A new study by UCSD scientists shows that modifying a gene that causes a cascade of damage after a heart attack appeared to reverse this inevitable pathway in mice, leaving their hearts remarkably healthy. Results published in Sciencescould lead to a new strategy to protect patients from the consequences of heart disease.
Depriving the heart of oxygen for a long time, as often happens in a heart attack, can greatly damage it. But those animals whose heart muscles have undergone genetic modification after heart attacks look basically normal in the weeks and months that follow.”
Eric Olson, PhD, director of the Hammon Center for Regenerative Science and Medicine and chair of molecular biology at UTSW
Eric Olson co-led the study with Rhonda Basil Doby, PhD, professor of molecular biology.
Since its discovery a decade ago, the CRISPR-Cas9 gene-editing system has been used by scientists to correct genetic mutations responsible for the disease, including work in Olson’s lab on Duchenne muscular dystrophy. However, Dr. Basil Dube explained that these mutation-caused diseases affect relatively small groups of people, while non-genetic diseases affect much larger numbers. For example, cardiovascular disease is the leading cause of death globally, killing around 19 million people each year.
Researchers recently discovered that much of the damage caused by a heart attack — an event characterized by blockage of the blood vessels that supply the heart, depriving it of oxygen — is caused by overactivity of a gene called CaMKIIδ. This gene plays a variety of roles in heart cell signaling and function. Hyperactivity occurs when the heart is stressed, driven by the oxidation of two amino acids methionine that are part of CaMKIIδ protein.
Dr.. Olson, Basil Dube and colleagues conclude that if this methionine could be converted to a different amino acid, oxidation would not occur, protecting the heart from CaMKIIδ Hyperactivity and subsequent damage after a heart attack.
To test this idea, Simon Lebek, MD, postdoctoral fellow, and other team members used CRISPR-Cas9 technology to edit CaMKIIδ The human heart cells grow in a petri dish. Tests showed that when unmodified heart cells were placed in a low-oxygen chamber, they developed many signs of damage and subsequently died. However, the modified cells were protected from damage and survived.
The researchers then tried a similar experiment on live mice, causing a heart attack in these animals by restricting blood flow to the heart’s main pumping chamber for 45 minutes and then plugging it back in. CaMKIIδ Gene editing components directly into the hearts of some animals. Both the genetically modified mice and those that had not had severely impaired heart function in the first 24 hours after their heart attacks. But while the gene-edited mice continued to deteriorate over time, the gene-edited ones steadily improved over the next few weeks, eventually achieving cardiac 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 its modification CaMKIIδ In other organs, including the liver, brain, or muscles. No negative side effects have been seen after almost a year of treatment, Dr. Olson and Basil Dobie said. The treatment also appeared to be permanent, they added, noting that the genetically modified mice were able to perform strenuous exercise similar to mice that did not have heart attacks.
Although this treatment needs great security and effectiveness Before it can be used in humans, the researchers suggest that gene editing could offer a promising solution for treating patients following a heart attack and could have potential for a range of other non-genetic diseases.
“Instead of targeting a gene mutation, we basically modified the normal gene to make sure it wouldn’t become harmfully overactive. It’s a novel way of using CRISPR-Cas9 gene editing,” said Dr. Basil Doby.
Dr. Olson holds the Pogue Distinguished Chair in Research on Congenital Heart Defects, the Robert A. Welch Distinguished Chair in Science, and the Annie and Willie Nelson Professor in Stem Cell Research.
Other UTSW researchers who contributed to this study include Francesco Cimillo, Xurde M. Caravia, Wei Tan, Hui Li, Kenian Chen, Lin Xu, and Ning Liu.
This study was funded by grants from the National Institutes of Health (R01HL130253, R01HL157281, and P50HD087351); the Leducq Foundation Transatlantic Excellence Network; Foundation Robert A. Welch (1-0025); German Research Foundation (5009 EGP / 1-1); German Heart Association. and Cancer Prevention and Research Institute of Texas (RP210099).