Category Archives: Human Genetics

LAS VEGAS, May 11, 2021 /PRNewswire/ -- Heligenics, Inc. today announced a new collaboration with The Jackson Laboratory (JAX). This joint project will make available the functional output of Variants of Unknown Significance (VUS) throughout key portion of the ERBB2 gene through the JAX Clinical Knowledgebase (CKB), a digital resource that connects clinicians and researchers around the globe in order to interpret complex cancer genomic profiles.

"This is a fabulous partnership that will help modernize and expand variant interpretation for key cancer genes," says Dr. Martin R. Schiller, CEO at Heligenics. "JAX is bringing a lot to the table and is a valued partner."

Heligenics' proprietary GigaAssay process measures causal functional impact of all mutants in a gene in 4 to 5 months while it takes other technologies decades to identify just a single marker. This collaboration will lead to future clinical trials, research grants, and publications to advance the fight against cancers, offering patients hope by identifying actionable ERBB2 variants for potential treatment.

CKB currently provides extensive information relevant to interpretation of cancer-related genomic data, including thousands of genevariant descriptions, therapies, as well as evidence of therapeutic efficacy, accessbile through a web-based application.

JAX-CKB can help increase clinician confidence in completeness and accuracy of the informationrelated to the patient's tumor genomic profile.For translational and clinical researchers, JAX-CKB provides thousands of literature citations, FDA drug labels,and clinical trials relative to a tumor's genomic mutational profile, resulting in a clear and up-to-datepicture of discoveries and active developments for a variety of biomarkers.

"Heligenics' GigaAssay technology has the potential to advance genomic interpretation, and we are excited for the opportunity to provide large scale interpretation of previously unknown genomic variants to our users, with the hope of connecting patients to relevant treatment options that otherwise may not have been identified," says Sara Patterson, Ph.D. manager, clinical analytics and curation at JAX.

The benefits of this new collaboration include:

"This collaboration with Heligenics will allow us to define new therapeutic targets for cancer patients," said Jens Rueter, M.D., medical director at JAX's Maine Cancer Genomics Initiative (MCGI). "Ultimately, this has the potential to lead to new treatment options for cancer patients, including the many patients and families affected by cancer in Maine."

Heligenics: Heligenics Incorporated, founded in 2018 to uncover the function of genetic variants on a massive scale for improved diagnostics and improved clinical trial design for developing new drugs.

Heligenics' key technology, the GigaAssay, was invented in the laboratory of Dr. Martin Schiller at the University of Nevada Las Vegas where he leads the Nevada Institute of Personalized Medicine. As the effect of most mutations on gene function is largely unknown, Heligenics comprehensively measures the functional significance of mutations in the human genome and has exclusive rights to the patent pending GigaAssay technology. To learn more, please visit http://www.Heligenics.com.

The Jackson Laboratory (JAX): Founded in 1929, JAX pioneered the use of mice as models for human disease. As an independent, 501(c)3 nonprofit biomedical research institution, JAX uniquely integrates its deep experience in mouse genetics with ground-breaking advances in human genomics to decipher the biological and genomic causes of human disease and drive medical progress.

JAX research breakthroughs have formed the foundation of modern medicine. Organ and bone marrow transplants, stem cell therapies, and in vitro fertilization all have a foundation in JAX research, and at least 26 Nobel Prizes are associated with JAX research, mouse models, and education programs.

Media Contact:

Heligenics, Inc.(415) 794-3403[emailprotected]

JAX Press TeamThe Jackson Laboratory(860) 837-2102[emailprotected]

SOURCE Heligenics, Inc.

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Heligenics & The Jackson Laboratory Announce New Collaboration on ERBB2 Breast Cancer Gene - PRNewswire

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Hum Genomics. 2021 May 10;15(1):27. doi: 10.1186/s40246-021-00326-3.

ABSTRACT

COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics, such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and we call for bypassing local politics in the interest of humankind on all continents.

PMID:33966626 | DOI:10.1186/s40246-021-00326-3

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COVID-19 one year into the pandemic: from genetics and genomics to therapy, vaccination, and policy - DocWire News

An international team of scientists led by The University of Manchester have discovered 179 kidney genes responsible for high blood pressure.

High blood pressure, known as silent killer, is one of the most common human diseases and remains the key risk factor for strokes and heart attacks.

High blood pressure - orhypertension- runs in families but the exact mechanisms through which genes influence individuals predisposition to hypertension is not clear.

The discoveries published in Nature Genetics, one of the worlds leading journals, shed new light on our understanding of genetic predisposition to high blood pressure.

The study, supported primarily by the British Heart Foundation and Kidney Research UK, was possible through access to huge datasets of human DNA and RNA from possibly the worlds largest repository of human kidney tissue-based omics.

The team led by Professor Maciej Tomaszewski at The University of Manchester characterised how information inherited in DNA translates into genetic predisposition to high blood through changes in activity of certain kidney genes.

These studies included comprehensive analyses conducted at various molecular levels of kidney tissue combining together DNA, RNA and other layers from the same set of kidney tissue samples.

They also used a statistical method - called Mendelian randomisation to screen for evidence of causal associations between thousands of variables and millions of genetic variants using the high-performance computing resources hosted at the University of Manchester.

Around 80 per cent of 179 genes discovered by the team have never before been associated with high blood pressure before. Some of these genes can be targeted by existing medicines creating new opportunities to treat high blood pressure.

Principal Investigator Maciej Tomaszewski, Professor of Cardiovascular Medicine and University of Manchester and a Consultant Physician said: Hypertension is a key driver of coronary heart disease and stroke and the single most important cause of disability and premature death worldwide.

Yet, our understanding of the role of genes in development of this condition has been incomplete.

Professor Tomaszewski is also a member of Manchester Academic Health Science Centre (MAHSC), a partnership between academia and NHS organisations in Greater Manchester to drive health research, improve health education and transform patient care.

Professor Fadi J Charchar, a senior author from Federation University, added: Our studies filled an important gap in our knowledge through uncovering new genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to genetic regulation of blood pressure and inherited susceptibility to hypertension.

Professor Andrew Morris, from The University of Manchester, commented: Through our unparalleled access to the kidney tissue resource, we provide evidence for the role of the kidney as the mediator of common genetic effects on blood pressure and a potentially causal role of blood pressure in the development of renal disease.

First author: Dr James Eales from The University of Manchester said: By explaining the molecular mechanisms of hypertension embedded in the kidney, our study will ultimately lead to advancements in patient-centred diagnostic accuracy in hypertension.

It will also lead to new targeted strategies to lowering blood pressure, thereby accelerating progress in precision medicine.

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'Causal' blood pressure genes found in the human kidney - The University of Manchester

May10,2021|The pandemic hasshowcased thebest and the worst of the scientific enterprise, including thesilos that existbetween disciplines as well as the extraordinary speed of discovery when the barriers come down. Exhibit A comes from the University of California, San Francisco (UCSF), whoseQuantitative Biosciences Institute(QBI) spearheaded a six-nation collaborative around COVID-19 that now has 26 potential treatments in clinical trials.

The unprecedented level of cross-disciplinary teamwork, inclusive of 25 institutions and 10 industry partners, effectively unblinded researchersto commonalities across genes and disease areas, according to QBI DirectorNevanKrogan, Ph.D., who is also aprofessor in the department of cellular and molecular pharmacology. It will take concerted effort to maintainthatinfrastructure and spirit tobetter prepare forthenext pandemicor to find cures for perennial problems such asbreast cancerandAlzheimersdisease.

Drug repurposing has beenone of thefocal pointsof the QBICoronavirus Research Group(QCRG), both because time was of the essence and many anti-cancer drugs on the market proved effective againstCOVID-19,Krogansays. The same genes being mutated in cancer are being hijacked by SARS-CoV-2, just asAlzheimersdiseaseandtheZika virus share the same Achilles heel.

This is not terribly surprising, he adds, since viruses are very smart and evolved to attackcells. But scientists are going to miss the signs if they are not comparing notes.

Without coordination, both time and funding may be wasted, saysKrogan. Hundreds of repurposed drugs are now in clinical trials for COVID-19, but many of them work through a process calledphospholipidosis(a discovery madeby fellow QCRG scientist Brian Shoichet,DOI: 10.1101/2021.03.23.436648)thatlikely has no value in combatting the virus, he adds. Hydroxychloroquine falls in that category. Do we really need 450 clinical trials onhydroxychloroquineor just one?

Through the pandemic-inspiredAccelerating COVID19 Therapeutic Interventions and Vaccines (ACTIV) publicprivate partnership, the National Institutes of Health has been funding studies of repurposed drugs under a master protocol.Krogansays he applauds efforts like this byprioritizingthe drugs that get into clinical trials. We just need to see more of that.

Other recently reported collaborative efforts include alarge-scale humangenetics studyconducted by researchers from VA Boston Healthcare System, the University of Cambridge, EMBLs European Bioinformatics Institute,andIstitutoItaliano diTecnologiato identify drugstargetingIFNAR2 and ACE2 proteins that could be repurposed for early management of COVID-19 to prevent disease progression.

The artificial intelligence platform ofCyclicawas also deployed todiscover another potential COVID-19 drug from repurposingin this casecapmatinib(Tabrecta),Novartis MET inhibitorused to treat patientswith non-small cell lung cancerin a partnershipinvolvingRyerson University and the University of Torontos Vector Institute.

The real value in drug repurposing comes from targeting human proteins with host-directed therapies,Krogansays. Viruses mutate very quickly, but people dont. A virus is never going to mutate enough to overcome its reliance on human proteins to infect cells, reducing concerns about resistance.

So, while many pharmaceutical companies may opt to conduct largescale drug screens to identify repurposing candidates, QBI is sticking to its data-driven approach to drug discovery that starts with unraveling the underlying biology bydocumenting howthe proteins of a virus interactwithproteins in the cells of its target human host.

The approach takes alittle longer initially,butthelong-term consequencesare much more profound, saysKrogan. Our hit rateis much higher in terms of what is of value andweareso much further ahead in terms of tweaking the compound[for improved potency].

Protein Interaction Map

QBI created aHost-Pathogen Map Initiativejointly with the Center for Emerging and Neglected Disease at UC-Berkeley several years ago to create maps of the contact points betweenviral and human proteinsto understand how problem viruses like Ebola and Zika hijack, rewire, and infect human cells,Krogansays. But the pandemic enlarged the effort to more than 200 researchers worldwide singularly focused on finding drug candidates to wipe out infection by SARS-CoV-2.

The launch of QCRG began internally by establishing a web of interactions among over 40 uniquely skilled groups of scientists, which were broken into 12 subgroups specific to differentbiological processesand technologies, he says. Proteomics,cell biology,genetics,virology,structural biology,molecular biology,biochemistry,microscopy,bioinformatics, and clinical specialists all quickly came togetherpartially out of fearonly to learn how connected they really were.

As a first step, the QCRG constructed aSARS-CoV-2 protein interaction map revealing 66druggable human proteins or host factors targeted by 69 compoundsincluding 29 already approvedbytheFood and Drug Administration and another12 in clinical trials.The group is particularly excitedabout the potential of two translational inhibitors that were subsequently shown to be highly effective against SARS-CoV-2 in clinical trials conducted in New York and Paris.

One of the drugs, a translationalregulationinhibitor known aszotatifin(a product of EffectorTherapeuticsco-founded by UCSF scientists, including KevanShokat), has just been FDA-approved for aphase 1 clinical trialwith $5 million in funding from theDefense Advanced Research Projects Agency, he reports.Zotatifinis currently being tested in patients with solid tumors,andresults of preclinical studies showing itsin vitroantiviral activity against SARS-CoV-2were reported last spring inNature(DOI: 10.1038/s41586-020-2286-9).

The other drug,plitidepsin(Aplidin), approved by the Australian Regulatory Agency for the treatment of multiple myeloma, was found to be27.5-fold more potent against SARS-CoV-2 thanremdesivir,asreported earlier this year inScience(DOI: 10.1126/science.abf4058). Researchersdemonstrated prophylactic treatment reduced viral replication in the lungs of mice by two orders of magnitude.

PharmaMar has already launched aphase 3 clinical trialusingplitidepsinas a treatmentforpatients hospitalized for management of moderate COVID-19 infection,Krogansays. The study has been approved to run in 12 countries at 27 different sites.

Cancer drugs targetinghuman proteinsoften need to be taken formonthsoryears,he adds. Butas a treatment for acute infection by SARS-CoV-2, patients need only a short course ofplitidepsinfor a few days.

The challenge now is how to sustain large-scale collaborationswithscientistsneeding to resume work on projectsput onpausewhilethey were battlingCOVID, saysKrogan. But he is determined not to backtrack because science moves faster when everyone is working together,and scientist trainees also seem to learn better.

In addition to QCRG and the Host-Pathogen Map Initiative, UCSF is involved in aCancer Cell Map Initiativelooking atthemolecular networks(based on protein-protein and genetic interactions) underlying cancer, he notes. It also has aPsychiatric Cell Map Initiativeto elucidate thephysical and genetic interaction networksassociated withneuropsychiatric disorderssuch asautism and schizophrenia.

Bigdiscoveriesin the future are going to come from scientific collaborationlike theseacross disease and specialty areas,Krogansays. There isso much overlap therewejust dont[otherwise]appreciate.

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Value Of Drug Repurposing May Lie In Host-Directed Therapies - Bio-IT World

The FINANCIAL -- An international team of scientists led by The University of Manchester have discovered 179 kidney genes responsible for high blood pressure.High blood pressure, known as silent killer, is one of the most common human diseases and remains the key risk factor for strokes and heart attacks.

According to The University of Manchester, high blood pressure - or hypertension- runs in families but the exact mechanisms through which genes influence individuals predisposition to hypertension is not clear.

The discoveries published in Nature Genetics, one of the worlds leading journals, shed new light on our understanding of genetic predisposition to high blood pressure.

The study, supported primarily by the British Heart Foundation and Kidney Research UK, was possible through access to huge datasets of human DNA and RNA from possibly the worlds largest repository of human kidney tissue-based omics.

The team led by Professor Maciej Tomaszewski at The University of Manchester characterised how information inherited in DNA translates into genetic predisposition to high blood through changes in activity of certain kidney genes.

These studies included comprehensive analyses conducted at various molecular levels of kidney tissue combining together DNA, RNA and other layers from the same set of kidney tissue samples.

They also used a statistical method - called Mendelian randomisation to screen for evidence of causal associations between thousands of variables and millions of genetic variants using the high-performance computing resources hosted at the University of Manchester.

Around 80 per cent of 179 genes discovered by the team have never before been associated with high blood pressure before. Some of these genes can be targeted by existing medicines creating new opportunities to treat high blood pressure, The University of Manchester notes.

Principal Investigator Maciej Tomaszewski, Professor of Cardiovascular Medicine and University of Manchester and a Consultant Physician said: Hypertension is a key driver of coronary heart disease and stroke and the single most important cause of disability and premature death worldwide.

Yet, our understanding of the role of genes in development of this condition has been incomplete.

Professor Tomaszewski is also a member of Manchester Academic Health Science Centre (MAHSC), a partnership between academia and NHS organisations in Greater Manchester to drive health research, improve health education and transform patient care.

Professor Fadi J Charchar, a senior author from Federation University, added: Our studies filled an important gap in our knowledge through uncovering new genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to genetic regulation of blood pressure and inherited susceptibility to hypertension.

Professor Andrew Morris, from The University of Manchester, commented: Through our unparalleled access to the kidney tissue resource, we provide evidence for the role of the kidney as the mediator of common genetic effects on blood pressure and a potentially causal role of blood pressure in the development of renal disease.

First author: Dr James Eales from The University of Manchester said: By explaining the molecular mechanisms of hypertension embedded in the kidney, our study will ultimately lead to advancements in patient-centred diagnostic accuracy in hypertension.

It will also lead to new targeted strategies to lowering blood pressure, thereby accelerating progress in precision medicine.

Professor Tomasz Guzik, from the University of Glasgow, said: These exciting discoveries uncover a range of new possible mechanisms of hypertension some related to blood vessels, kidneys but also body immune defences and pave the way for the development of novel genetic therapies for blood pressure.

Professor James Leiper, Associate Medical Director at the BHF said: We have known for many years that the kidney is a major regulator of blood pressure, but our understanding of precisely how the kidney controls blood pressure is incomplete.

The identification of this large set of genes that appear to directly affect blood pressure fills in an important missing piece of that puzzle. The researchers have also found a subset of these genes that are a potential new target for the treatment of hypertension.

This is important because many people taking existing medications still struggle to control their blood pressure. If doctors have more tools to work with then it will help stop thousands of lives being lost each year from this potentially preventable condition.

Professor Jeremy Hughes, kidney doctor and chair of trustees at Kidney Research UK said: "High blood pressure is both a cause and consequence of kidney disease and we need better treatments to protect patients from harm such as strokes and heart attacks.

This innovative study harnesses the power of a kidney tissue biobank and state-of-the-art genetic analysis to identify novel genes that link the kidney to high blood pressure. We hope this new knowledge will eventually lead to new treatments that benefit kidney patients."

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Causal' Blood Pressure Genes Found in the Human Kidney - The FINANCIAL

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- 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 Relations Courtney.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...

BOSTON and LONDON, May 11, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today announced data published in the New England Journal of Medicine (NEJM) evaluating the safety and efficacy of investigational gene therapy products, including OTL-101, for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID). Fifty (50) ADA-SCID patients were treated with investigational gene therapy composed of autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with a self-inactivating lentiviral vector (LVV) encoding the human ADA gene. Results showed 100% overall survival and 95% event-free survival (defined as survival in the absence of enzyme replacement therapy reinstitution or rescue allogeneic hematopoietic stem cell transplant (HSCT)) at two and three years.

The data were taken from three Phase 1/2 clinical studies (n=40), two conducted in the U.S. and one in the UK, as well as from a compassionate use program (n=10) in the UK. Results also showed sustained ADA gene expression, metabolic correction, and functional immune reconstitution in 48 out of the 50 patients. Discontinuation of immunoglobulin replacement therapy (IgRT) was seen in 26 out of 29 U.S. study patients (90%) who demonstrated sustained engraftment by two years and 19 out of 19 UK study patients (100%) who had sustained engraftment by three years. Additionally, no deaths, monoclonal expansion events, leukoproliferative complications, or emergence of replication-competent lentivirus were observed.

Results from a one-time treatment with experimental lentiviral HSC gene therapy for ADA-SCID are compelling, most notably the overall and event-free survival rates (100% and 95%, respectively) observed at two and three years post-treatment, said Donald Kohn, M.D., distinguished professor of Microbiology, Immunology & Molecular Genetics and Pediatrics at the University of California, Los Angeles (UCLA), member of the UCLA Broad Stem Cell Research Center, director of the UCLA Human Gene and Cell Therapy Program, and co-lead author of the NEJM paper. We saw no reports of graft versus host disease, and the ability to discontinue immunoglobulin replacement therapy over time in most patients is also notable for the gene therapy, contributing to its overall benefit-risk profile as a potential treatment for ADA-SCID.

ADA-SCID is a rare and life-threatening primary immunodeficiency caused by a genetic mutation that affects white blood cell production. Patients with ADA-SCID suffer from frequent, severe infections as well as non-immune symptoms including those affecting the gastrointestinal, skeletal and nervous systems. Without treatment, children born with ADA-SCID typically pass away by 2 years of age.

With sustained engraftment of up to three years, these data show the potential of HSC gene therapy to correct the underlying genetic cause of ADA-SCID, delivering positive outcomes in a single treatment, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard Therapeutics. We are encouraged by the results weve seen across this large dataset of 50 treated patients, and believe they reinforce the promise of the HSC gene therapy approach for treating and potentially curing certain life-threatening genetic diseases.

Results of Phase 1/2 Clinical Studies for ex vivo LVV HSC Gene Therapy

Fifty patients with ADA-SCID were treated with an investigational gene therapy composed of autologous CD34+ HSCs transduced ex vivo with a self-inactivating LVV encoding the human ADA gene. Thirty (30) subjects enrolled in the U.S. studies received OTL-101 as part of the registrational trials, which were conducted at the University of California, Los Angeles (UCLA), and the National Institutes of Health (NIH). Study patients in the UK received a very similar investigational HSC gene therapy product based on the same ADA LVV. An analysis was conducted to assess the safety and efficacy of the gene therapy for the treatment of ADA-SCID, which integrated two prospective, nonrandomized, Phase 1/2 clinical studies in the U.S. (using fresh and cryopreserved formulations) at two years follow-up, alongside a prospective, nonrandomized Phase 1/2 clinical study conducted in the UK (fresh formulation) and compassionate use patients treated with the same UK protocol with three years follow-up, used as supportive evidence.

Efficacy Data

Results published in NEJM from all 50 patients treated across the studies showed:

Results were comparable in U.S. study patients receiving the fresh formulation with those receiving the cryopreserved formulation as shown by median VCN in granulocytes and PBMCs, median CD3+ T-cell levels, and median ADA activity.

Safety Data

Across all patients, no deaths, events of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus were noted. Adverse events were reported in all patients, most of which were mild or moderate and considered related to conditioning. No autoimmune or graft versus host (GvHD) events were noted.

Two U.S. study patients and two UK study patients had serious adverse events of immune reconstitution inflammatory syndrome (IRIS), beginning approximately 3 and 14 months and 3 and 22 months post-infusion, respectively. These events were considered unrelated to gene therapy, resolved with supportive therapy and were linked to transitory immune dysregulation during immune reconstitution.

About ADA-SCID and OTL-101

ADA-SCID is a rare, life-threatening, inherited disease of the immune system caused by mutations in the ADA gene resulting in a lack of, or minimal, immune system development.1-4 The first symptoms of ADA-SCID typically manifest during infancy with recurrent severe bacterial, viral and fungal infections and overall failure to thrive, and without treatment the condition can be fatal within the first two years of life. The incidence of ADA-SCID is currently estimated to be one in 500,000 live births in the United States and between one in 200,000 and one in 1 million in Europe.3 OTL-101 is an investigational autologous ex vivo lentiviral hematopoietic stem cell-based gene therapy for the treatment of patients diagnosed with ADA-SCID. The registrational trials for OTL-101 recently concluded and were conducted at the University of California, Los Angeles (UCLA) and the National Institutes of Health (NIH). Orchard has worldwide rights to the OTL-101 program through license agreements with University of California, Los Angeles (UCLA), and UCL Business, Ltd. OTL-101 has received orphan drug designation from the FDA and the EMA for the treatment of ADA-SCID and Breakthrough Therapy Designation from the FDA. OTL-101 has also received a Rare Pediatric Disease Designation from the FDA.

The research was funded by Orchard Therapeutics with support from the National Institute of Allergy and Infectious Diseases, the National Heart, Lung and Blood Institute, and the National Human Genome Research Institute (all part of the U.S. National Institutes of Health); the California Institute for Regenerative Medicine; the U.K. National Institute for Health Researchs Biomedical Research Centre at Great Ormond Street Hospital for Children National Health Service Foundation Trust and University College London.

About Orchard Therapeutics

Orchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter and LinkedIn), including but not limited to investor presentations and investor fact sheets, U.S. Securities and Exchange Commission filings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, and the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, will be insufficient to support regulatory submissions or marketing approval in the US or EU, as applicable, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy in the EU; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards Annual Report on Form 10-K for the year ended December 31, 2020, as filed with the U.S. Securities and Exchange Commission (SEC), as well as subsequent filings and reports filed with the SEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaBenjamin NavonDirector, Corporate Communications+1 857-248-9454Benjamin.Navon@orchard-tx.com

1Orphanet. SCID due to ADA deficiency. 2Whitmore KV, Gaspar HB. Front Immunol. 2016;7:314. 3Kwan A, et al. JAMA. 2014;312:729-738. 4Sauer AV, et al. Front Immunol. 2012;3:265.

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Orchard Therapeutics Announces New England Journal of Medicine Publication of HSC Gene Therapy Data for ADA-SCID - BioSpace

A research team led by the Garvan Institute of Medical Research has mapped the unique genetic profile of the skeletons master regulator cells, known as osteocytes. Their study, published in the journal Nature Communications, outlines the genes that are switched on or off in osteocytes a type of bone cell that controls how other types of cells make or break down parts of the skeleton to maintain strong and healthy bones.

This new information provides a kind of genetic shortlist we can look to when diagnosing bone diseases that have a genetic component, said Garvans Dr Scott Youlten, first author on the study. Identifying this unique genetic pattern will also help us find new therapies for bone disease and better understand the impacts of current therapies on the skeleton.

The skeleton is a highly dynamic structure that changes shape and composition throughout a persons life. Osteocytes are the most abundant cell type in bone but have proved difficult to study because they are embedded within the hard mineral structure of the skeleton.

Inside the bone, osteocytes form a network similar in scale and complexity to the neurons in the brain (with over 23 trillion connections between 42 billion osteocytes) that monitors bone health and responds to ageing and damage by signalling other cells to build more bone or break down old bone. Diseases such as osteoporosis and rare genetic skeletal disorders arise from an imbalance in these processes.

To understand what genes are involved in controlling bone build-up or breakdown, the researchers isolated bone samples from different skeletal sites of experimental models to measure the average gene activity in osteocytes. Through this, they mapped a comprehensive osteocyte signature of 1239 genes that are switched on in osteocytes and that distinguish them from other cells. 77% of these genes have no previously known role in the skeleton and many were completely novel and only found in these critical cells.

Many of the genes we saw enriched in osteocytes are also found in neurons, which is interesting given these cells share similar physical characteristics and may suggest they are more closely related than we previously thought, said Dr Youlten.

A comparison of the osteocyte signature genes with human genetic association studies of osteoporosis identified new genes that may be associated with susceptibility to this common skeleton disease. Furthermore, many of these osteocyte genes were also shown to cause rare bone diseases.

Mapping the osteocyte transcriptome could help clinicians and researchers more easily establish whether a rare bone disease has a genetic cause, by looking through the shortlist of genes known to play an active role in controlling the skeleton, said Dr Youlten.

Co-senior author Professor Peter Croucher, Deputy Director of the Garvan Institute, said, The osteocyte transcriptome map gives researchers a picture of the whole landscape of genes that are switched on in osteocytes for the first time, rather than just a small glimpse.

The majority of genes that weve found to be active within osteocytes had no previously known role in bones, he said. This discovery will help us understand what controls the skeleton, which genes are important in rare and common skeletal diseases and help us identify new treatments that can stop development of bone disease and also restore lost bone.

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Mapping the genes that control the skeleton - Lab + Life Scientist

For most of human history people took it for granted that every form of life was a unique creation. In general this meant that each kind mated with its own kind to produce offspring. For our ancestors that was patently obvious. Lions did not mate with chimpanzees and so on. The differences between each plant and animal were seen as proof that a creator had been hard at work making all these different living creatures with a unique unchanging template for each. The differences were more than just superficial. Organisms were different down to the bone with no possibility of diverse species interbreeding. And once created the templates were set in stone with no changes possible. After all a powerful creator had willed it so. Perhaps it would have been better if that were really true.

But the reality is there was likely only one creation event. One can hypothesize about just who or what was the instigator of that event, but biology and genetics backed up by chemistry and paleontology tell us that all living organisms on Earth have a single common ancestor, a single celled creature with the ability to make copies of itself and its genetic code through the replication of DNA. This primordial process continues today in every living organism at the cellular level. Every living cell no matter from what living organism you might investigate including all plants and animals have the same engineered plan based on DNA. The difference is only the way the genetic material in each cell is arranged and the complexity. Also inherent in each cell is the potential to make subtle changes through mistakes in the replication process or outside influences. Almost all of those changes (mutations) are harmful or irrelevant but a very few give the organism a slight survival advantage providing the basis of biological evolution and species diversification.

The wonder isnt that all life on Earth has evolved from that ancient single cell ancestor, but that the single living cell evolved in the first place. The broad strokes of the panorama of species change are fairly well mapped out through Natural Selection and Variation Within Species. But although modern science can artificially construct the chemical building blocks of living creatures and we find those molecules occurring naturally even in the distant Cosmos, it cannot take those necessary chemical pieces and put them together to make a fully formed living cell. At least not yet.

The basic similarity of the structure of DNA and genetic codes of all living organisms has opened the door to the possibility of actually mating a lion and a chimpanzee at least at the test tube level. The technology known as gene-splicing or editing can exchange, replace, or remove genetic instructions between different unrelated life forms. As mentioned in previous columns, this is already happening to create hybrid organisms, especially for agricultural purposes. But there is no reason the same technology couldnt be used to combine and manipulate any genetic material from any organism.

Suppose a genetic instruction is discovered in the human genome that increases the risk of developing cancer, or deformities, or that might produce other deleterious effects. One could see if that bit of genetic material could be removed say from a female egg by gene editing how that might represent a positive breakthrough in medicine. We might also discover a genetic instruction in another animal that counters the aging process (the African mole rat and water bears come to mind) that could be grafted onto human DNA thus creating the same effect. Or finding the specific genetic instructions that allow some animals to grow back severed appendages and adapting those instructions to humans. Many other organisms have characteristics we might like to acquire and it is at least theoretically possible for us to do so through gene editing and splicing. Very recently human and chimpanzee DNA were successfully experimentally combined. Science has taught us that the ancient creation stories were way off the mark, but now we face a dilemma.

The question should be: How far down this road (or rabbit hole) do we want to go? In the ancient Egyptian religion many of their gods were part human and part animal. That was unquestioned truth to them, but mythology to us. (Ancient religions and folklore include dozens of human-animal hybrids, a subject for another article.) As it turns out, we now have the capability to turn that mythology back to truth, and should be mindful of the one undisputed law as we plunge down that road: That of unintended consequences.

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Science Voice: The common origin of life on Earth - Herald Review

The University of Maine will honor the achievements of the more than 2,000 UMaine students receiving degrees in 2021 with a virtual 218th Commencement presentation, highlighted by video of students in-person stage walks, congratulatory remarks by valedictorian Bailey West and a keynote by Dr. Edison Liu, president and CEO of The Jackson Laboratory.

Alumna Melissa Smith, chair and CEO of WEX in Portland, and Wayne Newell of Indian Township, a Passamaquoddy scholar and educator, will be awarded honorary degrees.

UMaine has 412 graduate students and 1,639 undergraduates receiving degrees in 2021. Following COVID-19 health and safety guidance, nearly 1,000 members of the Class of 2021 and Class of 2020 participated in commencement stage walks April 23May 3. Recordings of the livestreamed events over six days, which received a total of more than 12,400 views, will be part of the virtual presentation that will feature elements of UMaines traditional in-person commencement ceremony.

All graduates, including those unable to attend or who did not feel comfortable participating in the in-person stage walks, had the opportunity to submit images and photos to be included in the virtual presentation.

Music for the virtual commencement presentation has been provided by University of Maine Symphonic Band and Maine Steiners.

The virtual 218th Commencement presentation will be available in late May to ensure time for all video and photos to be submitted from the Classes of 2021 and 2020. Graduates will be notified of the time and date of the presentation, which will be available on the commencement website. The 218th Commencement program and a link to the Graduate Schools virtual hooding ceremonies also will be available on the website.

We are incredibly proud of the perseverance, tenacity and hard work that our seniors and graduate students demonstrated, particularly amid the challenges of the past three semesters, to successfully reach this point in their academic careers, says UMaine President Joan Ferrini-Mundy. This is a time to celebrate our graduates and the many people who have provided them support and encouragement.

Keynoting this years UMaine Commencement is Dr. Liu, who for nine years has led The Jackson Laboratory in Bar Harbor, an independent research institute focused on complex genetics and functional genomics with campuses in Maine, Connecticut and California. He also directs the National Cancer Institute-designated JAX Cancer Center. Dr. Liu is an international expert in cancer biology, systems genomics, human genetics, molecular epidemiology and translational medicine. His own scientific research has focused on the functional genomics of human cancers, particularly breast cancer, uncovering new oncogenes, and deciphering on a genomic scale the dynamics of gene regulation that modulate cancer biology.

Previously, he was the founding executive director of the Genome Institute of Singapore and the president of the Human Genome Organization and the scientific director of the National Cancer Institutes Division of Clinical Sciences in Bethesda, Maryland. Earlier in his career, Dr. Liu was a faculty member at the University of North Carolina at Chapel Hill, where he was the director of the UNC Lineberger Comprehensive Cancer Centers Specialized Program of Research Excellence in Breast Cancer; director of the Laboratory of Molecular Epidemiology at UNCs School of Public Health; and chief of medical genetics.

In addition to addresses from Dr. Liu and President Ferrini-Mundy, the virtual commencement presentation will feature congratulatory messages from other University of Maine System, UMaine and University of Maine Alumni Association leaders.

Among those being honored is 2021 Distinguished Maine Professor Hemant Pendse and this years Presidential Award winners.

UMaine valedictorian West of Stockton Springs, a biochemistry major and honors student, also is the Outstanding Graduating Student in the College of Natural Sciences, Forestry, and Agriculture. Drew Bennett of Brewer is the 2021 salutatorian. This year, UMaine named 13 Outstanding Graduating Students.

The honorary degree of Doctor of Humane Letters will be awarded to Smith, who received a UMaine bachelors degree in business administration with a major in accounting in 1991. As chair and CEO of WEX, a financial technology solutions provider that serves millions of companies worldwide, she leads the creation and execution of global strategy and development of talent and culture. Smith began her career at WEX as a senior financial analyst, and is the former CFO and president of the Americas.

Smith was the 2017 Mainebiz Business Leader of the Year and the 2012 Mainebiz Woman to Watch. In 2015, the Maine Womens Fund presented her with a Tribute to Women in Industry Award and, in 2013, the Girl Scouts of Maine presented her with a Women of Distinction Award. She is the co-founder of the Executive Womens Forum.

Newell, a member of the Passamaquoddy Nation, also will receive the honorary degree of Doctor of Humane Letters for his significant contributions to the Passamaquoddy people, the University of Maine, the state and the nation. Newell was the first Wabanki member of the UMS Board of Trustees and served on the National Advisory Council on Indian Education. The Department of the Interior designated him a national living treasure for his lifelong dedication of his talents to the preservation of the Passamaquoddy language and culture.

Newell, who has been legally blind since childhood, earned a masters degree from Harvard University, focused on linguistics. He worked in bilingual education in the Passamaquoddy Nation schools and authored The Passamaquoddy-Maliseet Dictionary: Peskotomuhkati-Wolastoqewi, a 1,200-page volume published by the University of Maine Press.

Contact: Margaret Nagle, nagle@maine.edu

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UMaine 2021 virtual commencement will honor two years of graduates - UMaine News - University of Maine - University of Maine