AAV9.LAMP2B gene therapy shows clinical benefit in Danon disease

1. In seven patients with Danon disease, a single infusion of adeno-associated virus serotype 9 carrying transgene LAMP2B (AVV9.LAMP2B) therapy (RP-A501) resulted in cardiac expression of the lysosomal-associated membrane 2 (LAMP2) protein.

2. Clinical improvement was observed in six patients who had normal left ventricular ejection fraction (LVEF) at baseline.

Evidence Rating Level: 2 (Good)

Study Rundown: Danon disease is a rare X-linked disease characterized by mutations in the LAMP2 gene, which lead to hypertrophic cardiomyopathy, conduction abnormalities, heart failure, and early death. Cardiac transplantation can prolong life in many patients but is not curative and is associated with serious complications. In vitro evidence suggests that genetic correction of the LAMP2B (a specific pathogenic isoform of Danon disease) could restore cardiomyocyte function. This phase one study investigated RP-A501 gene therapy among seven male patients with Danon disease between ages 11 and 21. A single infusion of RP-A501 was administered alongside an immunomodulatory regimen. One patient with impaired baseline LVEF developed grade four thrombotic microangiopathy with thrombocytopenia and experienced Danon disease progression, subsequently undergoing heart transplantation. In the remaining patients with normal baseline LVEF, cardiac expression of LAMP2 along with clinical improvements were observed between 24 and 54 months. Despite its small size and subjective symptom assessment by aware investigators, these results suggested that RP-A501 was generally safe and associated with cardiac expression of LAMP2 and clinical improvements by 54 months in male patients with Danon disease.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This was an open-label, non-randomized study evaluating the safety and efficacy of RP-A501, a gene therapy consisting of AAV9.LAMP2B transgene, in male patients with Danon disease. Male patients aged 8 or older (or 15 years for earlier cohorts) who had a confirmed or likely pathogenic LAMP2 variant with cardiac involvement and heart failure symptoms. Seven patients received a single intravenous infusion of RP-A501 in three cohorts with varying dosages: cohort 1 (6.7E13 copies/kg) for adults and adolescents (≥15 years of age), cohort 2 (1.1E14 copies/kg) for adults and adolescents, and cohort 3 (6.7E13 copies/kg) for pediatric patients (8-14 years of age). The primary outcomes were safety, myocardial LAMP2 transduction and expression, and stabilization or improvement of heart failure symptoms and cardiac structure. One patient, who received the high-dose RP-A501, developed complement-mediated thrombotic microangiography with resultant thrombocytopenia and acute kidney injury. This patient had an impaired LVEF (32%) at baseline and experienced disease progression leading to heart failure. They underwent heart transplantation five months after the treatment and the explanted heart demonstrated evidence of disease progression without immunologic complications. Between 24 and 54 months, the remaining six patients were found to have cardiac LAMP2 expression and demonstrated a reduction from baseline in or stabilization of left ventricular mass index, LVEF preservation, and reduction in or stabilization of levels of cardiac troponin I and pro-B-type natriuretic peptide. The most common adverse events were vomiting, headache, myopathy, and elevated alanine aminotransferase levels. This study suggested that RP-A501 was generally safe and associated with cardiac expression of LAMP2 and clinical improvements in male patients with Danon disease, prompting further investigation into its use.

Image: PD

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