There are more than 1,000 ways in which genes can be mutated to cause hypertrophic cardiomyopathy (HCM). But any one of the mutations has the same result: the heart thickens, it has trouble pumping blood, and eventually up to 1 in 500 people with the condition dies. The disease is the most common cause of sudden death in young athletes. There is no cure, but HHMI Investigator Christine Seidman, at Brigham and Women’s Hospital, has figured out how to prevent HCM symptoms from worsening in mice by shutting off some of the mutant genes that cause the disease.
Many of the mutations linked to HCM can be found in the genes that encode the heart muscle protein myosin. To develop new treatment strategies, Seidman focused on mutations in the mouse gene Myh6 that encodes myosin; HCM myosin mutations alter the heart’s ability to contract and relax. Her team designed small pieces of RNA, called RNAi (for RNA interference), that prevent the mutant gene from producing proteins. They used a virus that homes in on heart cells to deliver the RNAi to the correct location in the mice.
The experiment worked. For five months, mice with an HCM mutation in Myh6 showed no thickening or other changes in their hearts, according to her team’s report in Science on October 4, 2013. Although HCM could be prevented, existing damage wasn’t reversed; but it didn’t get worse, which is a benefit. Unfortunately, each RNAi targets only a single mutation. “There are nearly 1,000 human HCM mutations,” acknowledges Seidman, “and it would be an extraordinary effort to make an RNAi that was specific for each one.” As an alternative, her team also created an RNAi that targets common genetic variants that are tightly linked to a broad spectrum of mutations. Like the mutation-specific RNAi, this one worked for five months, making it a very promising method for targeting HCM mutations.
Next, Seidman wants to figure out why the RNAi becomes ineffective after five months. She suspects it’s getting used up and that a booster of inhibitor could extend its effectiveness.