Scientists in the UK are developing a new gene-editing tool that they hope may one day provide a cure for inherited heart defects.
The team at the John Radcliffe laboratory in Oxford, England believe they will be able to prevent the development of hereditary heart muscle diseases by rewriting faulty genes in people’s DNA.
Treatment targets heart muscle conditions called cardiomyopathy, and although these abnormalities can vary, they can sometimes lead to progressive heart failure, or even death.
Doctors can already trace genetic forms of the disease in families and confirm whether there is a genetic abnormality, but there is currently no cure.
Doctors are unable to prevent the disease from weakening the heart until a transplant is eventually required, and those with genetic cardiomyopathies have a 50-50 risk of passing on the defective genes to each of their children.
The research is being funded by a grant of 30 million pounds (35.6 million euros) from the research organization British Heart Foundation.
“Depending on the exact physiological abnormality at the level of the heart muscle cells, it affects the heart in a different way. Some of them will cause the heart to become too thick. Some of them will cause the heart to pump too weakly,” Professor Hugh Watkins, lead researcher and leader of the project called CureHeart, explained.
He has investigated how molecular genetics can be used to address hereditary causes of heart disease.
“They all have in common that they can cause progressive weakening of the heart and progressive heart failure, starting at a young age and progressing throughout life, sometimes to the point of requiring a heart transplant,” he said.
The disease has also affected well-known sports personalities.
Bolton footballer Fabrice Muamba suffered a heart attack during a televised FA Cup match from which he has since recovered, and England cricketer James Tayler was forced to retire in 2016 with a similar heart failure to Muamba.
Watkins says the incidence of cardiomyopathy is not as common as some other heart conditions, but it is still more prevalent than many of us realize.
“We know that one in 250 individuals will have this genetic susceptibility in all populations, from all ethnic and racial backgrounds,” he said.
“There is a particular class of genetic misspelling that can cause dilated cardiomyopathy to run in families, but is also responsible for many of the cases where we see heart failure in women after pregnancy or in people who drank too much alcohol or after chemotherapy, and the particular genetic defect affects 35 million people globally”.
Gene therapies that cut out mutant or incorrect sections of DNA already exist and have been used in patients for various diseases, but the researchers here are looking for a more precise gene-editing tool, Watkins explained.
“In the patients who have these conditions, our heart muscle conditions, everyone has a healthy copy of the gene, but despite that they get sick, and sometimes it’s because the defective copy interferes with the function of the healthy ones,” he said.
“So we have to specifically target the defective copy and leave the healthy one alone, and that’s a harder challenge than some of the other genetic medicines where it would be fine to just take out or manipulate both copies,” he added.
An editing tool that is already in use is called CRISPR.
This therapy removes an error in the gene, but Watkins says what these researchers want to do is rewrite or stop the faulty DNA.
“CRISPR cuts the DNA, both strands of DNA, you can compare it to a pair of scissors. So it’s pretty good if you want to take out a piece of DNA or inactivate both copies of the gene,” Watkins said.
“For our particular disorders, we’ll need more precision than that because we want to manipulate the defective copy but leave the healthy copy alone. So where we’re exploring genetic editing, we’re currently exploring a type of tool called base editing.
The team at Cureheart investigating the technology counts David Liu Broade among its ranks who discovered and developed this tool using chemistry in a laboratory.
As Watkins explains, the therapy can precisely rewrite individual letters in a DNA sequence.
Any cure is years away, and before any treatment can begin, long trials will be needed to test the safety of the treatment.
Watkins says that while the goal is to prevent the development of heart disease, the first human trials will likely be in people who are already in need of a transplant to determine that it works and is safe.
“If we can go in before the heart is seriously damaged, then you can certainly cure it. I don’t think we’ll start there, because to prove that it’s safe and effective, I think the realistic option is that we have to do our first attempt at “Individuals with fairly advanced, severe forms of damage from cardiomyopathy. In fact, people who already know they need a heart transplant,” he said.
“Any risk we have to take will be acceptable because they are already in a very risky, vulnerable position,” Watkins added.
“And then if they get transplanted, we get the heart out, we can explore it in minute detail and really be clear about what the genetic medicine has accomplished.”
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