{"doi":"10.1016/j.ymthe.2021.01.012","title":"Challenges at the Crossroads: Myopathy Trials in 2020 Hindsight","abstract":"Reports of clinical studies in gene therapy for two myopathies, Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM), have revealed tantalizing glimpses of efficacy, but the news has been partially offset by emerging safety concerns.1Mendell J.R. Sahenk Z. Lehman K. Nease C. Lowes L.P. Miller N.F. Iammarino M.A. Alfano L.N. Nicholl A. Al-Zaidy S. et al.Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial.JAMA Neurol. 2020; 77: 1122-1131Crossref PubMed Scopus (61) Google Scholar,2Shieh P.B. Bönnemann C.G. Müller-Felber W. Blaschek A. Dowling J.J. Kuntz N.L. Seferian A.M. Re: “Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular Myopathy” by Wilson and Flotte.Hum. Gene Ther. 2020; 31: 787Crossref PubMed Scopus (25) Google Scholar Although preclinical studies in disease models informed the design of these early-stage clinical trials, the emerging spectrum of safety issues urgently needs alternative models to enable mechanistic dissection and expedite development of improved gene therapies with much higher therapeutic indices. The etiologies of the vector-related serious adverse events (SAEs) are unclear, involve multiple organ systems, and are not necessarily identical across diseases and vectors. None were predicted by studies in existing pre-clinical myopathy models. Here we address a mix of common themes and disease-specific considerations, and attempt to identify opportunities for research to contribute evidence-based rationale to the choices at the crossroads. Similarities and distinctions between DMD and XLMTM, the vectors used, and the trial designs may be critical to the interpretation of the reported SAEs. For both diseases, respiratory insufficiency is a leading cause of death, but only in XLMTM is mechanical respiratory support often required at birth. DMD is typically asymptomatic in infancy, with an average age at diagnosis of 4 years, even later for the milder allelic variant of dystrophinopathy, Becker MD (BMD). DMD and BMD affect both skeletal and cardiac myocytes, while cardiomyopathy is not a recognized feature of XLMTM. Only XLMTM has an associated liver disease that, in severe cases, can autonomously progress to lethal “peliosis hepatis”. The phase 1 XLMTM ASPIRO trial showed impressive improvement in respiratory function as a primary endpoint in the initial 1.0 × 1014 adeno-associated virus (AAV) vg/kg patient group, partially de-risking the trial and incentivizing parents to consider enrollment of young XLMTM boys at the higher dose of 3.0 × 1014. However, three deaths occurred in the high-dose group months after vector administration, with a shared scenario of progressive liver dysfunction and intracellular cholestasis.2Shieh P.B. Bönnemann C.G. Müller-Felber W. Blaschek A. Dowling J.J. Kuntz N.L. Seferian A.M. Re: “Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular Myopathy” by Wilson and Flotte.Hum. Gene Ther. 2020; 31: 787Crossref PubMed Scopus (25) Google Scholar The available reports outline clinical evolution from liver insufficiency to lethal “sepsis,” raising concern for a delayed onset, treatment-related cytokine storm. In the DMD trials, the SAEs included subacute renal failure in the setting of thrombocytopenia, hemolytic anemia, and complement activation resembling thrombotic microangiopathy (TMA), with or without subacute cardiopulmonary insufficiency. Thus, the pathomechanisms may be distinct, as are both the diseases and vectors used (XLMTM-AAV8, DMD-AAV9). However, both capsids are highly hepatotropic, and delayed but severe liver dysfunction has also been reported in post-approval studies of Zolgensma, the AAV9-based gene therapy for spinal muscular atrophy (SMA).3Feldman A.G. Parsons J.A. Dutmer C.M. Veerapandiyan A. Hafberg E. Maloney N. Mack C.L. Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1.J","journal":"Molecular Therapy","year":2021,"id":207202,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":792285,"name":"Benjamin W. Kozyak","orcid":"0000-0002-4809-0960","position":1,"is_corresponding":false},{"id":283004,"name":"Hansell H. Stedman","orcid":"0000-0003-2700-1815","position":2,"is_corresponding":false},{"id":792284,"name":"Chris L. Greer","orcid":"0000-0002-6669-3941","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-18T23:51:45.688025Z","pmid":"33476580","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}