Viral Gene Therapy for Danon Disease: From LAMP2 Biology to Clinical Translation

Danon disease is a rare, highly penetrant and morbid X-linked cardioskeletal myopathy caused by loss-of-function variants in the lysosome-associated membrane protein 2 (LAMP2) gene. We review the rationale for LAMP2B gene replacement, the basis for adeno-associated virus serotype 9 (AAV9) vector selection, the first-in-human clinical evidence, and immunological barriers that define its therapeutic window.

Preclinical models demonstrating restoration of autophagic flux via human LAMP2B gene delivery have provided the basis for clinical translation. The first-in-human phase 1 clinical data highlights the progress of recombinant adeno-associated virus serotype 9 carrying human LAMP2B (AAV9.LAMP2B) gene therapy (RP-A501). Seven male patients received a single intravenous infusion of AAV9.LAMP2B with transient immunomodulation. Myocardial transduction was achieved; LAMP2B protein was detectable by immunohistochemistry, autophagic vacuoles were reduced, left ventricular mass index fell by a median of 23%, cardiac troponin I and natriuretic peptides declined, and functional class improved in all evaluable patients. Toxicity was dose-limiting. Emerging clinical data supports that viral LAMP2B gene therapy is a viable disease-modifying strategy, although from a small cohort, for Danon disease. The long-term durability of transgene expression, patient safety and toxicity profiles with exclusion of affected females remain unresolved. The pivotal single-arm phase 2 study (NCT06092034) is ongoing.

Abstract from PubMed (PMID 43018814). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.