Industry Leaders Advancing AAV Gene Therapy for Heart Failure

Introduction

Heart failure (HF) is a critical clinical syndrome defined by the heart’s inability to pump blood effectively to meet the body’s metabolic demands. This condition is not singular; it arises from a diverse set of underlying structural or functional disorders, broadly categorized as cardiomyopathies. These include severe genetic forms like Danon Disease Cardiomyopathy (due to LAMP2 mutations), Friedreich’s Ataxia (FA) Cardiomyopathy (FXN deficiency), and Pompe-Related Cardiomyopathy, as well as more common forms such as Dilated Cardiomyopathy (DCM), Hypertrophic Cardiomyopathy (HCM), and the symptomatic clinical syndrome of Congestive Heart Failure (CHF). While standard guidelines-directed medical therapy (GDMT) helps slow symptomatic progression, for many of these conditions, particularly the rare inherited cardiomyopathies, standard therapeutics offer limited benefit, leading to progressive decline and often requiring heart transplantation.

In response to this significant unmet medical need, a global effort led by several biotechnology companies is seeking to redefine heart failure treatment through Adeno-Associated Virus (AAV)-based gene therapy. The shared, transformative objective of these programs is to correct the underlying molecular pathology of cardiac decline—such as impaired calcium cycling (targeted by AskBio and Medera), lysosomal dysfunction (Rocket Pharmaceuticals), or sarcomere protein deficiency (Tenaya Therapeutics and Lexeo Therapeutics)—rather than simply managing symptoms.

These industry leaders are applying unique strategies, including targeted intracoronary infusion (AskBio, Medera) and high-efficiency systemic delivery using next-generation capsids (Affinia Therapeutics, Rocket, Tenaya, Lexeo), to target both broad heart failure populations (HFrEF, Ischemic HF) and specific monogenic diseases. The following sections detail the specific AAV programs, their mechanisms of action, and their clinical progress in addressing these diverse indications.

Congestive Heart Failure (CHF)

• Overview: Congestive heart failure (CHF) is the symptomatic phase of heart failure in which the heart’s inability to pump blood leads to systemic and pulmonary venous congestion, fluid overload, and tissue hypoperfusion. It is not a distinct disease but a clinical syndrome that occurs when cardiac output i

  s inadequate despite elevated filling pressures. CHF is classified as left-sided (pulmonary edema), right-sided (peripheral edema, ascites), or biventricular, and is most commonly driven by HFrEF (EF <40%) or HFpEF with diastolic dysfunction. Neurohormonal overdrive (RAAS, sympathetic) sustains volume retention, remodeling, and progressive decompensation.

• Progression to Heart Failure and Congestive Heart Failure: CHF is the end-stage manifestation of heart failure progression. It evolves through ACC/AHA stages C–D: Stage C (symptomatic HF with congestion) → Stage D (refractory CHF requiring inotropes, LVAD, or transplant). In cardiomyopathies, structural defects (e.g., LV dilation in DCM, hypertrophy in HCM) increase wall stress, reduce contractility, and accelerate CHF onset. Decompensation triggers include ischemia, arrhythmia, or non-compliance, leading to hospitalization (30-day readmission ~25%).
• Clinical Notes: CHF symptoms include dyspnea, orthopnea, PND, crackles, S3 gallop, JVD, edema, hepatomegaly, ascites, fatigue, and cachexia. Diagnosis: Echo (LVEF, diastolic parameters), BNP/NT-proBNP >400 pg/mL, chest X-ray (cardiomegaly, Kerley B lines). Management: GDMT (ARNI, beta-blockers, SGLT2i, MRA), loop/thiazide diuretics, CRT/ICD, LVAD/transplant. Emerging: AAV gene therapies (e.g., AB-1002, SRD-001) correct molecular defects to prevent CHF decompensation and reduce hospitalization.

Danon Disease Cardiomyopathy

• Overview: This is a rare X-linked dominant lysosomal storage disorder caused by mutations in the LAMP2 gene, leading to defective autophagy and glycogen accumulation in cardiac muscle cells. It primarily presents as a severe hypertrophic cardiomyopathy (HCM-like) with concentric left ventricular hypertrophy, often in childhood or adolescence, predominantly affecting males more severely than females.
• Progression to Heart Failure: Danon Disease frequently progresses to advanced heart failure. The hypertrophy evolves into dilated features in 11-12% of cases, resulting in systolic dysfunction, arrhythmias, and end-stage HF requiring transplantation. Males typically develop severe hypertrophy and HF in their second to third decades, with nearly all needing heart transplant or facing death from HF. Longitudinal studies show that changes in left ventricular structure (e.g., wall thinning and dilation) precede end-stage HF or death, making echocardiographic monitoring critical for risk stratification.
• Clinical Notes: Without treatment, prognosis is poor; enzyme replacement or gene therapy (e.g., AAV-based) is emerging but not yet standard. HF symptoms include dyspnea, fatigue, and edema, often leading to transplant in young patients.

Dilated Cardiomyopathy (DCM)

• Overview: DCM is characterized by ventricular chamber enlargement and systolic dysfunction, often idiopathic or genetic (e.g., BAG3 or LMNA mutations), affecting the left ventricle primarily and leading to reduced ejection fraction (<40%).
• Progression to Heart Failure: DCM is one of the most common direct causes of HF, specifically heart failure with reduced ejection fraction (HFrEF). The dilated, weakened heart fails to pump effectively, causing symptoms like fatigue, leg swelling, and shortness of breath. Complications include arrhythmias, valve regurgitation, thromboembolism, and sudden cardiac arrest, with 5-year mortality around 50% in advanced stages. It progresses through stages (A-D per ACC/AHA guidelines), from asymptomatic dysfunction to refractory end-stage HF requiring devices (e.g., LVAD) or transplant.
• Clinical Notes: Affects adults 20-60 years old more than women; reversible in some cases (e.g., alcohol-related), but genetic forms are irreversible. Management includes ACE inhibitors, beta-blockers, and SGLT2 inhibitors to slow progression.

Friedreich’s Ataxia (FA) Cardiomyopathy

• Overview: FA is an autosomal recessive neurodegenerative disorder due to FXN gene mutations, causing frataxin deficiency and mitochondrial iron overload. Cardiac involvement occurs in nearly all patients (~90%), manifesting as concentric hypertrophic cardiomyopathy by adolescence.
• Progression to Heart Failure: FA commonly progresses to severe HF, which is the leading cause of death (~60% of cases) in the third to fifth decade of life. The hypertrophy leads to diastolic dysfunction, fibrosis, arrhythmias, and eventual systolic failure with reduced ejection fraction. Early subclinical changes (e.g., impaired longitudinal strain) precede overt HF symptoms like exertional dyspnea. Congestive HF accounts for ~30% of fatalities, often compounded by arrhythmias.
• Clinical Notes: Neurological symptoms (ataxia) may mask early cardiac issues; screening with ECG/echo is essential. Antioxidant therapies (e.g., idebenone) show limited benefit; AAV gene therapy (e.g., LX2006) is in trials to halt progression.

Pompe-Related Cardiomyopathy

• Overview: Pompe disease (glycogen storage disease type II) results from GAA gene mutations causing lysosomal acid alpha-glucosidase deficiency and glycogen accumulation in muscles, including the heart. The classic infantile-onset form features massive hypertrophic cardiomyopathy.
• Progression to Heart Failure: Pompe disease, particularly in the infantile form, with severe obstructive hypertrophic cardiomyopathy can lead to cardiorespiratory failure and death by age 1 without treatment. It causes biventricular hypertrophy, outflow obstruction, and systolic/diastolic dysfunction, resulting in HF symptoms like poor feeding and hypotonia. In late-onset forms, cardiac involvement is rarer but can still progress to HF in childhood/juvenile cases. Enzyme replacement therapy (ERT, e.g., alglucosidase alfa) reverses early HF but may not prevent arrhythmias long-term.
• Clinical Notes: Infantile cases show extreme hypertrophy (e.g., obliterating ventricular cavities); late-onset is more skeletal-focused. ERT improves survival, but monitoring for residual HF is needed.

Hypertrophic Cardiomyopathy (HCM)

• Overview: HCM involves abnormal left ventricular wall thickening (≥15 mm) due to sarcomere mutations (e.g., MYBPC3), leading to dynamic outflow obstruction, ischemia, and fibrosis. It’s the most common genetic cardiomyopathy (1:500 prevalence).
• Progression to Heart Failure: While often asymptomatic initially, 5-7% HCM patients progress to advanced HF (nonobstructive end-stage or “burned-out” phase with EF <50%), characterized by dilation, wall thinning, and refractory dyspnea. This is increasingly recognized with better sudden death prevention (e.g., ICDs). HF risk rises with gradients ≥30 mm Hg, leading to NYHA Class III-IV symptoms and transplant need in ~1/15 cases. Progression involves stages: non-progressive (stable), classic (obstructive), adverse remodeling (fibrosis), and HF-related complications.
• Clinical Notes: Affects young adults/athletes; mavacamten (cardiac myosin inhibitor) treats obstruction. Advanced HF management includes septal reduction and transplant evaluation.

 

Industry Leaders and Their Programs

Several biotechnology companies now lead the global effort to redefine heart failure treatment through AAV-based gene therapy. These programs span common diseases like ischemic heart failure and HFrEF, as well as rare inherited cardiomyopathies where standard therapeutics offer limited benefit. While each company applies a unique mechanism of action and delivery strategy, the shared objective is to correct the underlying biology of cardiac decline—rather than merely slow symptoms.

AskBio — AB-1002 (I-1c Gene Therapy for Congestive Heart Failure / HFrEF)

AB-1002 is an investigational, one-time gene therapy delivered directly to the heart to promote production of a modified therapeutic inhibitor-1 (I-1c) protein, which blocks the activity of protein phosphatase 1 (PP1), a central mediator in congestive heart failure (CHF). The therapy has not been approved by regulatory authorities, and its efficacy and safety are still under evaluation. CHF occurs when the heart cannot pump effectively, causing blood to back up in the veins and leading to fluid congestion, shortness of breath, fatigue, and reduced exercise capacity.

• Mechanism
  AB-1002 is an AAV-based gene therapy that delivers a genetic construct encoding a I-1c. The modified I-1c protein inhibits PP1, a key regulator of calcium-handling proteins in cardiomyocytes. By suppressing PP1 activity, I-1c increases phosphorylation of central calcium cycling machinery, improves excitation–contraction coupling, and enhances systolic function. This mechanism aims to restore cardiomyocyte contractile performance and slow the progressive decline associated with chronic heart failure.
• Goal
  The therapy is intended to improve left-ventricular function, enhance cardiac output, reduce heart-failure symptoms, and modify disease course rather than simply provide symptomatic relief. Because impaired calcium cycling is a shared hallmark across many forms of heart failure, the goal is to create a potentially durable, single-dose treatment for broad HFrEF populations, not just rare genetic cardiomyopathies.
• Delivery
  AB-1002 is administered via intracoronary infusion, enabling concentrated delivery to the myocardium while minimizing systemic biodistribution and reducing overall vector dose. This cardiac-directed method aims to maximize transduction efficiency, limit off-target exposure, and reduce immunologic risk.
• Key Results (Phase 1, 12-month data, published in Nature Medicine)
  – No adverse events were attributed to AB-1002 across the full 12-month evaluation.
  – Participants demonstrated clinically meaningful improvements across multiple measures of heart-failure severity.
  – Improvements included left-ventricular ejection fraction, functional capacity, and biomarkers associated with disease progression.
  – Signal durability across 12 months suggests potential long-term benefit rather than temporary hemodynamic support.
• Recent Milestone
  In Oct 2025, Bayer and AskBio announced the publication of the full Phase 1 dataset in Nature Medicine, confirming safety and meaningful clinical improvements. The publication supports the therapeutic rationale and provides scientific validation from a peer-reviewed study.
• Trial Status
  AB-1002 has advanced into a Phase 2 randomized, placebo-controlled clinical study (GenePHIT) enrolling patients with non-ischemic cardiomyopathy and HFrEF. The Phase 1 trial included NYHA Class III heart-failure patients, and successful safety outcomes enabled dose expansion and progression to controlled clinical testing.

 

Medera — SRD-001/ SRD-002 (Regenerative Gene Therapy for Ischemic/Diastolic HF)

Medera is a rising competitor in ischemic heart failure, targeting a significantly larger patient population than rare genetic cardiomyopathies Medera’s lead candidate SRD-001 utilizes an AAV1 vector to deliver SERCA2a, the sarcoplasmic reticulum Ca2+-ATPase critical for calcium reuptake and cardiomyocyte relaxation.

• Mechanism

Medera’s SRD-001 (for HFrEF) and SRD-002 (for HFpEF) deliver the gene encoding  SERCA2a, the sarcoplasmic reticulum Ca2+-ATPase pump critical for calcium re-uptake and normal myocardial relaxation/contractility. The vector is AAV1-based (or cardiotropic AAV1) and delivered via intracoronary or minimally invasive infusion.

• Goal

Restore impaired calcium cycling in failing hearts (both reduced and preserved EF) and achieve durable improvement in contractile or diastolic function, addressing a large unmet population of ischemic or preserved-EF heart failure.

• Delivery

One-time intracoronary infusion of AAV1-SERCA2a using proprietary minimally invasive methodology, allowing broad myocardial coverage with lower systemic exposure.

• Key Results

Interim data from the MUSIC-HFpEF trial show favorable safety and early efficacy signals: in the low-dose cohort (3×10¹³ vg) no gene-therapy-related serious adverse events; improvements in NYHA class, 6-minute walk test, NT-proBNP and high-sensitivity troponin in several patients.

• Recent Milestone & Trial Status

The DSMB cleared the transition from Phase 1b to Phase 2; first patient dosed in 2025 at 4.5×10¹³ vg; enrollment is ongoing. Medera holds Fast Track designation for their HF gene therapy candidate.

 

Rocket Pharmaceuticals — RP-A601 / RP-A501 (LAMP2B Gene Therapy for Danon Disease)

• Mechanism

Rocket leads rare genetic cardiomyopathy gene therapy. RP-A501 delivers LAMP2B via AAV9 to Danon disease—an X-linked lysosomal disorder (LAMP2 mutation) causing impaired autophagy, cardiomyocyte metabolic collapse, massive hypertrophy, and rapid progression to heart failure/transplantation in children/adolescents. Single infusion restores autophagic clearance, reduces toxic glycogen buildup, and reverses structural hypertrophy in models and early clinical data. RP-A601 delivers PKP2 via AAVrh74 to PKP2-ACM—a desmosomal defect driving fibrofatty replacement, life-threatening arrhythmias, and RV-dominant failure.

• Goal

RP-A501: Restore lysosomal/autophagy function, halt cardiomyocyte enlargement, prevent contractility loss, delay/eliminate transplant. RP-A601: Rebuild desmosomes, reduce arrhythmia burden, stabilize RV function, extend survival.

• Delivery

Systemic IV infusion: AAV9 for RP-A501 (cardiac-optimized); AAVrh74 (8.0E13 GC/kg) for RP-A601 (single dose, outpatient-compatible).

• Key Results

RP-A501 (Phase 1, NEJM Mar 2025): ↓LV wall thickness, ↓CK/troponin, improved cardiac MRI structure, EF stabilization in rapid-decline stages.

RP-A601 (Phase 1, ASGCT May 15, 2025; n=3, up to 12 mo): Well-tolerated (mild-moderate AEs, transient ALT, 1 resolved immunosuppression SAE); 2/3 patients NYHA II→I (6/12 mo); stable RV systolic function; ↓arrhythmia burden; biopsy-confirmed ↑PKP2 expression (110–398% vs. baseline).

• Recent Milestone & Trial Status

RP-A501: FDA clinical hold (May 2025) due to patient event; lifted Aug 20, 2025; resume Phase 2 pivotal (n=12) at reduced dose (3.8×10¹³ GC/kg), sequential enrollment (3 pts), no C3 inhibitor, pediatric run-in.

RP-A601: RMAT granted (pre-July 2025); no further dose escalation; pivotal trial design ongoing.

RP-A701 (BAG3-DCM): IND cleared Jun 30, 2025; Phase 1 startup (dose-escalation in adults with ICDs).

Long-term 5–10 yr follow-up cohorts for durability; potentially curative in rare cardiomyopathy space.

 

Tenaya Therapeutics — TN-201 (MYBPC3 Correction for Hypertrophic Cardiomyopathy)

Tenaya Therapeutics is driving advances with its TN-201 program for MYBPC3-mutated HCM, a genetic cause of heart failure where deficiency of cardiac myosin binding protein C leads to sarcomeric disarray, hypertrophy, arrhythmias, and diastolic dysfunction.

• Mechanism

TN-201 corrects MYBPC3 mutations (~40% of genetic HCM), where MyBP-C deficiency disrupts sarcomere kinetics, triggering hypercontractility, LV hypertrophy, fibrosis, arrhythmias, and diastolic failure. AAV9-MYBPC3 restores full-length protein in cardiomyocytes, normalizing cross-bridge cycling, relieving stress, and halting pathologic remodeling — a curative strategy vs. symptomatic Rx (beta-blockers, mavacamten, septal reduction).

• Goal

Reverse hypertrophy, restore diastolic function, eliminate arrhythmias, prevent end-stage HF in ~400K MYBPC3-HCM patients (US/EU).

• Delivery

Systemic AAV9 IV infusion — non-invasive, high cardiac tropism, outpatient-compatible.

• Key Results

Preclinical (HCM mice/NHP): 40% LV wall reduction, arrhythmia elimination, diastolic improvement, >2-yr durability

Phase 1b biopsy (n=3, 52 weeks): MyBP-C ↑ (56%→59%, 62%→64%); all severe pts → NYHA I; ↓wall thickness up to 40% (into normal range); ↓injury biomarkers

• Recent Milestone & Trial Status

MyPEAK-1 (NCT05836259): Cohort 1 & 2 enrollment complete by May 2025

DSMB clearance July 30, 2025: unanimous, clean safety, dose escalation & expansion approved

Q4 2025 interim data: Cohort 1 longer-term + initial Cohort 2 (echo, biomarkers, safety)

Manufacturing scale-up underway for registrational trial 2026

 

Lexeo Therapeutics — LX2006 (Friedreich’s Ataxia–Associated Cardiomyopathy)

• Mechanism
  Lexeo Therapeutics is advancing AAV gene therapy for Friedreich’s ataxia cardiomyopathy, a major cause of mortality in FA. FA is caused by a deficiency of frataxin due to mutations in the FXN gene, resulting in mitochondrial dysfunction, cardiac hypertrophy, and progressive heart failure. LX2006 uses the AAVrh.10 vector to deliver a functional FXN gene intravenously, aiming to restore frataxin levels in myocardial cells. This approach targets the underlying mitochondrial defect, with early clinical data suggesting improvement in cardiac biomarkers, myocardial function, and potentially other neurologic measures.
• Goal
  Increase frataxin expression in the myocardium to rescue mitochondrial function, reduce cardiac hypertrophy, and prevent the progression to heart failure in patients with Friedreich’s ataxia and associated cardiomyopathy.
• Delivery
  Intravenous infusion of AAVrh.10-FXN, leveraging cardiac tropism for effective myocardial gene transfer and frataxin expression.
• Key Results
  In the Phase 1/2 SUNRISE-FA trial, interim data showed increases in left ventricular frataxin levels (via cardiac biopsy), clinically meaningful improvements in left ventricular mass index (LVMI), and stabilization or improvement in cardiac functional parameters among treated patients. A dose-dependent increase in frataxin was observed, and the safety profile has so far remained favorable.​
• Recent Milestone & Trial Status
  LX2006 holds several FDA designations (Breakthrough Therapy, RMAT, Orphan Drug, Rare Pediatric Disease) and is being studied in two open-label trials, with plans for a registrational study by 2026. Enrollment focuses on FA patients with established cardiomyopathy, and Lexeo is gathering natural history data to support future regulatory submissions.

 

Affinia Therapeutics — High-Efficiency Capsid Platform (Lead Program: AFTX-201)

• Mechanism

Affinia Therapeutics is pioneering next-generation AAV capsid engineering using proprietary AI/ML algorithms to design cardiotropic variants with >100-fold higher myocardial transduction efficiency compared to AAV9, enabling ultra-low-dose systemic delivery (as low as 1E13 vg/kg) while dramatically reducing liver off-target expression and immune-mediated toxicity. These engineered capsids have demonstrated robust, uniform cardiac gene transfer across preclinical models of BAG3-related DCM, post-ischemic heart failure, and pressure-overload hypertrophy. By minimizing vector load and hepatic exposure, Affinia’s platform addresses dose-limiting hepatotoxicity and anti-capsid immunity—two critical barriers that have constrained earlier cardiac gene therapies. The technology supports flexible transgene payloads, including full-length BAG3 (AFTX-201), anti-fibrotic factors, and metabolic modulators, positioning it as a versatile backbone for multiple partnered and internal programs.

• Goal

To deliver safer, more effective, and scalable systemic cardiac gene therapy capable of treating both rare monogenic cardiomyopathies (e.g., BAG3-DCM) and common forms of heart failure (e.g., ischemic, hypertensive), ultimately enabling one-time curative interventions and, in the future, repeat or chronic dosing paradigms through immune-evasive capsid designs. This platform aims to expand access to gene therapy beyond pediatric rare diseases into adult-onset, high-prevalence cardiac conditions.

• Recent Milestone & Trial Status

  • October 7, 2025: Closed $40M Series C financing led by NEA, with participation from Eli Lilly, Atlas Venture, F-Prime Capital, and GV (Google Ventures), to advance IND-enabling studies and initiate clinical trials.
  • Lead program AFTX-201 (full-length BAG3 in AI-optimized capsid) on track for IND submission in Q4 2025, targeting BAG3-associated DCM—a severe, early-onset form of heart failure with no disease-modifying treatments.
  • Preclinical partnerships (2024–2025) with Lilly and others for non-monogenic HF indications (ischemic remodeling, diastolic dysfunction).
  • UPBEAT Phase 1/2 trial (AFTX-201) planned for Q1 2026 initiation, evaluating safety, cardiac transduction efficiency, and early efficacy signals (LVEF, NT-proBNP, 6MWT) in adult DCM patients.
  • Manufacturing scale-up underway with suspension-based production and analytical comparability to support commercial-grade supply.
  • Long-term vision: Platform licensing for third-party transgenes and multi-indication pipeline in genetic and acquired cardiomyopathies.

Conclusion

Heart failure (HF) remains a leading cause of mortality with limited long-term options. AAV-based gene therapy represents a fundamental paradigm shift, moving beyond symptom management to correct the underlying molecular deficits. The industry is pursuing parallel strategies: restoring foundational cellular processes for common conditions like HFrEF (AskBio, Medera) and replacing faulty genes for rare monogenic diseases (Rocket, Tenaya, Lexeo). Coupled with delivery innovation, such as next-generation capsids (Affinia), these programs show promising Phase 1/2 results, demonstrating safety and functional improvements. The path forward requires proving long-term durability and translating these potentially transformative, single-dose interventions into standard care across the heart failure spectrum.

 

Author: Jin Qiu

References:

1. Medera Advances Cardiac AAV Gene Therapy to Phase 2 for Heart Failure
2. AskBio’s AAV Gene Therapy for Heart Failure Shows Promising Safety and Efficacy Data
3. Affinia Therapeutics Closes $40 Million Series C to Advance AAV Gene Therapy for Heart Failure
4. Rocket Pharma’s AAV Gene Therapy Shows Promise in Inherited Heart Disease
5. Rocket Pharmaceuticals AAV Gene Therapy for Danon Disease Receives FDA Clearance to Resume Clinical Trial
6. Tenaya Therapeutics’ MYPEAK-1 Trial Demonstrates Improved Outcomes with AAV Gene Therapy for Heart Disease
7. Tenaya Therapeutics Advances Cardiovascular AAV Gene Therapies TN-201 & TN-401 After Positive DSMB Reviews
8. Lexeo May Gain Faster FDA Approval for Friedreich’s Ataxia Gene Therapy