Rationale and Design of MUSIC-HFpEF: a Phase 1b, Pilot Trial Evaluating the Safety and Pharmacodynamic Effects of AAV1.SERCA2A in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) has limited therapeutic options. Abnormal calcium handling through impaired sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) activity contributes to diastolic dysfunction. AAV1.SERCA2A, an Adeno-Associated Virus Serotype 1 (AAV1) vector encoding SERCA2a, may improve myocardial relaxation in HFpEF. Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Preserved Ejection Fraction (MUSIC-HFpEF) is a Phase 1b, open-label, multicenter trial (NCT06061549) currently enrolling 10 patients with hemodynamically confirmed HFpEF. Patients receive a one-time intracoronary infusion of AAV1.SERCA2A. The primary objective is to assess safety and tolerability; secondary endpoints include effects on resting and exercise hemodynamics, echocardiographic measures of relaxation, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and functional status. MUSIC-HFpEF is the first-in-human trial of SERCA2a gene therapy in HFpEF. Findings will inform the feasibility, safety, and potential clinical benefit of targeted gene therapy in this population. The study is enrolling participants and aims to clarify the safety profile and potential benefits of administering a single dose of AAV1.SERCA2A to individuals with HFpEF.