Cardiovascular disease remains a worldwide challenge, causing undue strain on the health system and contributing substantial patient burden. For decades, our medical response has been focused on treating symptoms, slowing progression, and mechanically repairing issues. However, even the best surgeon is unable to physically re-plumb the pipes in all individuals. The ugly truth is that many hearts may also be sabotaged by not only lifestyle-related factors, but by their genetic blueprints.
These traditional established approaches will remain important for many patients; however, we are moving past mere damage control. Rather than treating only the downstream effects of disease, gene therapy aims to address the underlying cause of the leaking or clogged pipes, not just the water on the floor. Depending on the biological effect or genetic issue, three main strategies have emerged:
- Gene addition: Introducing a functional copy of a gene
- Gene silencing: Blocking the expression or quieting the gene
- Gene editing: Editing the deoxyribonucleic acid (DNA) to correct a mistake
As of this writing, no gene therapies have obtained Food and Drug Administration (FDA) approval for cardiovascular applications, so this blog focuses on investigational approaches that are in various stages of research, development, and clinical trials.
The delivery dilemma: Getting genetic therapies to the right tissue
Selecting the right therapeutic strategy is only part of the challenge. Gene therapies must also be delivered safely, efficiently, and selectively to the intended tissue. For cardiovascular applications, this can be especially complex. A therapy may need to travel through the bloodstream, reach the intended cardiac or vascular tissue, avoid unintended uptake in other organs, and limit immune system interference.
Today, many cardiovascular gene therapy programs rely on two major delivery approaches: viral vectors and lipid nanoparticles.
For cardiac applications, adeno-associated virus (AAV) vectors are commonly used because some natural AAVs—including adeno-associated virus 9 (AAV9), adeno-associated virus rhesus isolate 10 (AAVrh.10), and adeno-associated virus rhesus isolate 74 (AAVrh.74)—show affinity for heart tissue. However, these vectors aren’t perfect. They can still reach non-target tissues, and some patients may have pre-existing immunity from prior exposure to naturally occurring AAVs.
To address these limitations, researchers are developing engineered capsids (proteins comprising the outside of AAVs) designed to improve cardiac delivery, reduce off-target exposure, lower required doses, and potentially avoid immune recognition.
Lipid nanoparticles
Lipid nanoparticles (LNPs) are another delivery approach. These microscopic lipid-based particles (oily bubbles) can encapsulate and protect fragile genetic cargo—including messenger ribonucleic acid (mRNA) to express a therapeutic protein, small interfering ribonucleic acid (siRNA) to suppress the expression of a disease-causing protein, or clustered regularly interspaced short palindromic repeats (CRISPR) components for gene editing—until the material reaches target cells.
LNPs are familiar to many people because they were used in coronavirus disease 2019 (COVID-19) mRNA vaccines. In cardiovascular gene therapy, they’re being explored as a nonviral delivery platform, particularly for therapies intended to act in the liver or other tissues involved in lipid metabolism.
Gene therapy approaches in cardiovascular clinical research
Because cardiovascular disease includes a broad range of conditions, clinical research programs are targeting different anatomical systems and biological mechanisms. Current investigational approaches include therapies for cardiomyopathies, inherited arrhythmias, atherosclerotic cardiovascular disease, ischemic heart disease, and peripheral artery disease.
1. Cardiomyopathies: Addressing inherited causes of weakened or thickened heart muscle
Cardiomyopathies can cause the heart muscle to become abnormally stretched, thickened, or stiff. These changes can reduce pumping efficiency and may lead to symptoms such as shortness of breath, fatigue, arrhythmias, or heart failure. Several investigational gene therapies are focused on inherited cardiomyopathies linked to specific genes.
BAG3-associated dilated cardiomyopathy
Mutations in the Bcl-2-associated athanogene 3 (BAG3) gene can reduce production or function of a protein important for maintaining cardiac muscle structure. In some patients, this can contribute to dilated cardiomyopathy, a condition in which the heart chambers enlarge and the heart’s pumping ability declines.
Two investigational programs are evaluating AAV-based approaches designed to deliver a functional BAG3 gene:
- Affinia Therapeutics is evaluating an engineered capsid approach intended to improve cardiac delivery and address limitations associated with natural AAV vectors.
- Rocket Pharmaceuticals is evaluating an AAVrh.74-based approach to deliver a functional BAG3 transgene.
Both programs are designed to deliver BAG3 to cardiac muscle cells with the goal of restoring BAG3 protein levels and supporting heart muscle structure and function.
MYBPC3-associated hypertrophic cardiomyopathy
Mutations in myosin binding protein C3 (MYBPC3) are among the most common genetic causes of hypertrophic cardiomyopathy, a condition characterized by thickened heart muscle and impaired relaxation or contraction. Because patients can have many different pathogenic variants across the MYBPC3 gene, one investigational strategy is to deliver a functional copy of the gene rather than create separate therapies for each mutation.
Tenaya Therapeutics is evaluating TN-201, an investigational therapy that uses a recombinant AAV9 vector to deliver a functional MYBPC3 gene to cardiac muscle cells. The goal is to improve cardiac protein expression and support more normal heart muscle function.
2. Familial arrhythmias: Targeting the heart’s electrical system
Some inherited cardiovascular conditions primarily affect the heart’s electrical signaling rather than its physical structure. These conditions can disrupt normal rhythm and increase the risk of serious arrhythmias.
One area of active clinical research is arrhythmogenic right ventricular cardiomyopathy, also referred to as arrhythmogenic right ventricular dysplasia. This condition is often associated with mutations in plakophilin-2 (PKP2), a gene involved in proteins that help cardiac cells adhere to one another. When this structure is disrupted, cardiac tissue can be replaced by fibrofatty tissue, increasing the risk of abnormal rhythms.
Several companies are investigating gene therapy approaches designed to deliver a functional human PKP2 gene:
- Rocket Pharmaceuticals is evaluating an AAVrh.74-based platform.
- Tenaya Therapeutics is evaluating an AAV9-based approach.
- Lexeo Therapeutics is evaluating an AAVrh.10-based approach.
These programs are exploring whether gene delivery can help address the underlying cellular adhesion defect associated with PKP2-related disease.
3. Atherosclerotic cardiovascular disease: Targeting lipid metabolism and disease progression
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally. If genetic cardiomyopathies are a structural crisis, ASCVD is the ultimate plumbing catastrophe. Over decades, a mixture of fat, cholesterol, calcium, cells, and cellular debris hardens into stubborn arterial plaques. This catastrophe amplifies every other cardiovascular problem once they manifest. ASCVD is attributable to a complexity of causes and risk factors, including lifestyle, age, familial predisposition, and a multitude of comorbidities. Atherosclerosis acts as a massive metabolic magnifier for a patient who already has a weak pump or clogged pipes, increasing the risk that the entire system fails that much faster.
Gene-based therapies in this area often focus on modifying lipid metabolism or reducing disease-associated proteins.
Silence Therapeutics and SLN360: Reducing lipoprotein(a)
Silence Therapeutics’ SLN360 is an investigational siRNA therapy designed to reduce production of lipoprotein(a), or Lp(a). Elevated Lp(a) is recognized as a causal risk factor for cardiovascular disease.
SLN360 is designed to bind to and degrade lipoprotein(a) gene (LPA) mRNA before it can be translated into apolipoprotein(a), a key component of Lp(a). By reducing Lp(a) production, researchers are evaluating whether the therapy may help reduce cardiovascular risk in patients with elevated Lp(a).
CRISPR Therapeutics and CTX310: Targeting ANGPTL3
CRISPR Therapeutics is evaluating CTX310, an investigational in vivo CRISPR-Cas9 therapy delivered by lipid nanoparticles. The therapy is designed to target angiopoietin-like 3 (ANGPTL3), a gene involved in lipid metabolism.
ANGPTL3 helps regulate enzymes that clear circulating lipids. Disrupting ANGPTL3 may increase lipid clearance and reduce low-density lipoprotein (LDL) cholesterol and triglycerides in patients with difficult-to-treat lipid disorders. This approach remains investigational and requires continued evaluation for safety, durability, and clinical benefit.
4. Ischemia and peripheral artery disease: Exploring regenerative and angiogenic approaches
Ischemia occurs when tissue does not receive enough oxygen-rich blood. In the heart, ischemia can contribute to angina, myocardial infarction, and ischemic heart disease. In the limbs, reduced blood flow can contribute to peripheral artery disease, which may cause pain, impaired mobility, and tissue damage.
Several investigational gene therapy strategies are focused on encouraging tissue repair, improving blood flow, or supporting vascular function.
YAP Therapeutics and YAP101: Supporting cardiac regeneration
Adult cardiomyocytes have limited regenerative capacity after injury. Following myocardial damage, scar tissue can replace functional heart muscle, contributing to long-term impairment.
YAP Therapeutics is evaluating YAP101, an investigational therapy delivered by a heart-targeted AAV vector. The therapy uses short hairpin ribonucleic acid (shRNA) to silence Salvador 1, a component of the Hippo signaling pathway. Because the Hippo pathway helps regulate cell growth, temporary modulation of this pathway may support cardiac regeneration and reduce fibrotic tissue. Additional clinical research is needed to determine whether this approach can safely improve cardiac function.
Sanofi and Ad2/HIF-1α/VP16: Promoting angiogenesis
Sanofi has evaluated an investigational adenoviral therapy, adenovirus type 2/hypoxia-inducible factor-1 alpha/VP16 (Ad2/HIF-1α/VP16), for peripheral artery disease. This therapy is designed to deliver an engineered transcription factor related to hypoxia-inducible factor 1-alpha, a molecule involved in the body’s response to low oxygen levels.
The goal of this approach is to stimulate angiogenesis, or the formation of new blood vessels, in ischemic tissue. By promoting new vessel growth, researchers aim to improve blood flow in areas affected by peripheral artery disease.
Libella Gene Therapeutics and hTERT: Exploring vascular aging pathways
Libella Gene Therapeutics has explored an AAV-based approach designed to deliver human telomerase reverse transcriptase (hTERT) to vascular cells. Telomeres are protective structures at the ends of chromosomes that shorten as cells divide, and telomerase can help maintain telomere length.
This approach is based on the hypothesis that supporting telomere maintenance may help address aspects of cellular aging involved in vascular disease. As with other emerging approaches, further evidence is needed to establish safety, efficacy, and clinical relevance.
Looking ahead: A more precise future for cardiovascular care
Gene therapy is expanding the cardiovascular research landscape by giving investigators new ways to study and potentially address the biological drivers of disease. For certain inherited or molecularly defined conditions, these approaches may shift treatment from long-term symptom management toward more targeted intervention.
However, the field remains complex. Delivery, durability, immune response, off-target effects, long-term safety, and patient selection are all critical questions that clinical research must continue to answer.
As viral vectors, lipid nanoparticles, ribonucleic acid (RNA)-based therapies, and gene-editing technologies advance, cardiovascular care may become increasingly precise. The most meaningful progress will depend on rigorous clinical evidence, transparent communication, and careful evaluation of both potential benefit and risk.
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