Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'.

Muscular Dystrophy Association (MDA) has invested over $125M in the development of gene therapy for neuromuscular diseases (NMDs) over the past 20 years. As a lead initiator of progress in this important field of medicine and to help ensure continued progress towards therapies for patients, MDA organized a dedicated summit in January 2022 to address emerging challenges in safely delivering AAV gene therapies with a focus on their application in NMD. In this meeting, chaired by Carsten Bönnemann (NINDS, NIH) and Barry Byrne (University of Florida), academic and industry experts and stakeholders convened to openly discuss adverse events linked to clinical trials, as well as other challenges emerging in preclinical studies associated with difficulties in the translation of AAV gene therapies.

[1]  T. Gillingwater,et al.  Timing is everything: Clinical evidence supports pre-symptomatic treatment for spinal muscular atrophy , 2022, Cell reports. Medicine.

[2]  K. Keyhanian,et al.  Gene Therapy in Amyotrophic Lateral Sclerosis , 2022, Cells.

[3]  F. Muntoni,et al.  INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy , 2022, Journal of neuromuscular diseases.

[4]  R. Samulski,et al.  Addressing high dose AAV toxicity – ‘one and done’ or ‘slower and lower’? , 2022, Expert opinion on biological therapy.

[5]  L. Servais,et al.  OP018: ASPIRO gene therapy trial in X-Linked Myotubular Myopathy (XLMTM): Update on preliminary efficacy and safety findings , 2022, Genetics in Medicine.

[6]  Chady H Hakim,et al.  Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models , 2021, Nature Communications.

[7]  B. Kamath,et al.  Intrahepatic Cholestasis Is a Clinically Significant Feature Associated with Natural History of X-Linked Myotubular Myopathy (XLMTM): A Case Series and Biopsy Report , 2021, Journal of neuromuscular diseases.

[8]  Dhwanil A. Dalwadi,et al.  AAV integration in human hepatocytes. , 2021, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  A. D’Amico,et al.  Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies , 2021, Orphanet Journal of Rare Diseases.

[10]  K. Meyer,et al.  Onasemnogene abeparvovec-xioi: a gene replacement strategy for the treatment of infants diagnosed with spinal muscular atrophy. , 2021, Drugs of today.

[11]  T. Kaisho,et al.  Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy , 2021, Frontiers in Immunology.

[12]  S. Boye,et al.  Current Clinical Applications of In Vivo Gene Therapy with AAVs , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  Meera Sridharan,et al.  Complement in Secondary Thrombotic Microangiopathy , 2020, Kidney International Reports.

[14]  J. Dowling,et al.  Re: “Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular Myopathy” by Wilson and Flotte , 2020, Human Gene Therapy.

[15]  J. Rasko,et al.  Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B. , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  Amy G. Feldman,et al.  Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type I. , 2020, The Journal of pediatrics.

[17]  J. F. Wright,et al.  Codon Modification and PAMPs in Clinical AAV Vectors: The Tortoise or the Hare? , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  R. Herzog,et al.  Immune Responses to Viral Gene Therapy Vectors , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  B. Byrne,et al.  Advancements in AAV-mediated Gene Therapy for Pompe Disease , 2019, Journal of neuromuscular diseases.

[20]  Z. Xiang,et al.  The Effect of CpG Sequences on Capsid-Specific CD8+ T Cell Responses to AAV Vector Gene Transfer. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[21]  James M. Allen,et al.  Development of Novel Micro-dystrophins with Enhanced Functionality , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  Charles A. Gersbach,et al.  Long-term Evaluation of AAV-CRISPR Genome Editing for Duchenne Muscular Dystrophy , 2018, Nature Medicine.

[23]  B. Byrne.  Safety First: Perspective on Patient-Centered Development of AAV Gene Therapy Products. , 2018, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  J. Prieto,et al.  Improvement of Adeno-Associated Virus-Mediated Liver Transduction Efficacy by Regional Administration in Macaca fascicularis. , 2017, Human gene therapy. Clinical development.

[25]  C. Gersbach,et al.  Engineering Delivery Vehicles for Genome Editing. , 2016, Annual review of chemical and biomolecular engineering.

[26]  D. Armao,et al.  Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy , 2015, Molecular therapy. Methods & clinical development.

[27]  J. F. Wright,et al.  Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment , 2014, Biomedicines.

[28]  J. Mendell,et al.  Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. , 2013, Human gene therapy.

[29]  T. Ohmori,et al.  Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  J. Mendell,et al.  Dystrophin immunity in Duchenne's muscular dystrophy. , 2010, The New England journal of medicine.

[31]  V. Haurigot,et al.  Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. , 2010, Blood.

[32]  M. Main,et al.  Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: Implication for clinical trials , 2010, Neuromuscular Disorders.

[33]  Daniel G. Miller,et al.  AAV Vector Integration Sites in Mouse Hepatocellular Carcinoma , 2007, Science.

[34]  C. Grady,et al.  What makes clinical research ethical? , 2000, JAMA.

[35]  C. Lutz,et al.  Effect of genetic background on the dystrophic phenotype in mdx mice. , 2016, Human molecular genetics.