Tenaya gene therapy for deadly heart condition boosts long-term survival in mice

Tenaya Therapeutics’ gene therapy for an inherited heart condition that can cause sudden death appears to be effective in mice, new data show. 

In a journal article published March 18 in Nature Communications Medicine, Tenaya scientists reported that a single dose of the company’s gene therapy for arrhythmogenic right ventricular cardiomyopathy, or ARVC, prevented the disease from setting in or slowed its progression in mice that had already developed it. Mouse models of ARVC that received the treatment also had longer life spans than those that didn’t.

ARVC is a genetic condition caused by a mutation in the gene PKP2 that renders it unable to encode the PKP2 protein, which is required to maintain the heart’s structure and function. While patients may live without symptoms for years, the normal heart muscle is quietly being replaced with fatty tissue, usually beginning in the right ventricle. In some cases, this leads to abnormal heart rhythms and sudden death, which is often the very first symptom. In all of them, the amount of blood the heart can pump is reduced, gradually causing it to fail. Complications set in prior to age 40 on average, and about 1 in 1,000 to 1 in 5,000 people have the disease. There are no treatments for the underlying pathology. 

Tenaya’s gene therapy, TN-401, restores production of the PKP2 protein by replacing its parent gene. The first set of experiments in the new study assessed whether it could prevent disease in mice that hadn’t yet developed the condition. Adult animals were given either a control solution or a single dose of the treatment before the gene for PKP2 was knocked out. The mice that received the therapy did not go on to develop arrhythmias nor structural changes in their hearts, unlike the untreated mice. The median life span of the treatment group was at least 58 weeks, many times the median 4.7 weeks of the sick controls. 

In another set of experiments, the researchers studied whether TN-401 could reverse disease in mice with ARVC that had already developed cardiac remodeling. This was a difficult task given that the mice would normally die within three to six weeks without treatment, they noted. But four weeks after TN-401 was administered—and nine weeks after the PKP2 gene had been chemically knocked out in the mice—the scientists showed that some pathological changes were prevented or reversed in the hearts’ ventricles. The therapy also reduced arrhythmias, though not to a statistically significant degree. 

As for survival, the mice that received the therapy had a median life span of greater than or equal to 50 weeks, “comparable to the survival benefit observed in the preventative mode of treatment,” the researchers wrote. 

The article also summarized data from tolerability studies on TN-401, which showed that greater than 10 times the efficacious dose was tolerable in healthy mice. The researchers wrote that the results of toxicology studies, which were not included in the paper, showed that the therapy was safe in mice and primates. 

Tenaya received FDA clearance in the fall to launch human studies of TN-401, which has both orphan-drug and fast-track designations from the agency. The company anticipates launching the trial, called RIDGE-1, in the second half of 2024, according to a Monday press release