Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease

作者：Barry Greenberg, Matthew R.G. Taylor, Eric A. Adler, Steven D. Colan, David Ricks, Paul Yarabe, Pavan K. Battiprolu, Gaurav Y. Shah, Kinnari Patel, Matthew P. Coggins, Susanna Carou-Keenan, Jonathan D. Schwartz, Joseph William Rossano · 发表于：New England Journal of Medicine · 年份：2024 · DOI：10.1056/nejmoa2412392 · 被引用次数：92 · 研究领域：Cardiomyopathy and Myosin Studies、Nuclear Structure and Function、Cardiac electrophysiology and arrhythmias

BACKGROUND: ), which encodes the LAMP2 protein. In male patients, the predominant phenotype is progressive cardiac hypertrophy, cardiac dysfunction, and early death. There are no directed therapies for the disease. METHODS: , which encodes an isoform of LAMP2. The primary outcomes were the safety and toxic effects of RP-A501, myocardial LAMP2 transduction and protein expression, stabilization of or reduction in heart-failure symptoms, and stabilization of or improvement in cardiac structure and function. Key secondary outcomes were sustained reduction in or stabilization of symptoms, immunologic response to RP-A501, end-stage heart failure, and overall survival. Exploratory outcomes included improvement in serologic markers of cardiac disease, patient-reported outcomes, and quality-of-life assessments. RESULTS: RP-A501 infusion was administered to seven male patients with Danon disease: five who were 15 years of age or older and two who were between 11 and 14 years of age. All the patients received a transient immunomodulatory regimen of prednisone, tacrolimus or sirolimus, and rituximab. Phase 1 data over 24 to 54 months, including interim data from a long-term follow-up study, are reported here. One patient had complement-mediated thrombotic microangiopathy (grade 4) with thrombocytopenia and acute kidney injury. Three patients had glucocorticoid-related exacerbation (grade 3) of Danon disease-related skeletal myopathy. One patient with left ventricular systolic dysfunction...