In a development that has the potential of offering protection to patients with heart attacks, researchers from the University of Texas Southwestern (UTSW) have demonstrated that editing a gene that prompts a cascade of damage after a heart attack appeared to reverse this inevitable course in mice, leaving their hearts remarkably unharmed.
Commenting on the findings of the study reported in the journal Science recently, Dr Eric Olson, Director of the Hamon Center for Regenerative Science and Medicine and Chair of Molecular Biology at UTSW, who co-led the study with Prof Rhonda Bassel-Duby, said, “Usually, depriving the heart of oxygen for an extended period, as often happens in a heart attack, will damage it substantially.”
“But those animals whose heart muscles were subjected to gene editing after induced heart attacks seem to be essentially normal in the weeks and months afterwards,” he added.
Since its discovery more than a decade ago, scientists have been using the CRISPR-Cas9 gene editing system to correct genetic mutations that cause disease, including work on Duchenne muscular dystrophy.
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The researchers then tried a similar experiment in live mice, triggering a heart attack in these animals by restricting blood flow to their heart’s main pumping chamber for 45 minutes and then delivering CaMKIIδ gene editing components directly to some animals’ hearts.
A gene called CaMKII, recently discovered by researchers, has several functions in the signalling and operation of cardiac cells and contributes significantly to heart attack damage when it is overactive.
The overactivation occurs when the heart is stressed, prompted by the oxidation of two methionine amino acids that form part of the CaMKIIδ protein.
The research team reasoned that if these methionines could be converted to a different amino acid, oxidation will not occur, thereby sparing the heart from CaMKIIδ overactivation and subsequent damage after a heart attack.
To test this idea, Dr Simon Lebek, a postdoctoral fellow, and other members of the team used CRISPR-Cas9 to edit CaMKIIδ in human heart cells growing in labs.
They found during their tests that when unedited heart cells were placed into a low-oxygen chamber, they developed numerous markers of damage and subsequently died. However, the edited cells remained protected from damage and survived.
The researchers noted that all mice, regardless of whether they received gene editing or not, had severely compromised heart function in the first 24 hours after their heart attacks.
However, while the condition of the mice without the gene editing continued to worsen over time, those that received gene editing steadily improved over the next few weeks, ultimately achieving cardiac function that was nearly indistinguishable from before their heart attacks, they said.
Furthermore, the researchers found no evidence of edited CaMKIIδ in other organs, including the liver, brain, or muscles, indicating that the gene editing appeared to be limited to the heart.
Drs Olson and Bassel-Duby said that treatment appeared to be durable, noting that gene-edited mice were able to do heavy exercise, similar to mice that had never had a heart attack.
“Rather than targeting a genetic mutation, we essentially modified a normal gene to make sure it would not become harmfully overactive. It is a new way of using CRISPR-Cas9 gene editing,” Dr Bassel-Duby said.