?Autism is the fastest growing developmental disorder in the United States with that affects about 1 in 68 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 12-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, NAC'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 Statement: Public Health Relevance: Autism is the fastest growing developmental disorder in the United States. Moreover, it is estimated that 1 in every 68 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.
NIH Spending Category: Autism; Behavioral and Social Science; Brain Disorders; Fragile X Syndrome; Intellectual and Developmental Disabilities (IDD); Mental Health; Neurosciences; Orphan Drug; Pediatric; Rare Diseases
Project Terms: Acetylcysteine; Address; Adverse effects; Affect; Americas; Animal Model; Antioxidants; antiporter; Astrocytes; Attenuated; autism spectrum disorder; Autistic Disorder; Behavior; Behavioral; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Caregivers; Caring; Central Nervous System Diseases; Child; Childhood; Clinical; Collaborations; Complex; cost; Cysteine; Cystine; Data; design; Development; developmental disease/disorder; Diagnosis; Disease; Double-Blind Method; Drug Design; Drug Kinetics; Drug Regulations; Drug Targeting; Early Diagnosis; efficacy testing; Etiology; extracellular; Family; Fragile X Syndrome; Functional disorder; Genes; Genetic Predisposition to Disease; glutamatergic signaling; Glutamates; Glutathione; Goals; Hereditary Disease; Hippocampus (Brain); improved; In Vitro; in vivo; Individual; Intention; Knock-out; Lead; Long-Term Depression (Physiology); Long-Term Potentiation; meetings; Mental disorders; mitochondrial dysfunction; Modeling; Molecular Target; mouse model; Mutation; Neuraxis; Neurobiology; neurotransmission; Nonverbal Communication; novel; Orphan; Oxidative Stress; Pathway interactions; Patients; Pervasive Development Disorder; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Placebo Control; Play; pre-clinical; Pre-Clinical Model; preclinical study; Prevalence; Prodrugs; Production; Property; public health relevance; Quality of life; Reduced Glutathione; Reporting; research study; Rett Syndrome; Risk; Rodent; Rodent Model; Role; Signal Transduction; Small Business Innovation Research Grant; small molecule; Social Interaction; Source; success; Symptoms; Syndrome; System; Testing; Therapeutic; therapeutic target; tool; Treatment Protocols; United States; Work
