Can gene therapy achieve what decades of heart failure treatment could not — restoring cardiac function?

Heart failure affects more than 64 million people worldwide and remains one of the leading causes of hospitalisation and death despite significant advances in cardiovascular medicine. Over the past two decades, treatments such as beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), SGLT2 inhibitors and mineralocorticoid receptor antagonists have helped patients live longer and reduced the risk of complications.

Yet these therapies largely focus on slowing disease progression rather than repairing the underlying damage within the heart muscle itself.

This unmet need has renewed interest in an area once considered one of cardiovascular medicine's biggest disappointments: gene therapy. Early attempts to treat heart failure by delivering therapeutic genes directly to the heart generated excitement but ultimately fell short in large clinical trials, raising doubts about whether the approach could ever work in practice.

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However, advances in viral vector technology, gene delivery systems and molecular understanding of heart failure have prompted researchers to revisit the field with renewed optimism.

Several next-generation therapies are now being evaluated globally, with scientists hoping they can address the cellular defects that drive heart failure rather than simply manage symptoms.

Firstpost spoke with Dr Amar Singhal, Director of Cardiology at Sri Balaji Action Medical Institute (Delhi) about why cardiac gene therapy is attracting renewed attention, the scientific breakthroughs behind its revival and whether it could eventually transform treatment for patients with advanced heart failure.

Dr Singhal: The renewed interest stems from a much better understanding of why earlier trials failed. Initial studies, including the CUPID and CUPID-2 trials targeting the SERCA2a gene, showed encouraging early results but failed to deliver consistent benefits in larger patient populations. That led many to question whether cardiac gene therapy was a viable approach.

Subsequent research revealed that the problem was not necessarily the therapeutic target itself but the way the genes were delivered. In many cases, only a small proportion of heart muscle cells actually received and expressed the therapeutic gene. Researchers identified issues such as inadequate gene delivery, poor transduction efficiency, limitations of viral vectors and an incomplete understanding of heart-failure biology.

At the same time, although modern treatments such as SGLT2 inhibitors, ARNIs, beta-blockers and mineralocorticoid receptor antagonists have significantly improved outcomes, they mainly slow disease progression. They do not directly correct the molecular dysfunction within failing heart muscle cells. Gene therapy offers the possibility of addressing those underlying defects.

Dr Singhal: Several important breakthroughs have changed the landscape. Modern adeno-associated virus (AAV) vectors have been engineered to become more cardiotropic, meaning they can target heart tissue more effectively while reducing exposure to other organs.

Delivery techniques have also improved significantly. Advanced intracoronary and catheter-based infusion methods allow a greater amount of therapeutic material to reach heart muscle cells. One of the biggest challenges in earlier trials was poor uptake of therapeutic genes by the heart, and newer delivery systems are helping overcome that obstacle.

In addition, scientists are now able to identify more precise therapeutic targets and, in some cases, use technologies capable of permanently modifying disease-causing genes. Together, these advances have greatly increased confidence in the field.

How do the latest gene therapies differ from conventional heart-failure treatments?

Dr Singhal: Conventional therapies primarily manage symptoms and slow progression of the disease. Gene therapies aim to restore the fundamental cellular processes that become impaired in heart failure.

A major focus has been SERCA2a, a protein responsible for regulating calcium movement within heart muscle cells. Proper calcium handling is essential for the heart to contract and relax efficiently. In heart failure, this mechanism becomes disrupted, reducing the heart's pumping capacity.

By restoring SERCA2a activity, gene therapies seek to improve both contraction and relaxation of the heart muscle, potentially addressing the disease at a much deeper biological level than current medications.

What are the biggest hurdles that still need to be overcome?

Dr Singhal: Delivery remains one of the most significant challenges. The heart is a difficult organ to target, and achieving efficient gene uptake across millions of cardiomyocytes without exposing other organs to excessive vector doses remains complex.

Another challenge is immunity. Some patients already have antibodies against viral vectors such as AAV, which can neutralise the therapy before it reaches the heart. Immune responses may also limit the possibility of repeat dosing.

Long-term safety is equally important because these therapies are designed to produce durable biological effects. Researchers must also identify which patient groups are most likely to benefit. Finally, manufacturing high-quality viral vectors at commercial scale remains technically demanding and expensive.

If current clinical trials succeed, how could gene therapy reshape heart-failure treatment?

Dr Singhal: The impact could be transformative. Instead of focusing primarily on slowing disease progression, physicians may be able to restore impaired cardiac function through a one-time or infrequent treatment.

Successful gene therapies could reduce hospitalisations, improve quality of life and potentially delay or prevent the need for mechanical heart-support devices or heart transplantation. It would also move heart-failure treatment toward a far more personalised approach, where therapies are designed to target specific molecular defects in individual patients.

Will these therapies be affordable and accessible?

Dr Singhal: In the short and medium term, cardiac gene therapies are likely to remain expensive. Manufacturing viral vectors, performing specialised procedures and providing long-term monitoring involve substantial costs. Access will initially be concentrated in specialised centres.

However, there is reason for optimism over the longer term. If these therapies can reduce repeated hospital admissions, advanced interventions and transplant requirements, they may ultimately prove cost-effective. As technology matures and production becomes more scalable, accessibility is also likely to improve.