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HHMI researchers have designed an inhibitor that can reduce the expression of the mutated gene that causes hypertrophic cardiomyopathy, a potentially fatal heart condition. 
Investigator, Brigham and Women's Hospital
HHMI researchers have designed an inhibitor that can reduce the expression of the mutated gene that causes hypertrophic cardiomyopathy, a potentially fatal heart condition. 

When a young athlete dies suddenly on a sports field, the cause is more often than not hypertrophic cardiomyopathy, a genetic disease that leads to malformation of the heart muscle. Now, Howard Hughes Medical Institute (HHMI) researchers have designed an inhibitor that can reduce the expression of the mutated gene that causes the condition. When mice prone to hypertrophic cardiomyopathy received the inhibitor, they were protected from disease—and the associated cardiac electrical abnormalities —for months, the team reported October 4, 2013 in the journal Science.

 “This is a really exciting opportunity to address the root genetic cause of a disease rather than the resulting symptoms,” says Christine Seidman, an HHMI investigator at Brigham and Women’s Hospital and senior author of the new study.

Hypertrophic cardiomyopathy (HCM) results from mutations in genes that encode components of myosins, proteins integral to heart muscles. The mutations cause enlargement of not only individual contractile elements that help the heart pump blood, but thickening of an entire side of the heart. The symptoms of HCM can go unnoticed for years, until it causes sudden cardiac arrest. The disease, which affects up to one in 500 people, is the leading cause of nonviolent deaths in young adults.

More than a thousand unique mutations in myosin genes have been linked to HCM, and it takes just one mutated copy of the gene—inherited from only one parent—to cause symptoms. In an attempt to test new treatment strategies, Seidman’s group decided to first focus on a mutation for which they had a well-researched mouse model, in a gene called Myh6. Mice with the Myh6 mutation develop thickening of the heart muscle and measurable changes, at a molecular level, to the functioning of proteins and cells that make up the muscle tissue.

Seidman’s group aimed to target the mutated copy of Myh6 with RNAi, strands of RNA which bind to matching RNAs and block them from being used to encode proteins.

 “You have to be able to discriminate between the RNAs that are derived from the normal gene and the mutant copy,” Seidman says. “By manipulating the RNAi sequence we produced one with high specificity for the mutant RNA.”

Her lab put the RNAi into a virus that targets heart cells so that the inhibitor would be delivered to the right place in the body. For five months, mice with the Myh6 mutation that had received the inhibitor remained disease-free, with no signs of heart muscle thickening or cellular changes in the heart. But to translate this RNA inhibitor strategy to human patients, Seidman’s team was well aware, would only be useful in patients who had the specific HCM mutation for which the RNAi had been designed, and not for any of the other mutations that cause disease.

“There are hundreds and hundreds of mutations,” she says. “To design an RNAi for every one would be a painstaking task.”

So they tested whether they could use a broader approach to turn off the Myh6 mutation in mice. Rather than make an RNAi complementary to the disease-causing mutation, they developed a new RNAi that bound to sequences that vary naturally between different strains of mice, called polymorphisms. Since the RNAi shuts down the protein production from the entire mutant RNA, it doesn’t matter whether it’s bound to the exact spot of the mutation or to a nearby polymorphism, Seidman explains.

“Creating a bank of RNAi to bind to all the possible polymorphisms that reside close to the many different HCM mutations in people would be much more doable than creating RNAi for every mutation,” she says.

Using this approach many HCM mutations could be shut down by selecting the right polymorphism-targeting RNAi—one present on the mutated copy of the gene but not the normal copy. Seidman tested the approach, and like the mutation-targeting RNAi, the new version also successfully stopped disease from developing in mice with Myh6 mutations. But once again, the effect was only temporary—after about five months, the RNAi got used up, Seidman suspects. A regular booster of the inhibitor could potentially offer a longer-term treatment, although the scientists haven’t yet expanded their study to test that.

Before the drug reaches clinical trials in people, there are a plethora of questions to answer, she says, including whether the virus that carries the RNAi to heart muscles causes any inflammatory side effects, whether the technique works in forms of hypertrophic cardiomyopathy other than the one tested, and whether they drug could reverse the disease once symptoms have already appeared.