From mutation to medication: gene therapy’s role in cardiovascular disease

Gene therapy is emerging as a transformative approach in the treatment of cardiovascular disease, with the potential to correct underlying genetic abnormalities and provide long-lasting effects. Advances in molecular biology and delivery technologies have led to the development of novel therapies targeting conditions such as heart failure, cardiomyopathy, and amyloidosis. These investigational therapies employ a variety of strategies, including viral vector-mediated gene delivery, RNA-targeting methods, and gene editing tools like CRISPR-Cas9. As clinical trials demonstrate promising early results, gene therapy is advancing from experimental science toward becoming a viable treatment option.

Heart Failure:

• AB-1002: A gene therapy for congestive heart failure with reduced ejection fraction has received FDA Fast Track Designation.¹ In a phase I trial (NCT04179643), presented at ESC 2025, AB-1002 demonstrated no treatment-emergent or serious adverse events and showed clinically meaningful improvement in multiple efficacy endpoints.^2,3 AB-1002 is designed to increase the production of protein inhibitor 1 (I-1c), which blocks protein phosphatase 1 – a key phosphatase associated with congestive heart failure. The AB-1002 phase II trial (GenePHIT; NCT05598333), designed to evaluate efficacy, safety, and tolerability is currently recruiting.⁴
• A phase I study (NCT03409627) of INXN-4001 for the treatment of heart failure was completed in 2020 in patients with a left ventricular assist device (LVAD).⁵ INXN-4001 is a multigenic, triple effector plasmid therapy, delivered via a retrograde coronary sinus infusion (RCSI). INXN-4001 was designed to express SDF-1α, VEGF165, and S100A1, which effect progenitor cell recruitment, angiogenesis, and improve calcium metabolism.⁶ The phase I study met its primary endpoints, showing improvements in patient reported outcomes and a good safety profile.

Hypertrophic Cardiomyopathy:

• RP A601 is a one-time gene therapy under investigation for the treatment of plakophilin-2 related arrhythmogenic cardiomyopathy (PKP2-ACM), an inherited condition caused by mutations in the PKP2 gene. RP A601 is designed to deliver the coding sequence of PKP2a via a recombinant adeno-associated viral (AAV) vector. The FDA has granted regenerative medicine advanced therapy (RMAT) designation for RP A601, following positive safety and efficacy findings from the ongoing phase 1 study (NCT05885412).^7,8 Preliminary results from the trial were presented at the 2025 Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT).⁹
• LX2021 gene therapy is currently in preclinical development for the treatment of desmoplakin (DSP) cardiomyopathy, a subtype of arrhythmogenic cardiomyopathy (ACM).¹⁰ LX2021 delivers functional connexin 43 (Cx43) protein, which can be significantly reduced in cardiac muscle cell junctions in patients with ACM, potentially restoring Cx43 levels.

Amyloidosis:

• NXC-201 is an autologous CAR-T therapy targeting BCMA under development for relapsed/refractory AL amyloidosis. Findings from the phase Ib/IIa NEXICART-1 study (NCT04720313) of NXC-201 were presented at ASGCT 2024.^11,12 NXC-201 showed positive response rates and durable effects in patients not exposed to prior BCMA-targeted bispecific antibodies. Following the findings, NEXICART-2 (NCT06097832), a phase Ib dose expansion study was launched mid-2024.¹³

Friedreich’s Ataxia Cardiomyopathy:

• The safety and effectiveness of AAVrh.10hFXN, an AAV-based gene therapy, is being studied in a phase Ia and Ib trial (NCT05302271) for the treatment of cardiomyopathy linked to Friedreich’s ataxia (FA).¹⁴ Patients with FA have a mutation in the FXN gene that causes a disruption in the production of the protein frataxin, which is essential for mitochondrial and cardiac function. Intravenous AAVrh.10hFXN transfers the FXN gene to myocardial cells, increasing the levels of frataxin. An estimated 80% of people with FA develop FA cardiomyopathy.¹⁵

Although gene therapies offer a promising future in the treatment of cardiovascular disease, there are challenges that need to be considered during the development of these therapeutics. For example, efficient and targeted gene delivery to effected cells remains a challenge, which needs to be overcome to prevent off-target effects. Some viral vectors can also trigger immune responses, potentially limiting their effectiveness and causing adverse effects. It is important that the long-term safety and efficacy of gene therapies is carefully evaluated in clinical trials. Despite these challenges, gene therapy holds significant promise for treating a range of cardiovascular diseases, offering the potential to address underlying genetic causes and provide durable therapeutic benefits. 

References 

1. AskBio. AskBio receives FDA Fast Track Designation for AB-1002 investigational gene therapy program in congestive heart failure. 2025. [Press release]. Available at: https://www.askbio.com/askbio-receives-fda-fast-track-designation-for-ab-1002-investigational-gene-therapy-program-in-congestive-heart-failure/ (accessed 22 July 2025).
2. ClinicalTrials.gov. AB-1002 in Patients With Class III Heart Failure (NAN-CS101). ClinicalTrials.gov identifier: NCT04179643. Available at: clinicaltrials.gov/study/NCT04179643 (accessed 21 July 2025).
3. Hajjar R, et al. NAN-CS101: A first-in-human Phase 1 open-label dose-escalation study of AB-1002 gene therapy for the treatment of NYHA class III HF. Oral presentation. ESC Heart Failure Meeting 2025, Belgrade, 19 May 2025.
4. ClinicalTrials.gov. Phosphatase Inhibition by Intracoronary Gene Therapy in Subjects With Non-Ischemic NYHA Class III Heart Failure (GenePHIT). ClinicalTrials.gov identifier: NCT05598333. Available at: clinicaltrials.gov/study/NCT05598333 (accessed 21 July 2025).
5. ClinicalTrials.gov. Novel INXN-4001 Triple Effector Plasmid in Heart Failure. ClinicalTrials.gov identifier: NCT03409627. Available at: clinicaltrials.gov/study/NCT03409627 (accessed 21 July 2025).
6. Precigen. Precigen Triple-Gene Provides Six-month Follow-up Data from Phase I Study of INXN-4001, a Multigenic Investigational Therapeutic Candidate for Heart Failure. Available at: investors.precigen.com/news-releases/news-release-details/precigen-triple-gene-provides-six-month-follow-data-phase-i (accessed 21 July 2025).
7. Businesswire. Rocket Pharmaceuticals Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for RP-A601 Gene Therapy for PKP2-Arrhythmogenic Cardiomyopathy. 2025. [Press release]. Available at: www.businesswire.com/news/home/20250716926875/en/ (accessed 21 July 2025).
8. ClinicalTrials.gov. A Phase 1, Dose Escalation Trial of RP-A601 in Subjects With PKP2 Variant-Mediated Arrhythmogenic Cardiomyopathy (PKP2-ACM). ClinicalTrials.gov identifier: NCT05885412. Available at: www.clinicaltrials.gov/study/NCT05885412 (accessed 21 July 2025).
9. Greenberg BH. Preliminary Data from a Phase I Gene Therapy Trial of RP-A601 (AAVrh.74-PKP2a) for Adult Patients with PKP2-Arrhythmogenic Cardiomyopathy (PKP2-ACM). Presented at: ASGCT, New Orleans, 15 May 2025.
10. LEXEO therapeutics. Desmoplakin Cardiomyopathy. Available at: www.lexeotx.com/programs/cardiac-programs/desmoplakin-cardiomyopathy/ (accessed 21 July 2025).
11. ClinicalTrials.gov. NXC-201 (formerly HBI0101) Multiple Myeloma. ClinicalTrials.gov identifier: NCT04720313. Available at: clinicaltrials.gov/study/NCT04720313 (accessed 21 July 2025).
12. IMMIX BIOPHARMA. Immix Biopharma Announces Positive NXC-201 Relapsed/Refractory AL Amyloidosis Clinical Data in ASGCT 2024 Late Breaking Oral Presentation. 2024. [Press release]. Available at: https://immixbio.com/immix-biopharma-announces-positive-nxc-201-relapsed-refractory-al-amyloidosis-clinical-data-in-asgct-2024-late-breaking-oral-presentation/ (accessed 21 July 2025).
13. ClinicalTrials.gov. Study of NXC-201 CAR-T in Patients With Light Chain (AL) Amyloidosis (NEXICART-2). ClinicalTrials.gov identifier: NCT06097832. Available at: www.clinicaltrials.gov/study/NCT06097832 (accessed 21 July 2025).
14. ClinicalTrials.gov. Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich’s Ataxia. ClinicalTrials.gov identifier: NCT05302271. Available at: www.clinicaltrials.gov/study/NCT05302271 (accessed 21 July 2025).
15. LEXEO therapeutics. Friedreich’s Ataxia. Available at: https://www.lexeotx.com/programs/cardiac-programs/friedreichs-ataxia/ (accessed 21 July 2025).

Further content in cardiovascular disease.

Editor: Victoria Smith, Senior Content Editor.

Disclosures: This article was created by the touchCARDIO team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.

Cite: From Mutation to Medication: Gene Therapy’s Role in Cardiac Repair. touchCARDIO. 22 July 2025.

Related content:

• First Asymptomatic Gene Carrier Dosed in Pioneering Trial for Rare ATTRv Amyloidosis: the ACT-EARLY Study
• Q&A with Dr Sean Zheng: touchCARDIO Future Leader 2025
• Monitoring Disease Progression in Transthyretin Amyloid Cardiomyopathy

SIGN UP to touchCARDIOLOGY!

Register Register

Join our global community today for access to thousands of peer-reviewed articles, expert insights and learn-on-the-go education across 150+ specialties, plus concise email updates and newsletters so you never miss out.