In a groundbreaking development, UT Southwestern researchers have taken a step forward in the fight against dilated cardiomyopathy. (DCM), an inherited heart condition that affects one in 250 people worldwide. Through the innovative use of gene editing technology, they are paving the way for new possibilities and hope for those living with this condition, offering them the opportunity for a better quality of life.
The researchers used the CRISPR-Cas9 gene editing system to correct the mutations responsible for the condition in human cells and in a mouse model of the disease. The research could lead to treatments sooner rather than later, the team says.
“The pace of this field is truly impressive,” said Eric Olson, Ph.D., president and professor of Molecular Biology at UTSW, in a statement. “I hope that if this moves to patients, we’re not talking decades from now, we’re talking years from now.”
Dr. Olson’s co-leaders on the study are Rhonda Bassel-Duby, Ph.D., professor of Molecular Biology, and Takahiko Nishiyama, MD, Ph.D., a postdoctoral fellow in Olson’s lab.
‘Reverse’ the characteristics of the disease
“All of the disease features that we see due to these mutations were reversed with CRISPR-Cas9 therapy. It is fair to say that the success of this approach completely exceeded our expectations,” Olson said.
DCM is caused by mutations in a gene known as RNA-binding motif protein 20 (RBM20) that affects the production of hundreds of proteins in heart muscle cells responsible for the pumping action of the heart, UTSW said.
The disease creates havoc throughout the heart.
UTSW, one of the nation’s leading academic medical centers, said the disease wreaks havoc throughout the heart, gradually destroying its ability to contract and causing it to become extremely enlarged and fail over time, the university said. Current treatment is limited to drugs, which can improve contractile function but do not provide a permanent solution, or a heart transplant, which is often not an option due to a shortage of donor organs, UTSW said.
Olson, Bassel-Duby, Nishiyama, and their colleagues searched for CRISPR-Cas9, a popular tool for genetic research that was recognized with the Nobel Prize in Chemistry in 2020. It is a system that allows researchers to correct potentially disease-causing mutations in important genes
The US Food and Drug Administration has approved only one clinical trial using this technology to treat sickle cell disease.
Could be used to treat other genetic diseases
Olson said that CRISPR-Cas9 has the potential to treat other genetic diseases. He and his colleagues have used CRISPR gene editing to develop a technique to halt the progression of Duchenne muscular dystrophy in animal models, UTSW said.
To determine the feasibility of the technique for DCM, the team used a virus to deliver CRISPR-Cas9 components to heart muscle cells derived from human cells that carry two different types of DCM-causing mutations. Scientists used the technology to swap out a single nucleotide, the basic unit of DNA, to correct one type of mutation. In another set of cells, they replaced a piece of mutated RBM20 DNA with a healthy segment of this gene, UTSW said.
After treatment with CRISPR-Cas9, the mutant cells gradually lost the characteristics inherent to DCM: the protein produced by RBM20 moved to its normal place in the nucleus, and the cells began to produce healthy proteins.
When the team gave the CRISPR-Cas9 treatment to week-old mice carrying one of the mutations, the animals never developed enlarged hearts and had normal lifespans, UTSW said. The untreated mice showed symptoms similar to those of human DCM patients, she said.
Challenges remain before use in patients
Several challenges remain before the therapy can be used in patients with DCM, the researchers said.
There is still work to be done to ensure that the effects of CRISPR-Cas9 are permanent and precise, and that the smallest possible dose is delivered, UTSW said. It remains to be determined whether the treatment could be used in patients whose disease is more advanced.
Olson holds the Pogue Distinguished Chair in Heart Birth Defects Research; the Robert A. Welch Distinguished Chair of Science; and the Annie and Willie Nelson Chair in Stem Cell Research. He is also director of the Hamon Center for Regenerative Science and Medicine.
The study was funded by grants from the National Institutes of Health, the Leducq Foundation Transatlantic Network of Excellence, a postdoctoral fellowship from the Uehara Memorial Foundation, and a Japan Heart Foundation/Bayer Yakuhin Overseas Research Fellowship.
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