Forward Genetic Screen to Identify Novel Therapeutic Entry Points of an Autism Spectrum Disorder
Abstract
Despite a sharp rise in the number of individuals diagnosed with autism in the past three decades, we do not have targeted therapies for this devastating disorder. The only approved medications for autism treat aggressive and self-injurious behaviors but not the core features of autism: language impairment, poor socialization, and restricted interests. This proposal aims to identify therapeutic entry points for autism spectrum disorders and ultimately translate those discoveries into treatments for individuals with autism. This proposal addresses a key area of interest for the Fiscal Year 2016 Autism Research Program Idea Award of identifying and assessing novel therapeutics for valid preclinical models. In order to identify these potential therapies, we propose to identify key molecular pathways that modulate the abundance of a protein that is encoded by a key autism gene, SHANK3. By identifying and harnessing these key molecular pathways, we aim to normalize the abundance of SHANK3 in those individuals who make too little of this important protein for the pathogenesis of autism. In this proposal, we will use powerful genetic techniques to confirm the role of these pathways in regulating SHANK3 and improve phenotypes in mice deficient for this gene, a validated model for autism. This will set the stage for identifying chemical compounds that can modulate these same pathways and be used as novel therapies for autism spectrum disorders. This work is innovated because it uses an unbiased and large-scale screen to identify therapeutic entry points upstream of an autism spectrum disorder gene. Previous efforts to identify therapeutic entry point for autism have focused on downstream consequences of mutations in autism causing genes. While this information is useful, it fails to account for the plethora of changes that occur downstream of autism genes. By taking an approach to normalize abundance of the protein product of an autism causing gene, we are not limited by our lack of understanding of all downstream effects of mutation in autism causing genes. Furthermore, this approach focuses on druggable targets and does not rely on using unproven methods such as viral transduction of cerebral neurons for efficacy. The impact on autism research includes both short- and long-term consequences. In the short term, this work will lead to immediate development of therapeutic targets that can be developed for a genetically defined form of autism due to mutation in the SHANK3 gene. But, the long-term consequences are perhaps more profound. If successful, this approach could provide a blueprint for the many other genetically defined forms of autism due to reduced abundance of the protein product such as due to mutations in SYNGAP1, Neurexins and Neuroligins. Moreover, this work will increase knowledge of the complex molecular biology of the synapse, which itself could result in identifying novel therapeutic entry points.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710232
Entities
People
- Jimmy Holder
Organizations
- Baylor College of Medicine
- United States Army