Basic Biology IV
Autism Spectrum Disorders (ASDs) are a heritable group of neurodevelopmental disorders that affect the verbal, social, and behavioral abilities of affected individuals. There are no pharmacological treatments for ASDs, in part because of a lack of validated cellular and animal models. Phelan-McDermid Syndrome (PMDS) is a progressive neurodevelopmental disorder characterized by developmental delay, absent or severely impaired speech, and an increased risk of autism. PMDS results from chromosomal mutations in or deletions of the neural protein, Shank3. In preliminary experiments, we derived neurons from PMDS patients and used several of these neural lines to identify specific functional defects in PMDS neurons. We propose to characterize patient-derived neurons from a broader patient base and explore the role of Shank-3 and other genes in these defects. Finally, we will try to identify factors that can reverse the functional defects of PMDS neurons, either by augmenting Shank3 protein levels or by modifying its downstream effectors. This research will provide essential information about the causative molecular changes that underlie PMDS, and could help us identify new avenues for therapeutic development. More generally, our studies will provide critical new tools for the study and treatment of ASDs.
Statement of Benefit to California:
Autism Spectrum Disorders (ASDs) affect approximately 1 in 110 children in California. In addition to emotional and financial hardships imposed by ASDs on affected children and their families, the state bears an enormous economic responsibility to treat and educate those afflicted. Recent estimates suggest that the lifetime cost of caring for an ASD-affected individual can exceed $3 million; school districts or regional centers paid for 70% of the therapies received by respondents., No effective medications exist for ASDs despite the severe impact on society and the prospects for developing such treatments in the near future are very low. Drug development requires validated animal or cellular models to identify targets and to screen for drugs, and very few such models exist for ASDs. The proposed research could improve the prospects for developing pharmacological therapies for ASDs. We have already developed a cellular model for studying Phelan-McDermid Syndrome (PMDS), a neurodevelopmental disorder associated with autism, and have begun to understand the cellular and molecular deficits that underlie this disease. We propose to further characterize alterations in neurons of a broader diversity of PMDS patients, and to study the interaction of genes affected in this genetic disorder. If successful, our research will identify potential drug targets for PMDS and will result in important new tools to understand the cellular and molecular causes of ASDs.
The overall goal of this proposal is to use patient-derived induced pluripotent cells (iPSC) to study neuronal defects in patients with Phelan McDermid Syndrome (PMDS), a neurodevelopmental disorder caused by mutations in the SHANK3 gene associated with high risk of autism and/or schizophrenia. Having previously identified specific defects in neurons from PMDS patients, the applicant seeks to extend these studies by broadening the patient base and further investigating the observed neurological phenotypes (Aims 1 and 2). In the third Aim, the applicant proposes to explore the underlying role of SHANK3 and other genes in contributing to the mechanism of disease. Significance and Innovation - The proposed study is highly related to a similar project for which the PI is already funded. Reviewers felt that the impact of these studies would prove incremental, even if complete scientific overlap were avoided. - The proposal is of limited innovation, largely seeking to extend the applicant’s previous findings by creating additional variant lines and making use of his/her routine analytical pipeline. The value to be added from such studies is unclear. - The proposal addresses an important area of study, as the molecular mechanisms contributing to autism and related disorders are poorly understood. Potential insights could lead to new avenues of therapeutic development for conditions that reflect a significantly unmet medical need. Feasibility and Experimental Design - While Aim 3 explores new directions that includes SHANK3 rescue and knockdown experiments, reviewers found it to be poorly developed and lacking in experimental detail. - All of the proposed experiments are technically feasible, although there is little discussion of data interpretation and pitfalls. - It is not clear why the applicant continues to use retroviral vectors for iPSC generation rather than more state of the art, integration-free techniques. Principal Investigator (PI) and Research Team - The PI is an outstanding investigator with an excellent track record of publications in high impact journals. His/her expertise is highly relevant for all aspects of the proposal. Responsiveness to the RFA No relevant concerns were highlighted by the reviewers under this review criterion.