Targeting System Xc- for the treatment of the Autism Spectrum Disorder subpopulations, Fragile X syndrome and Phelan-McDermid syndrome

DESCRIPTION provided by applicant Autism is the fastest growing developmental disorder in the United States with that affects about in children Thus not surprisingly the cost and burden on families patients and caregivers is enormous Associated with autism spectral disorder are other pervasive developmental disorders that include Rett syndrome Phelan McDermid syndrome and Fragile X syndrome These ASD associated syndromes are classified as rare genetic diseases and have limited or no treatment options As such there is an immediate need to develop more effective and better tolerated medications for these patients The overall goal of this Phase I SBIR is to further characterize and test the efficacy of our novel first in class pro drugs that target the orphan Fragile X and Rett syndromes with the long term objective of improving the lives of individuals suffering from autism Recently a week double blind placebo controlled treatment regimen of N acetylcysteine NAC a glutamatergic modulator and an antioxidant resulted in a marked decrease in irritability in children with autism with few side effects While the promise of NAC in autism is great its ability to cross the blood brain barrier is low To address this Promentis has developed several lead small molecules that successfully deliver NAC to the brain far superior to NAC itself and have further confirmed their preclinical proof of efficacy in rodent models of mental illness Ultimately NACandapos s early success in treating a major symptom of autism removes substantial risk from the project and increases the chances that Promentis will be successful in preclinical studies and subsequent Phase I clinical trials We propose to conduct proof of efficacy experiments of our novel pro drugs in rodent animal models of autism with the intention of developing a lead molecule to meet FDA requirements for IND filing PUBLIC HEALTH RELEVANCE Autism is the fastest growing developmental disorder in the United States Moreover it is estimated that in every children in America are diagnosed with Autism or an Autism spectrum disorders While there is no known cure for these complex debilitating disorders there is a wealth of data indicating that both oxidative stress and imbalances in glutamate neurotransmission play a significant role in their etiology and pathological progression particularly in Fragile X and Phelan McDermid syndromes both of which are rare genetic disorders Therefore targeting these pathways may result in effective therapeutics The primary goal of this Phase I SBIR is to determine the in vivo and in vitro efficacy of a novel set of pro drugs to be used for the potential treatment of Fragile X and Phelan McDermid syndromes