Benefiting from technological and conceptual groundwork and positive early data, gene therapies are advancing in the clinic for cardiovascular diseases including congestive heart failure, chronic refractory angina and cardiomyopathy.
Precision medicines—and particularly gene therapies—are coming for heart disease. That’s according to Faraz Ali, CEO of Tenaya Therapeutics, a California-based biotech focused on developing practice-changing cardiovascular therapies.
Cardiovascular diseases are the leading cause of death worldwide, claiming nearly 18 million lives annually, according to the World Health Organization. The disease category itself refers to a diverse set of conditions that afflict the heart and blood vessels, ranging from highly prevalent disorders such as heart failure and coronary artery disease to the rarer cases of cardiomyopathy associated with Duchenne muscular dystrophy or transthyretin amyloidosis.
In most cases, the first intervention option for cardiovascular disease is a change in lifestyle, including diet and exercise patterns. Medications are prescribed on a symptomatic basis—aspirin, for instance, thins the blood and combats clotting, while beta blockers slow down the heartbeat and help lower blood pressure.
But another therapeutic class, gene therapies, is starting to gain traction in this space. “We now have some early successes,” Ali told BioSpace, noting Rocket Pharmaceuticals’ work in Danon disease and Lexeo Therapeutics’ progress in Friedreich’s ataxia cardiomyopathy. “Now you have two examples of an AAV gene therapy for genetic cardiomyopathy where there’s early clinical benefit.”
The concept of gene therapy—using a healthy gene to improve or restore the expression of a certain protein—has at this point been validated as an effective treatment approach, Ali continued. Additionally, the techniques and tools that scientists use to identify and isolate genes of interest and package them into therapeutic particles have been highly refined, he said.
Here, BioSpace reviews five promising gene therapies being investigated for cardiovascular indications.
Renova Therapeutics’ RT-100
Indication: Congestive heart failure
The most mature asset on this list is Renova’s RT-100, which the California–based biotech is developing for congestive heart failure (CHF).
Afflicting more than 6 million Americans, CHF is linked to a variety of causes, including infections, blood clots or other cardiovascular conditions such as high blood pressure, heart inflammation or coronary artery disease.
According to Renova’s website, RT-100 works by delivering a copy of the AC6 gene, which encodes a protein found in heart muscles and plays a central role in regulating heart function. RT-100’s mechanism of action allows it to boost the content of the AC6 protein in the heart, improving the organ’s function.
In 2016, Renova published Phase II findings for RT-100 in JAMA Cardiology, touting a significant increase in left ventricular peak versus placebo at 4 weeks. Left ventricular peak is a key measure of left ventricular diastolic function that is typically compromised in heart failure patients. The gene therapy also significantly improved left ventricular ejection fraction at the same time point.
RT-100 was found to be safe for CHF patients, with no increase in arrhythmias, according to Renova. Two patients died, one in the active treatment group and another in the placebo arm. The rate of hospitalization for heart failure was likewise comparable between the RT-100 and placebo groups.
The study was small, however, enrolling only 56 patients, of whom 42 were dosed with RT-100. Renova was preparing to submit its plan for a pivotal Phase IIb/III study to the FDA as of May 2024. If successful in the Phase IIb part, RT-100 would then move on to the Phase III portion of the trial, setting the gene therapy up for a regulatory filing.
XyloCor’s XC001
Indication: Chronic refractory angina
Close behind Renova is XyloCor Therapeutics, which is targeting chronic refractory angina with XC001. In particular, the biotech is focusing on patients who are ineligible for coronary artery bypass and percutaneous coronary intervention, and who have tried and failed all other available pharmacologic options.
Affecting some 10 million people in the U.S., angina is a cardiovascular symptom that refers to chest pain or discomfort, typically due to plaques that obstruct the flow of oxygenated blood into the heart, forcing the organ to pump harder and faster. Angina is eased by addressing the underlying cardiovascular disease causing it, usually through the use of anticoagulants, blood pressure medication and cholesterol-lowering drugs.
Patients who continue to suffer from angina despite receiving optimal medical therapy develop chronic refractory angina.
XC001 addresses angina by delivering a copy of the VEGF gene into the heart, which promotes the development of new blood vessels that bypass existing obstructions and restore healthy levels of oxygen in heart muscles, according to XyloCor’s website.
In May 2024, XyloCor released final findings from the Phase II portion of its Phase I/II EXACT clinical trial, demonstrating that the gene therapy was safe and had “transformative disease-modifying potential” in patients with chronic refractory angina, the company said at the time. The data, published simultaneously in Circulation: Cardiovascular Interventions, showed that XC001 could significantly improve exercise duration, angina frequency and chest pain in patients.
XyloCor president and CEO Al Gianchetti said at the time that the biotech was preparing its next clinical trial to advance the development of XC001. According to a July 2024 press release, XyloCor will start a Phase IIb study for XC001 in chronic refractory angina, though the company has yet to provide a detailed timeline.
Regenexbio’s RGX-202
Indication: Cardiomyopathy in Duchenne muscular dystrophy
One of the hottest targets in biopharma, Duchenne muscular dystrophy (DMD) is a rare neurodegenerative disease marked by weakness and wasting in patients, who are typically diagnosed between the ages of three and six years. The disease mostly affects boys, at a frequency of 1 in 3,500 live births worldwide.
DMD is caused by mutations in the DMD gene on the X chromosome, which encodes the dystrophin protein, a crucial component of muscle cells. Alterations in the DMD gene lead to faulty dystrophin, in turn progressively compromising muscles across the body, including the trunk and limbs. Ultimately, DMD can also affect the heart muscles, leading to life-threatening complications.
Regenxbio is proposing RGX-202 as a one-time treatment for DMD. The investigational gene therapy works by delivering the microdystrophin transgene that codes for a dystrophin protein bearing an amino acid chain called a C-terminal domain. According to the biotech, this add-on domain has been shown in preclinical assessments to help make heart muscles more robust, in turn helping to preserve the healthy function of the organ.
In August 2024, Regenxbio reported interim data from the Phase I/II AFFINITY DUCHENNE trial, touting 77.2% and 46.5% microdystrophin expression in patients 5.8 and 8.5 years of age, respectively. The biotech at the time called these findings “robust,” adding that they “support plans for accelerated approval.” In November, the company announced that it has aligned with the FDA on the pivotal phase of AFFINITY DUCHENNE, for which the first patient had been dosed.
AFFINITY DUCHENNE is expected to be completed in December 2025, with a Biologics License Application scheduled for 2026.
AskBio’s AB-1002
Indication: Congestive heart failure
Joining Renova against CHF is Bayer subsidiary Asklepios BioPharmaceutical, or AskBio. The North Carolina–based biotech is advancing AB-1002, a one-time gene therapy designed to boost the expression of a specific protein inhibitor in the heart.
According to AskBio’s website, one potential cause of CHF is the downregulation of the inhibitor of protein phosphatase 1 (PP1) in the heart. PP1 is an important regulator of cellular pathways, and in the heart, it plays a central role in restoring the contractility of muscles to basal levels. Precise control over the action of PP1 is critical in maintaining the healthy function of the heart, and its excessive enzymatic activity has been linked to heart failure. AskBio’s AB-1002 seeks to address this particular cause of CHF by delivering a gene into the heart muscles, promoting their production of an inhibitory protein to PP1.
In November 2023, the biotech presented early Phase I data for AB-1002, showing that at the 12-month follow-up, a single dose of the gene therapy led to “clinically meaningful improvements” in left ventricular ejection fraction and symptoms in three patients, who also saw better exercise function. AB-1002 is currently being studied in the Phase II GenePHIT study, for which the first patient was randomized in February. The study’s primary completion date is October 2026.
Tenaya Therapeutics’ TN-201
Indication: Hypertrophic cardiomyopathy
Tenaya is taking a precision medicine approach to cardiovascular diseases, disaggregating patients into smaller subgroups according to biomarkers and targeting specific disease-causing genes.
“We’re taking a page out of the playbook of oncology,” Ali said of the company’s drug development philosophy. “We don’t just talk about breast cancer, right? We talk about breast cancer with a specific mutation that allows for more precise development and a more enriched study and potentially larger effect sizes.”
This approach has produced Tenaya’s lead asset TN-201, an investigational gene therapy delivered using an adeno-associated virus vector and targeting mutations in the MYBPC3 gene.
According to the biotech, approximately 20% of hypertrophic cardiomyopathy patients in the U.S.—corresponding to around 120,000 people—harbor mutations in the MYBPC3 gene, which in turn leads to an insufficiency in a key protein involved in regulating heart contraction. As a result, patients with this genetic anomaly have abnormally thick heart walls, which could give rise to several life-threatening complications such as heart failure and cardiac dysfunction.
Last month, Tenaya released early Phase Ib/II data for TN-201, demonstrating that after receiving a 3E13-vg/kg dose of the gene therapy, patients showed detectable levels of the vector DNA in their heart tissues, as well as signs of transgene RNA expression. Over time, levels of the TN-201 mRNA and the myosin-binding protein C also increased. Clinical markers of the disease also stabilized or gradually improved in two patients who had received TN-201.
At the time, CMO Whit Tingley said these data “provide important de-risking” of the TN-201 program and will allow the company to enroll patients into a higher-dose cohort. Still, investors were underwhelmed, sending Tenaya’s stocks tanking 50% following the readout.
William Blair analysts attributed the selloff to the RNA expression data, which was “significantly lower than what was observed in preclinical models.” More data from this study are expected this year, according to Tenaya.
https://www.biospace.com/drug-development/5-cardio-gene-therapies-on-the-near-horizon
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