• Barry Greenberg, Matthew Taylor, Eric Adler, Steven Colan, David Ricks, Paul Yarabe, Pavan Battiprolu, Gaurav Shah, Kinnari Patel, Matthew Coggins, Susanna Carou-Keenan, Jonathan D Schwartz, and Joseph W Rossano.
• From the University of California, San Diego Medical Center, La Jolla (B.G., E.A.); University of Colorado Anschutz Medical Campus, Aurora (M.T.); Boston's Children's Hospital, Harvard Medical School, Boston (S.C.); Rocket Pharmaceuticals, Cranbury, NJ (D.R., P.Y., P.B., G.S., K.P., M.C., S.C.-K., J.D.S.); and Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania (J.W.R.) - both in Philadelphia.
• N. Engl. J. Med. 2024 Nov 18.

BackgroundDanon disease is a rare, X-linked, monogenic cardiomyopathy caused by mutations in the lysosomal-associated membrane 2 gene (LAMP2), 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.MethodsIn this phase 1 study, we evaluated the safety and efficacy of a single infusion of RP-A501, a recombinant adeno-associated virus serotype 9 containing the transgene LAMP2B, 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.ResultsRP-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 at baseline had progressive heart failure and underwent transplantation 5 months after infusion. In the six patients with normal left ventricular ejection fraction at baseline, we observed cardiac LAMP2 protein expression and a reduction from baseline in or stabilization of the left ventricular mass index, preservation of left ventricular ejection fraction, and reduction in or stabilization of the levels of cardiac troponin I and N-terminal pro-B-type natriuretic peptide. At 24 to 54 months, all the patients were alive, with complete resolution of side effects.ConclusionsA single infusion of RP-A501 appeared to be safe and was associated with cardiac LAMP2 expression and evidence of clinical improvement over a period of 24 to 54 months. (Funded by Rocket Pharmaceuticals; ClinicalTrials.gov number, NCT03882437.).Copyright © 2024 Massachusetts Medical Society.

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