UK scientists are developing a new gene-editing tool that they hope could one day provide a cure for inherited heart defects.
The team at the John Radcliffe laboratory in Oxford, England, believes they will be able to prevent the development of inherited heart muscle diseases by rewriting defective genes in people’s DNA.
The therapy targets heart muscle conditions called cardiomyopathy, and while these abnormalities can vary, they can sometimes cause progressive heart failure or even death.
Doctors can now trace genetic forms of the disease in families and confirm if there is a genetic abnormality, but there is still no cure.
Doctors are unable to prevent the disease from weakening the heart until eventually a transplant is needed, and those with genetic cardiomyopathies have a 50 to 50 risk of passing the defective genes to each of their children.
The research is being funded by a £30 million (€35.6 million) grant from the British Heart Foundation research charity.
“Depending on the precise physiological abnormality of the heart muscle cell level, it affects the heart in a different way. Some of them will make the heart feel very thick. Hugh Watkins, lead researcher and head of the project called CureHeart, explained.
He is investigating how molecular genetics can be used to treat inherited causes of heart disease.
“They all have in common that they can cause progressive weakening of the heart and progressive heart failure, starting at young ages and progressing throughout life, sometimes to the point of needing a heart transplant,” he said.
The disease has also struck well-known sports personalities.
Bolton footballer Fabrice Muamba had a heart attack during a televised FA Cup match from which he recovered, and England cricketer James Tayler was forced into retirement in 2016 with a heart defect similar to his own. Goods
Watkins says the prevalence of cardiomyopathy isn’t as common as some other heart conditions, but it’s still more widespread 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 in families, but it is also responsible for many of the cases where we see heart failure in women after pregnancy or in individuals who have drank too much alcohol or after chemotherapy, and this defect specific genetic disorder affects 35 million people worldwide”.
Gene therapies that cut mutated or incorrect sections of DNA already exist and have been used in patients for various diseases, but researchers here are looking for a more accurate gene editing tool, explained Watkins.
“In patients who have these conditions, our heart muscle all has a healthy copy of the gene, but despite that, they get sick and sometimes that’s because the defective copy interferes with the function of healthy ones,” he said.
“So we have to specifically target the defective copy and leave the healthy one alone and that’s a more difficult challenge than some of the other gene drugs where it would be nice to just take out or manipulate the two copies,” he added.
One editing tool that is already in use is called CRISPR.
This therapy eliminates an error in the gene, but Watkins says what these researchers want to do is rewrite or silence the defective DNA.
“CRISPR cuts the DNA, both strands of the DNA, you can compare it to scissors. So this is really good if you want to take a piece of DNA or inactivate both copies of the gene,” Watkins said.
“For our specific disorders, we’re going to need more precision than that, because we want to handle the bad copy but leave the healthy copy alone. So where we are exploring gene editing, we are currently exploring a type of tool called a base editor.”
The Cureheart team investigating the technology counts David Liu Broade among their ranks who discovered and developed this tool using chemistry in the laboratory.
As Watkins explains, the therapy can precisely rewrite single 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 therapy.
Watkins says that while the goal is to prevent the development of heart disease, the first human trials will likely be on people who already need a transplant to establish that it works and is safe.
“If we can intervene before the heart is severely damaged, then you can heal it for sure. I don’t think we’ll start there, because to prove it’s safe and effective, I think the realistic option is that we’re going to have to do our first trials in individuals with very advanced and severe forms of cardiomyopathy damage. 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 and vulnerable position,” added Watkins.
“And then if they do the transplant, we extract the heart, we can explore it down to the smallest detail and really get clarity on what genetic medicine has achieved.”
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