CRISPR Gene Editing Advances in Heart Failure, Cystic Fibrosis, and Cholesterol Treatment

Researchers have developed three distinct CRISPR-based gene editing approaches targeting heart failure, cystic fibrosis, and elevated cholesterol, marking significant advances in the application of gene editing technology to common and rare diseases. The techniques range from mitochondrial enhancement to non-viral gene insertion and single-dose lipid lowering.

Rice University and Baylor College of Medicine researchers developed a nonediting CRISPR system that regulates gene expression to increase mitochondrial production in heart cells, addressing the energy crisis that underlies heart failure. Heart failure impacts 6.8 million Americans, with 1 in 4 adults in the U.S. expected to develop the condition during their lifetime. One third of patients develop heart failure after a heart attack as the heart struggles to recoup and maintain energy.

The system functions as an "on" switch, prompting cells to assemble more mitochondria by controlling internal regulatory pathways. "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," said Isaac Hilton, associate professor of bioengineering at Rice and corresponding author on the study published in Molecular Therapy. "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 production of the regulatory protein, amplifying mitochondrial function and cellular energy levels. When applied to human cardiomyocytes, the heart cells responsible for 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.

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."

In a separate development, UCLA researchers developed a lipid nanoparticle-based gene-editing approach capable of inserting an entire healthy gene into human airway cells, restoring key biological function in a laboratory model of cystic fibrosis. The study shows that lipid nanoparticles, tiny fat-based particles widely used to deliver mRNA vaccines, can be engineered to carry the complex molecular cargo required for precise insertion of a large full-length gene into the genome without using viral vectors.

Cystic fibrosis is caused by mutations in a single gene, the cystic fibrosis transmembrane conductance regulator, or CFTR, which encodes a channel that helps move chloride and water across the surface of airway cells. When the channel does not function properly, mucus in the lungs becomes thick and sticky, trapping bacteria and leading to chronic infections and progressive lung damage. Although highly effective drugs known as CFTR modulators have transformed care for many people with cystic fibrosis, about 10% of patients produce little or no CFTR protein at all, leaving nothing for those drugs to act on.

Since there are over 1,700 different mutations in the CFTR gene that can cause cystic fibrosis, the team looked to develop a universal approach that could correct any of these errors in a single edit rather than individually. The particles were engineered to transport three gene-editing components simultaneously: CRISPR machinery to cut DNA at a precise location, guide molecules to target the correct genomic site, and a DNA template encoding a full, functional copy of the CFTR gene.

The researchers tested the system in lab-grown human airway cells carrying a severe cystic fibrosis mutation that does not respond to existing drugs. The nanoparticles successfully delivered a healthy CFTR gene into about 3-4% of the cells. Despite that relatively small fraction of corrected cells, the treatment restored between 88% and 100% of normal CFTR channel function across the cell population.

The replacement CFTR gene was designed to maximize protein production once it entered the cell, enabling even a small number of corrected cells to have an outsized effect. That gene design, known as codon optimization, was developed by collaborators in Donald Kohn's lab at UCLA and boosts CFTR protein production without altering the protein itself.

Unlike approaches that deliver messenger RNA, which must be repeatedly re-dosed, the new strategy inserts the corrected gene directly into the genome, potentially allowing cells and their descendants to continue producing functional CFTR over time.

A phase 1, first-in-human trial of a CRISPR-Cas9 gene editing therapy targeting cholesterol was presented at the American Heart Association Scientific Sessions and published in The New England Journal of Medicine. The therapy targets ANGPTL3, a gene shown to regulate LDL and triglyceride metabolism, and was given as a single intravenous infusion to patients with elevated lipids despite standard therapies.

The patients had a dose-dependent reduction of up to nearly 50% for LDL-C, and nearly 55% for triglycerides. There were no serious adverse effects related to the therapy in the initial data, though long-term follow-up is still ongoing. The CRISPR approach is supported by human genetics: people with naturally occurring loss-of-function mutations that affect ANGPTL3 were shown to have lower rates of cardiovascular disease.

The phase 1 study was designed to assess early safety only. While the therapy reduces LDL-C and triglycerides, it does not yet show whether this will lead to decreased cardiovascular mortality. The research was supported by Baylor College of Medicine, the American Heart Association and the National Institutes of Health.