Rare Daily staff

Researchers at Université de Montréal and CHU Sainte-Justine Research Center  report that the cancer drug trametinib may reverse heart damage in patients with Noonan Syndrome, part of a group or rare diseases known as RASopathies.

Noonan Syndrome (NS) is a rare genetic syndrome usually evident at birth and often linked to early-onset, severe heart disease. The condition is caused by activating mutations of proteins belonging to the Ras and mitogen-activated protein kinase families.

The researchers show that trametinib, a cancer drug that works by inhibiting the kinase protein MEK, can reverse hypertrophic cardiomyopathy and valvular obstruction in patients with RIT1-associated NS. The researchers reported their findings in a study in the Journal of the American College of Cardiology.

‘’Up to this finding, our therapeutic options were limited to surgery, including heart transplant, and symptomatic relief with medication,” said the study’s lead author Gregor Andelfinger, a pediatric cardiologist at CHU Sainte-Justine, a researcher at Sainte-Justine University Hospital Research Center, and an associate research professor in the pediatrics department of Université de Montréal. “Trametinib treatment is the first approach specifically targeted to the molecular cause of RASopathies.”

The study reported results in the first two patients in whom the researchers were able to reverse heart disease. Adelfinger said it paves the way for larger trials, which are now needed.

Infants less than six months old with NS, hypertrophic cardiomyopathy, and congestive heart failure normally have a poor prognosis, with a one-year survival rate of 34 percent. In the new study, the Sainte Justine clinical teams used trametinib, an inhibitor targeted specifically against the activating nature of the mutations, to try to treat NS in two patients.

They observed dramatic improvement of clinical and cardiac status in the patients only three months after treatment. Hypertrophy regressed in both patients, with sustained improvement over a total of 17 months of treatment, and normalization of laboratory values. One of the patients, who required ventilation, could be extubated after six weeks of treatment. Both patients showed better overall growth after treatment was started.

Because of the role MEK plays in signaling heart growth, Andelfinger believes studies with a larger number of participants are now required to evaluate long-term side effects, optimal dosing and optimal treatment windows, as well as investigate this treatment for other types of heart disease.  It is conceivable that MEK inhibition may prove most effective during a fixed time window before the onset of irreversible cardiac remodeling in RASopathies, including those caused by genes other than RIT1.

“The findings described in this report suggest that a life-threatening form of heart disease affecting young infants might be treatable, which, if true, would be unprecedented and so meaningful for the families whose lives this devastating problem touches,” said Bruce Gelb, director of the Mindich Child Health and Development Institute at the Icahn School of Medicine at Mount Sinai in New York City. “Now we need to perform a proper clinical trial to prove that this drug is definitely working for this particular problem.”

Photo: Gregor Andelfinger, a pediatric cardiologist at CHU Sainte-Justine, a researcher at Sainte-Justine University Hospital Research Center, and an associate research professor in the pediatrics department of Université de Montréal

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