FDA-Approved Drug Treats a Rare Cardiac Disease

Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies.About 1 in 2,500 babies born in the United States each year have Noonan syndrome (NS), a genetic disorder that results in severe heart defects, among other symptoms. A mutation in a gene called PTPN11 which encodes for the tyrosine phosphatase Shp2, causes the condition. To identify a potential target for therapy, a team of Yale researchers studied mouse models of the disease.

Led by professor of pharmacology and of comparative medicine Anton Bennett, the team focused on a protein called PZR, which was first identified by them to be altered in the hearts of NS mice. They found that PZR interacted abnormally with a mutated form of an enzyme, Shp2, in two different models of NS. After discovering how PZR interacted abnormally with Shp2 in the hearts of NS mice, the researchers then used an existing chemotherapy drug, dasatinib, to target the interaction.

“We identified an FDA-approved drug that at much lower doses is effective in restoring the cardiac function of both mouse models of NS,” said Bennett. The study result suggests that dasatinib and similar drugs at low doses could be effective treatment for NS-related cardiovascular defects and should be considered for clinical trials.

Source : Science tech daily

Draft by: Juilee Mhatre


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