboratory geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. ACMG's mission is to improve health through the clinical and laboratory practice of medical genetics as well as through advocacy, education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health. Four overarching strategies guide ACMG's work: 1) to reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG journal. ACMG's website, http://www.acmg.net offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Contact: Kathy Moran, MBA[emailprotected]

SOURCE American College of Medical Genetics and Genomics

http://www.acmg.net

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Global Team of Cancer Genetic Specialists Provides New Guidance for Individuals with PALB2 Gene Variants: ACMG Clinical Practice Resource to Help...