A study has for the first time uncovered a gene linked to childhood-onset familial dilated cardiomyopathy, one of the most common heart muscle diseases in children. The researchers hope their findings will lead to gene therapies that offer much better prospects for patients than current treatments.
Current estimates suggest around 1 in 1,000 people has dilated cardiomyopathy (DCM) - a disease that gradually weakens and enlarges the heart muscle, which can result in heart failure and premature death.
DCM is a genetically complex disease, and is associated with mutations in at least 40 genes. However, the underlying causes of over half of cases remain unknown. The disease has no cure, although treatments currently available can help control symptoms and prevent complications.
In their study, published in Nature Genetics, the authors - who come from centers in India, Italy and Japan as well as the US - also found a link between DCM and excessive activity in a protein called mTOR, which can be blocked by several drugs that have already been approved by the Food and Drug Administration.
One of the drugs that inhibit mTOR (which stands for mammalian target of rapamycin) is rapamycin, which is currently mainly used to suppress the immune system following organ transplantation. Preliminary results from the study suggest the drug may be able to halt progress of DCM.
The study was led by the Icahn School of Medicine at Mount Sinai in New York, NY, where Valentin Fuster, who describes the findings as "extraordinary," is professor in Medicine, Cardiology. Speaking about DCM, he notes:
"One day we hope to have therapeutic treatments for all of the different genetic variations that contribute to this complex disease, not just medications that delay heart failure."
He says the new findings may lead to the first of those treatments, offering new hope to patients who have no other medical recourse.
Rare mutations in RAF1 gene accounted for 10% of childhood-onset DCM
For the study, senior author Bruce Gelb and colleagues sequenced DNA from more than 500 adults and children with DCM, and over 1,000 unaffected controls. The samples were drawn from several different ethnic groups in different countries so as to maximize the genetic information about the disease.
The researchers say the next step is to study this biological mechanism in a mammalian model and generate data to support a clinical trial for DCM patients who have these genetic variants.
From the sequencing they found rare mutations in the RAF1 genes of 3 of the cohorts (South Indian, North Indian and Japanese). The patients with these mutations were also more likely to have been diagnosed with DCM in childhood. The mutations accounted for around 10% of childhood-onset cases of DCM in the studied cohorts.
It is the presence of these RAF1 mutations that appear to increased activity of mTOR, says the team, which validated the findings by modeling the mutations in zebrafish.
When they treated the zebrafish that had the same genetic changes with rapamycin, their heart defects were partially reversed, and their mTOR levels normalized.
Prof. Gelb says as there are currently no effective genetic treatments, "finding that commercially available drugs may be effective for patients with childhood-onset, RAF1-induced DCM is a remarkable advance."
"The critical next step is to study this biological mechanism in a mammalian model and generate data to support a clinical trial of rapamycin or a related drug for DCM patients who have these genetic variants," he concludes.
Leading cardiologists at the Mount Sinai Hospital recently contributed to the development of a new classification system for cardiomyopathies. Called MOGE(S), the new system was inspired by the TNM staging method used to classify malignant tumors, and allows for a common language and code to be used across the relevant medical community.