by Nancy Fliesler, Children's Hospital Boston

Gene therapy could potentially restore the orderly structure of dyads in heart muscle (as in the top image) and help reverse heart failure. Credit: Fujian Lu, PhD, Pu Lab, Boston Children’s Hospital

Our heart muscle is studded with tiny dyads, intricately designed structures that manage incoming electrical signals and calcium release to coordinate our heartbeats. Could gene therapy help maintain dyads' structure and boost the function of failing hearts? A new study suggests it can.

"We know that in heart failure from many causes, dyads become disorganized," says study leader William Pu, MD, director of Basic and Translational Cardiovascular Research at Boston Children's Hospital. "Dyad disorganization is not usually an originator of heart failure, but can worsen it. Having a way to preserve dyad organization could be an approach to treating many different types of heart failure."

In previous work, Pu and colleagues showed that a protein called cardiomyopathy-associated 5 (CMYA5) is important for assembling and stabilizing dyads. Now, they've figured out a way to deliver extra CMYA5 to heart muscle cells, or cardiomyocytes, through gene therapy.

The promising early results appear in Nature Biomedical Engineering.

CMYA5 gene therapy improves dyad structure, heart function

The team first whittled down the CMYA5 gene to those portions that appear most important to its function.

"The CMYA5 protein is enormous, much too large to put into a gene therapy vector," Pu explains. "So we had to engineer the protein to make it small enough to fit."

The researchers then conducted several tests, starting with a mouse model in which the CMYA5 gene was knocked out. The mice showed disorganization of their dyads and had weakened heart function. But both problems were reversed when they received gene therapy, delivered by a non-infectious adeno-associated virus.

The team then turned to genetically normal mice that had high-pressure loads on their hearts. This cardiac stress led to disorganized dyads and simulated the effects of medical conditions that lead to heart failure, such as stenosis or narrowing of the aortic valve, hypertension, and coarctation of the aorta.

Mice that received mini-CMYA5 gene therapy had improved dyad structure, improved heart function, and reduced cardiac hypertrophy on echocardiograms and did not develop heart failure. The gene therapy improved myocardial outcomes even when cardiac dysfunction was already established.

Other experiments looked at the effects of mini-CMYA5 gene therapy on human cardiomyocytes derived from stem cells. These cardiomyocytes typically don't make dyads, perhaps because they are not fully mature, notes Pu.

The miniatured CMYA5 helped the cardiomyocytes make some of the structures of dyads, helped organize the dyads' architecture and coordination of calcium release, and increased the cells' contractile force.

Potential applications in arrhythmia and myopathies

Pu notes that CMYA5 gene therapy could potentially improve arrhythmias by helping coordinate calcium release. It might also improve myopathies in skeletal muscle, which also has high levels of CMYA5.

His team, for now, is focused on the basics: understanding why there is less CMYA5 protein in heart failure, how this contributes to dyad disorganization, and how to optimize mini-CMYA5 to make it more powerful.

"Mini-CMYA5 protected against heart failure in the models we used, but the protection was incomplete," Pu says. "There's room for improvement."

More information: Fujian Lu et al, Virally delivered CMYA5 enhances the assembly of cardiac dyads, Nature Biomedical Engineering (2024). DOI: 10.1038/s41551-024-01253-z

Journal information: Nature Biomedical Engineering 

Provided by Children's Hospital Boston