In the USA, a Phase I trial in Danon’s disease assessed the safety and efficacy of a gene therapy, RP-A501, consisting of intravenous injection of a recombinant serotype 9 adeno-associated virus containing the LAMP2B transgene over a follow-up period of 2 to 4.5 years. It included seven male patients (two aged 11 and 14 and five aged 15 to 21) who were pretreated with immunomodulators. All had heart failure at inclusion, classified as NYHA II.
Adverse events:
- Most were mild to moderate, unrelated to gene therapy, and those that were more severe did not result in sequelae.
- Several serious adverse events were reported in the only patient with a reduced left ventricular ejection fraction at inclusion (he was 21 years old at the time), who had received a high dose of treatment (1.1×1014 genome copies per kg).
- He underwent heart transplantation 5 months after treatment with RP-A501 due to progression of cardiomyopathy, and his clinical condition was stabilized 3 years later.
Efficacy results:
- After a follow-up of 4.5 years, all patients were stable.
- The clinical efficacy of RP-A501, as assessed by cardiac biomarkers, cardiac imaging and symptom improvement, was demonstrated in the six patients with normal left ventricular ejection fraction at baseline.
- No evidence of progression of heart failure was found in these patients (improvement in NYHA class and KCCQ-12 scores), the oldest being 24 years old at the end of follow-up.
- LAMP2 protein expression was observed in cardiomyocytes in all patients at one year.
Based on these results, a Phase II trial has been set up. It aims to evaluate a dose of 6.7×1013 genome copies per kg in 12 male patients aged 8 or over in the USA, Germany, Italy and the UK.
