Project Details

A preclinical trial of MEK inhibitor as a therapeutic approach for Noonan syndrome

Pau Castel, PhD

Summary

BACKGROUND: Noonan syndrome is a neurodevelopmental disorder that affects approximately 1 out of every 1000 newborns, being the second most common multiple congenital anomaly disorder after Down syndrome. Cardiovascular defects, which include valve stenosis and hypertrophic cardiomyopathy, are often found in these children and contribute to significant morbidity and mortality. GAP: Despite the extensive knowledge regarding the pathogenesis of Noonan syndrome, preclinical studies testing novel therapies to treat the cardiovascular defects are limited. Given the involvement of the mitogenic activated protein kinase (MAPK) pathway in this disorder, our study will assess the benefit of oral MEK inhibitors in a preclinical mouse model of Noonan syndrome. HYPOTHESIS: I hypothesize that the pharmacological treatment with MEK inhibitor in a Noonan syndrome juvenile population ameliorates the cardiovascular phenotype. METHODS: Cohorts of 4-week-old (juvenile) C57BL/6N mice that carry the germline mutation RIT1M90I and exhibit classic features of Noonan syndrome, including cardiovascular defects, will be used to test the efficacy of the FDA-approved MEK inhibitor trametinib. Cardiovascular function will be assessed by heart morphology and histology. RESULTS: Our results indicate that a daily oral dose of trametinib at 1 mg/kg, following a weekday-on weekend-off schedule during a 20-week period, improves significantly the cardiovascular phenotype of these mice. We observe statistically significant decrease in heart weight-to-body weight ratio in mice treated with trametinib compared to placebo littermates. In addition, our results show a decrease in proliferating cells in the heart. The treatment was well tolerated, and no adverse events were reported. IMPACT: This research intends to bridge the gap between the lack of proper preclinical studies in the juvenile setting and clinical trials in children affected with NS-associated cardiovascular complications. If successful, the results from our study will be rapidly translated into the bedside (~1-2 years) by providing the scientific evidence required to initiate a clinical trial.