Abstract Body (Do not enter title and authors here): Hypothesis & Purpose:
Danon disease (DD) is an X-linked cardiomyopathy (CMP) caused by LAMP2 mutations resulting in LAMP2 deficiency. Male DD patients (pts) develop rapidly progressive severe hypertrophic CMP causing mortality at median age 19-20y. We tested whether RP-A501, an adeno-associated virus serotype 9 encoding a normal human LAMP2 isoform B (AAV9.LAMP2B) can be administered safely and reverse DD phenotype.

Study Design & Methods:
Phase 1 trial (NCT03882437) of male DD pts with LAMP2 mutations and CMP in cohorts: ≥15y (n=5; adult/adolescent) and 8-14y (n=2; pediatric). Pts were followed for 24-36m post-RP-A501.

Sample Size:
7

Population Studied:
Male DD pts with no LAMP2 expression, NYHA Class II symptoms, and LV hypertrophy

Intervention:
Single IV infusion of RP-A501 at 6.7x10¹³ GC/kg (low dose) or 1.1x10¹⁴ GC/kg (high dose). Immunomodulation (IM): 2-3m prednisone, tacrolimus/sirolimus, and rituximab.

Power Calculations:
N/A

Primary Endpoints:
Safety, LAMP2 expression

Secondary Endpoints:
Sustained LAMP2 expression, disease stabilization and clinical improvement

Outcomes:
Seven males with DD age 12-21y (median 18.3y) received RP-A501 (N=5 low dose and N=2 high dose).

Most adverse events (AEs) were non-serious. All RP-A501- or IM-related AEs were manageable and reversible. One pt had an RP-A501-related grade 4 AE (SAE) of thrombotic microangiopathy and renal failure (with full recovery). Grade 3 steroid-related myopathy with full recovery occurred in 3 adult pts. No RP-A501- or steroid-related SAEs were seen in pediatric pts receiving enhanced IM (sirolimus, reduced-dose steroid).

All pts are alive and stable up to 4.5y follow-up. One pt with baseline LV systolic dysfunction had progressive heart failure attributed to DD and required heart transplant 5m post-RP-A501. All evaluable (6/6) pts had cardiac LAMP2 expression at 12m (sustained up to 36m). In 6/6 pts, BNP improved/stabilized and troponin improved at most recent evaluation (54m adult/adolescent; 24m ped). LV mass index was reduced by ≥10% at 12-24m post RP-A501 in 6/6 pts. Improvements in NYHA Class and KCCQ score in 6/6 pts persisted up to 4.5y follow-up.

RP-A501 was associated with acceptable safety and conferred sustained myocardial LAMP2 expression, with stabilized and largely improved serologic, echocardiographic, and clinical CMP parameters. In contrast to demonstrated rapid decline and early mortality in DD, all pts are alive and 6/6 evaluable pts are NYHA Class I at 24-54m follow-up.