Gene editing halts damage in mice after heart attacks in new study

Gene editing halts damage in mice after heart attacks in new study

Gene editing halts damage in mice after heart attacks in new study

The figure shows cross sections of mouse hearts with damaged areas in red. Treatment with virus-expressing CRISPR components reduces cardiac damage after ischemic injury. Credit: UT Southwest

Editing a gene that triggers a cascade of damage after a heart attack appeared to reverse this inevitable course in mice, leaving their hearts remarkably unscathed, a new study by UT Southwestern scientists has shown. The findings, published in Sciencecould lead to a new strategy to protect patients from the consequences of heart disease.

“Usually, depriving the heart of oxygen for a long period of time, as often happens in a heart attack, will substantially damage it. But those animals whose heart muscles underwent gene editing after induced heart attacks seem be essentially normal in the weeks and months afterward,” said Eric Olson, Ph.D., Director of the Hamon Center for Regenerative Medicine and Science and Chair of Molecular Biology at UTSW, who co-led the study with Rhonda Bassel-Duby, Ph.D., Professor of Molecular Biology.

Since its discovery a decade ago, scientists have used the CRISPR-Cas9 gene-editing system to correct the gene mutations responsible for the disease, including the Olson lab’s work on Duchenne muscular dystrophy. However, Dr. Bassel-Duby explained, these diseases caused by mutations affect relatively small groups of people, while non-genetic diseases affect much larger numbers. For example, cardiovascular disease is the leading cause of death worldwide, killing an estimated 19 million people each year.

Researchers recently discovered that much of the damage from a heart attack, an event characterized by blockage of the blood vessels that feed the heart, starving it of oxygen, is caused by overactivation of a gene called CaMKIIδ. This gene plays a variety of roles in cardiac cell signaling and function. Overactivation occurs when the heart is stressed, caused by the oxidation of two methionine amino acids that are part of the CaMKIIδ protein.

Drs. Olson and Bassel-Duby and their colleagues reasoned that if these methionines could be converted to a different amino acid, oxidation would not occur, thus preventing the heart from CaMKIIδ overactivation and subsequent damage after a heart attack.

To test this idea, Simon Lebek, MD, a postdoctoral fellow, and other team members used CRISPR-Cas9 to edit CaMKIIδ in human heart cells growing in a petri dish. Tests showed that when raw heart cells were placed in a low-oxygen chamber, they developed numerous markers of damage and subsequently died. However, the edited cells were protected from damage and survived.

The researchers then tried a similar experiment on live mice, inducing a heart attack in these animals by restricting blood flow to their heart’s main pumping chamber for 45 minutes and then administering CaMKIIδ gene-editing components directly into the hearts of some animals. Both mice that received gene editing and those that did not have severely compromised heart function in the first 24 hours after their heart attacks. But while the mice without the gene editing continued to get worse over time, those given the gene editing steadily improved over the next few weeks, eventually achieving heart function that was almost indistinguishable from before their heart attacks.

Further research showed that gene editing appeared to be isolated from the heart; there was no evidence of editing CaMKIIδ in other organs, including the liver, brain, or muscles. No negative side effects were seen nearly a year after treatment, Drs. Olson and Bassel-Duby said. The treatment also appeared to be long-lasting, they added, noting that the genetically modified mice could exercise vigorously in a similar way to mice that had never had heart attacks.

Although this treatment will need substantial safety and efficacy studies before it can be used in humans, the researchers suggest that gene editing could offer a promising solution for treating patients after heart attack and could have potential for a variety of other ways. non-genetic diseases. .

“Rather than targeting a gene mutation, we essentially tweaked a normal gene to make sure it doesn’t become hyperactive in a harmful way. It’s a new way of using CRISPR-Cas9 gene editing,” Dr. Bassel-Duby said.

Dr. Olson holds the Pogue Distinguished Chair in Congenital Heart Defects Research, the Robert A. Welch Distinguished Chair in Science, and the Annie and Willie Nelson Chair in Stem Cell Research.

Other UTSW researchers who contributed to this study include Francesco Chemello, Xurde M. Caravia, Wei Tan, Hui Li, Kenyan Chen, Lin Xu, and Ning Liu.

More information:
Simon Lebek et al, Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for heart disease, Science (2023). DOI: 10.1126/science.ade1105

Provided by UT Southwestern Medical Center

Citation: Gene editing halts damage in mice after heart attacks in a new study (January 23, 2023) Retrieved January 23, 2023 from -mice-heart.html

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