Monthly Archives: May 2021

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