AAV gene therapies for inherited cardiomyopathies
E Nicoletti, M Kasetty, M Chitty-Lopez, C Ronk, S Rizvi, J D SchwartzAbstract
Background/Introduction
Inherited cardiomyopathies such as Danon disease (DD), PKP2 arrhythmogenic cardiomyopathy (PKP2-ACM), and BAG3-related dilated cardiomyopathy (BAG3-DCM) are characterized by significant morbidity, progressive heart failure, and premature mortality. Current therapies palliate some symptoms, but do not address the underlying genetic defects. Adeno-associated viral (AAV) vectors enable cardiotropic delivery of functional genes to terminally differentiated cardiomyocytes, offering the potential to modify the disease course by restoring protein expression and cellular function.
Purpose
To describe the clinical development of AAV-based gene therapy programs for DD, PKP2-ACM, and BAG3-DCM, contextualized by ongoing natural history studies (NHS).
Methods
In a Phase 1 clinical study in males with DD, treatment with RP-A501 (AAV9.LAMP2B) resulted in LAMP2B protein expression, stabilization/reduction of left ventricular mass index (LVMI), and improvement in heart failure (HF) symptoms1. The ongoing Phase 2 interventional study evaluates the efficacy and safety of RP-A501 in male patients >8 years old with pathogenic LAMP2 variants; primary endpoints include myocardial LAMP2 protein expression and reduction in LVMI. The DD NHS is a global, multicenter observational study collecting both retrospective and prospective clinical data for males and females. Preliminary results from an ongoing Phase 1 study of RP-A601 (AAVrh.74-PKP2a) in patients with PKP2-ACM demonstrated cardiac transduction, increased PKP2 protein expression and stabilization/improvement in arrhythmia burden, heart function and quality of life2. A multicenter, observational NHS collecting longitudinal data and clinical outcomes for patients with PKP2-ACM is ongoing. A BAG3 gene therapy (RP-A701; AAVrh.74-BAG3) is entering Phase 1 supported by evidence that BAG3 regulates sarcomere integrity, autophagy, apoptosis, and excitation-contraction coupling in cardiomyocytes3.
Results
RP-A501 is in a global multi-center Phase 2 study enrolling males age ≥ 8 years with pathogenic LAMP2 variants with a primary endpoint of LAMP2 protein expression and reduction in ventricular hypertrophy. NHS in patients with DD and PKP2-ACM are ongoing to describe further disease progression and clinical outcomes, contextualizing trial findings. A Phase 1 study of RP-A701 in patients with BAG3-DCM has been initiated. Across programs, strategies to mitigate risks associated with systemic AAV infusion include protocol-directed immunomodulation and laboratory monitoring.
Conclusions
AAV-mediated gene therapies have the potential to alter the natural history of DD, PKP2-ACM, and BAG3-associated DCM by addressing the underlying causative genetic deficits.