{"doi":"10.1016/j.ymthe.2020.07.009","title":"Broader Implications of Progressive Liver Dysfunction and Lethal Sepsis in Two Boys following Systemic High-Dose AAV","abstract":"By virtue of their transformational power, the technologies at the core of the gene therapy community have brought widespread public attention to the unique burden of previously neglected orphan diseases. On June 23, a report from Audentes Therapeutics of the tragic death of two patients with X-linked myotubular myopathy (XLMTM)1Audentes Therapeutics. Statement from Audentes ~ June 23rd, 2020. https://www.joshuafrase.org/get-involved/recensus-study.php.Google Scholar brought into ever sharper focus an added dimension of this burden. XLMTM is recognized for its devastating prognosis in terms of standardized metrics, including disability-adjusted life years and healthy life expectancy. Highly publicized reports of the earliest results of Audentes’ ASPIRO gene therapy trial revealed a spectacular therapeutic response. Both the specifics and the broader context of the unexpected adverse events illustrate why, for patients and their families, the stakes have never been higher as the limitations of initially promising therapies become fully known only through advanced phase clinical trials. Transparency to enable a better understanding of the clinical pathology will be essential to inform the risk-benefit calculus for XLMTM patients contemplating enrollment in future trials, but also for the broader community to enable rationale design of improved gene therapy vectors. The specifics of Audentes’ letter addressed to the “XLMTM Patient Community” can be briefly summarized: two of the three older patients in the AT132 (AAV8-MTM1) high dose cohort (3 × 1014 vg/kg) died following clinically similar courses, approximately 4–6 weeks post-administration, in the setting of progressive liver dysfunction and sepsis. The observation of serious adverse events (SAEs) of hepatobiliary disease included all three of the older patients in this dose cohort. Four of six patients previously treated at 1 × 1014 vg/kg had no liver SAEs, despite previous histories of hepatobiliary disease associated with XLMTM. Understanding the broader context of these SAEs is critical to defining the pathway forward. It begins with the devastating disease first described by Spiro et al.2Spiro A.J. Shy G.M. Gonatas N.K. Myotubular myopathy. Persistence of fetal muscle in an adolescent boy.Arch Neurol. 1966; 14: 1-14Crossref PubMed Scopus (300) Google Scholar in 1966 and christened myotubular myopathy on the basis of the histological appearance of the centronuclear myocytes resembling fetal myotubes. The protein product of the X-linked gene (MTM1), myotubularin, is a ubiquitously expressed phosphatidylinositol 3-phosphate (PI(3)P) phosphatase.3Laporte J. Hu L.J. Kretz C. Mandel J.L. Kioschis P. Coy J.F. Klauck S.M. Poustka A. Dahl N. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast.Nat. Genet. 1996; 13: 175-182Crossref PubMed Scopus (534) Google Scholar,4Taylor G.S. Maehama T. Dixon J.E. Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate.Proc. Natl. Acad. Sci. USA. 2000; 97: 8910-8915Crossref PubMed Scopus (288) Google Scholar The resulting lipid second messenger is involved in endosome trafficking, autophagy, desmin filament architecture, mitochondrial dynamics, muscle excitation-contraction coupling, and regulation of the ubiquitin-proteasome pathway.5Al-Qusairi L. Weiss N. Toussaint A. Berbey C. Messaddeq N. Kretz C. Sanoudou D. Beggs A.H. Allard B. Mandel J.L. et al.T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase.Proc. Natl. Acad. Sci. USA. 2009; 106: 18763-18768Crossref PubMed Scopus (149) Google Scholar,6Hnia K. Tronchère H. Tomczak K.K. Amoasii L. Schultz P. Beggs A.H. Payrastre B. Mandel J.L. Laporte J. Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeleta","journal":"Molecular Therapy","year":2020,"id":54937,"datarank":0.6892679775201885,"base_score":4.59511985013459,"endowment":4.59511985013459,"self_citation_contribution":0.6892679775201885,"citation_network_contribution":0.0,"self_endowment_contribution":0.6892679775201885,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":98,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":283840,"name":"Yuva Gambhir","orcid":null,"position":1,"is_corresponding":false},{"id":283003,"name":"Jean Bennett","orcid":"0000-0003-3378-8263","position":2,"is_corresponding":false},{"id":283004,"name":"Hansell H. Stedman","orcid":"0000-0003-2700-1815","position":3,"is_corresponding":false},{"id":283002,"name":"Leon Morales","orcid":"0000-0003-3079-8183","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:04:14.743014Z","pmid":"32710826","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":[]}