New CRISPR technique boosts mitochondrial function to treat heart failure

After a heart attack, the heart struggles to recoup and maintain energy. One third of patients develop heart failure as a result ⎯ a condition that impacts 6.8 million Americans and carries a high lifetime risk with 1 in 4 adults in the U.S. expected to develop the condition during their lifetime. This makes finding a lasting treatment a medical priority.

Because heart failure is fundamentally an energy crisis for the heart, mitochondria, organelles that live inside most cells and produce the energy cells need to function, could be a critical ally in recovery. Using a CRISPR-based technique, researchers at Rice University and Baylor College of Medicine induced heart cells to increase mitochondria production to optimal levels, opening a path toward a new therapy for heart failure.

Previous research has shown that turning on specific genes can increase mitochondrial number and function. However, older strategies forced the cells into overdrive, which caused cellular malfunction. We used a new technique that controls internal regulatory pathways, allowing the cell to safely make more mitochondria without burning out."

Mario Escobar, assistant research professor of bioengineering at Rice and first author on a study published in Molecular Therapy

CRISPR, or clustered regularly interspaced short palindromic repeats, is a revolutionary gene-editing technology that has made it possible to target and edit specific genes, enabling therapeutic breakthroughs in curing inherited blindness, muscular dystrophy and, most recently, Huntington's disease.

The researchers developed a nonediting CRISPR system that specifically regulates gene expression and functions as an "on" switch, prompting the cell to assemble more mitochondria.

Isaac Hilton, associate professor of bioengineering at Rice and corresponding author on the study, said that "what makes this work powerful is the level of control."

"Rather than forcing the cell to overproduce a gene, we used CRISPR to nudge and fine-tune its natural regulatory systems in a measured way," Hilton said. "That allows us to boost mitochondrial performance while preserving balance in the cell, which is a key requirement for safe clinical translation."

When tested across various human cell types, the system successfully increased the production of the regulatory protein, amplifying mitochondrial function and cellular energy levels. Crucially, when applied to human cardiomyocytes ⎯ the heart cells responsible for the pumping contractions ⎯ the system improved their rate of oxygen consumption, an indicator of improved mitochondrial function. The researchers found similar improvements in mitochondrial function when they tested the system in an animal model as well as in adult human heart donor tissue from both normal and diseased hearts.

"These results are very promising for the development of future treatments for heart failure and other metabolic diseases," Escobar said.

Current treatments for heart failure focus on reducing the cardiac energy demand to match the impaired energy supply.

"Conventional approaches can cause additional complications over time as they do not address the root of the problem," said Ravi Ghanta , professor of surgery at Baylor and co-corresponding author on the study. "As heart failure is expected to become more prevalent, it is especially critical that we focus our efforts on developing effective treatment. This work is an important step in that direction."

The research was supported by Baylor College of Medicine, the American Heart Association (917025, 25TPA1463933, 959536) and the National Institutes of Health (R01HL147921, R15HL168688, R01HL166280, R01HL163258, R35GM143532). The content in this press release is solely the responsibility of the authors and does not necessarily represent the official views of funding entities.