Gene therapies have been proven effective to treat a handful of rare diseases caused by genetic mutations. Now, researchers at Boston Children’s Hospital have created a gene therapy technique they say might work not just in an inherited form of heart arrhythmia, but also in more common cardiac diseases marked by irregular heartbeats.
In two studies published in the journal Circulation, scientists at Boston Children’s built what could be the first human tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), a potentially lethal form of arrhythmia that's triggered by exercise or sudden emotional stress. Using that model, they developed a gene therapy procedure that aims to treat CPVT by restoring calcium regulation.
“Our hope is to give gene therapy in a single dose that would work indefinitely,” said Vassilios Bezzerides, who was involved in both studies, in a statement. “Our work provides proof-of-concept for a translatable gene therapy strategy to treat an inherited cardiac arrhythmia.”
Current treatments for CPVT including beta blockers and surgery are not enough. To develop more effective methods, the Boston Children’s team first set out to understand CPVT at the molecular level.
Mutations in the RYR2 gene cause about half of all CPVT cases, according to the National Institutes of Health. The gene is involved in releasing calcium, which is critical for initiating heart muscle contraction. The researchers reprogrammed blood cells from two patients who had RYR2-associated CPVT into induced pluripotent stem cells. From those cells, they made heart muscle tissue models that mimic what’s seen in the actual disease.
By inducing contraction and simulating exercise, they found that while calcium waves moved evenly through healthy heart tissues, they moved at different speeds in CPVT models, leading to arrhythmias.
Further investigation revealed that an enzyme called CaM kinase (CaMKII) chemically modifies RYR2 to release calcium. However, mutations in RYR2 disrupt that process and cause excessive calcium in the cells, the team found.
“Nature designed CaMKII as part of the fight-or-flight response,” William Pu, senior author of both studies, explained in the statement. “When you get excited, you release more calcium so the heart can beat faster. But when RYR2 is mutated, the channel is leaky, so the cell releases way too much calcium, which causes arrhythmia.”
In the model, the researchers eliminated arrhythmias by blocking CaMKII modification on RYR2 or simply suppressing CaMKII itself with AIP, a peptide inhibitor of CaMKII.
Translating the results from lab dishes to animals required a subtler approach, because CaMKII acts on many tissues aside from the heart. Enter the gene therapy.
Rather than delivering a functional gene to replace the abnormal RYR2, Bezzerides, Pu and colleagues used a viral vector that selectively traveled to the heart and expressed AIP. In a mouse model of CPVT, the inhibitor reached about half of heart cells—enough to suppress arrhythmias—but it didn't accumulate in non-heart tissues, the team reported.
Boston Children’s is among several organizations working on applying gene therapy to heart disease. Philadelphia-based XyloCor Therapeutics recently raised $17 million in a series A to advance gene therapies for coronary artery disease. The company’s lead candidate, XC001, designed to stimulate new blood vessel growth, has received FDA fast-track designation.
Bezzerides and Pu hope their CPVT model could be used to screen patients for clinical trial enrollment or aid in drug development. As for the gene therapy approach, the researchers plan to refine it and test it in larger animal models before initiating human testing. They hope it could be effective for RYR2-mutated CPVT—and perhaps other more common heart diseases.
“In mouse models of many forms of heart disease, such as ischemic cardiomyopathy, atrial fibrillation, or hypertrophic cardiomyopathy, chronic CaMKII activation is detrimental,” Pu explained. “It is possible that our gene therapy approach to CaMKII inhibition could improve outcomes in these other types of heart disease.”