January 20, 2026Open Access
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
Key Result
MUSIC-HFpEF is a first-in-human pilot study evaluating the safety and efficacy of SERCA2a gene therapy in patients with HFpEF, with a primary endpoint of change in PCWP.
Key Points
- Assess the safety and pharmacodynamic effects of AAV1.SERCA2A in patients with HFpEF.
- Phase 1b, open-label, multicenter trial
- Enrollment of 10 patients with confirmed HFpEF
- One-time intracoronary infusion of AAV1.SERCA2A
- Assessment of hemodynamics and echocardiographic measures
- Evaluation of NT-proBNP and functional status
- First-in-human trial of SERCA2A gene therapy in HFpEF
- Primary focus on safety and tolerability
- Secondary endpoints include improved hemodynamics and relaxation measures
Study Design
Type
RCT (n=10)
Blinding
Open-label
Randomization
null
Multicenter
Yes
Structured PICO
Does a one-time intracoronary infusion of AAV1.SERCA2A improve safety, tolerability, and exercise hemodynamics in patients with hemodynamically confirmed HFpEF?
P
Population
10 male or female patients aged ≥ 50 years with hemodynamically confirmed heart failure with preserved ejection fraction (LVEF ≥ 50%). Key inclusion: symptomatic HFpEF (NYHA Class II-III) with recent HF hospitalization or elevated NT-proBNP/LA volume, and resting PCWP/LVEDP ≥ 15 mmHg or exercise PCWP ≥ 25 mmHg at 20 W. Key exclusions: NYHA Class IV, recent IV diuretic therapy, history of LVEF < 50%, recent MI or active angina, cardiac amyloidosis, and persistent/permanent atrial fibrillation.
I
Intervention
AAV1.SERCA2A (Adeno-Associated Virus Serotype 1 vector encoding SERCA2a) administered as a one-time intracoronary infusion at a fixed dose of 3 × 10^13 vector genomes (Cohort A) or 4.5 × 10^13 vector genomes (Cohort B), co-administered with intravenous nitroglycerin.
O
Outcome
Safety and tolerability (all-cause mortality, treatment-emergent adverse events, cell-mediated immune reaction, and ECG/lab shifts) from Day 1 through Week 52, and change from baseline to Week 24 and Week 52 in PCWP during maximal exercise and submaximal (20 W) steady-state exercise.safety
The MUSIC-HFpEF trial protocol outlines the first-in-human study to evaluate the safety, tolerability, and preliminary hemodynamic efficacy of SERCA2a gene therapy in patients with HFpEF.
Main Result
Effect estimate: null (95% CI null)
p-value: p=null
Limitations
- Descriptive assesssment without inferential analysis due to small sample size
- Potential lack of generalizability due to specific inclusion criteria.
Abstract
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.