$2.6 Million NIH Grant Supports Search for Genetic Cure for Hypertrophic Cardiomyopathy

Fourteen million people around the globe have hypertrophic cardiomyopathy (HCM), a deadly condition that is frequently undiagnosed, even though it is the most common genetic heart disease.

HCM can be traced many times to a mutation in a single gene, but currently, a safe way to address the mutation with gene-editing treatment does not exist. A recent $2.6 million NIH grant to fund gene editing research could lead to a game-changing advancement in treatment, announced the University of Pennsylvania (UP). The research will be led by Sherry Gao, Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering (CBE) and Bioengineering (BE) within Penn Engineering, and Zheng Sun, Associate Professor in Endocrinology, Diabetes, and Metabolism at Baylor College of Medicine.

One of the biggest challenges of gene editing is the danger of modifying “off-targets,” which are portions of RNA and DNA that should not be touched. “If you want to correct a single mutation in 3 billion letters of DNA, you are correcting one letter,” said Sun. Gene editing only works if it is immensely precise, modifying the sole genetic target that underlies a condition.

Gao and her team hope to build on a split adenine base editor (sABE) that her lab developed in 2023. An sABE is a type of gene editor that uses an innovative method to reduce the risk of off-target mutations. “We split the editor into two proteins that only work when joined by a small molecule,” said Gao. “It’s like a switch — when you don’t have the small molecule, there’s no gene-editing activity.”

Funding from the NIH grant will enable Gao’s lab to test small molecule candidates to determine if they can activate the sABE tool. Candidates will consist of drugs that clinical trials have proved safe for human use.

While Gao’s lab at Penn Engineering concentrates on finding the right activating molecule, Sun’s lab at Baylor will test the split-based editing tools in animals to see if they can fix a mutation in a gene that underlies about 40% of familial HCM cases. Gao and Sun hope their research will yield improved safety of gene editing tools and lead to advancements in treating HCM.