Early Translational II
Autism and autism spectrum disorders (ASD) are complex neurodevelopmental diseases that affect 1 in 150 children in the United States. Such diseases are mainly characterized by deficits in verbal communication, impaired social interaction, and limited and repetitive interests and behavior. Because autism is a complex spectrum of disorders, a different combination of genetic mutations is likely to play a role in each individual. One of the major impediments to ASD research is the lack of relevant human disease models. ASD animal models are limited and cannot reproduce the important language and social behavior impairment of ASD patients. Moreover, mouse models do not represent the vast human genetic variation. Reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, iPSCs) has been accomplished using human cells. Isogenic pluripotent cells are attractive from the prospective to understanding complex diseases, such as ASD. Our preliminary data provide evidence for an unexplored developmental window in ASD wherein potential therapies could be successfully employed. The model recapitulates early stages of ASD and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. By testing whether drugs have differential effects in iPSC-derived neurons from different ASD backgrounds, we can begin to unravel how genetic variation in ASD dictates responses to different drugs or modulation of different pathways. If we succeed, we may find new molecular mechanisms in ASD and new compounds that may interfere and rescue these pathways. The impact of this approach is significant, since it will help better design and anticipate results for translational medicine. Moreover, the collection and molecular/cellular characterization of these iPSCs will be an extremely valuable tool to understand the fundamental mechanism behind ASD. The current proposal uses human somatic cells converted into iPSC-derived neurons. The proposed experiments bring our analyses to real human cell models for the first time. We anticipate gaining insights into the causal molecular mechanisms of ASD and to discover potential biomarkers and specific therapeutic targets for ASD.
Statement of Benefit to California:
Autism spectrum disorders, including Rett syndrome, Angelman syndrome, Timothy syndrome, Fragile X syndrome, Tuberous sclerosis, Asperger syndrome or childhood disintegrative disorder, affect many Californian children. In the absence of a functionally effective cure or early diagnostic tool, the cost of caring for patients with such pediatric diseases is high, in addition to a major personal and family impact since childhood. The strikingly high prevalence of ASD, dramatically increasing over the past years, has led to the emotional view that ASD can be traced to a single source, such as vaccine, preservatives or other environmental factors. Such perspective has a negative impact on science and society in general. Our major goal is to develop a drug-screening platform to rescue deficiencies showed from neurons derived from induced pluripotent stem cells generated from patients with ASD. If successful, our model will bring novel insights on the dentification of potential diagnostics for early detection of ASD risk, or ability to predict severity of particular symptoms. In addition, the development of this type of pharmacological therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies (providing banks of inducible pluripotent stem cells) in California with consequent economic benefit.
This application for a Development Candidate Feasibility (DCF) Award focuses on induced pluripotent stem cell (iPSC)-derived neuronal models for autism spectrum disorders (ASD). The applicant presents preliminary data describing a phenotype in iPSC-derived neurons from patients with an ASD prototype disease with a known genetic mutation as well as patients with sporadic ASD. The applicant proposes to extend this work in three Specific Aims: (1) to test specific pharmacological compounds for their potential to rescue the phenotypes of these ASD neurons; (2) to establish and optimize phenotypic readouts for a high throughput drug screening platform; and (3) to generate and phenotype iPSC-derived neurons from twenty more sporadic ASD patients and ten age/gender-matched controls. Reviewers agreed that ASD represent a tremendous unmet medical need, as there is a high incidence of disease and no currently effective therapies. Establishing a cellular model of ASD could have a very significant impact, as patient neurons are inaccessible and disease mechanisms are poorly understood. Reviewers also noted that drugs identified by screening ASD neurons are unlikely to be discovered by any other means. One reviewer cautioned that because ASD is complex and involves many genes, the therapeutic effects of pharmacological compounds may be limited to the specific patient set screened. However, this reviewer noted that compounds may work on shared pathways that are affected in multiple patients and, regardless, the discovery of any drug for use in any ASD patient would have a remarkable impact. The reviewers described the preliminary data as exciting and extremely impressive. They noted that the phenotypic data from ASD neurons are the most convincing they have seen and have already led to the discovery of a novel autism-associated gene and a compound that rescues a neuronal phenotype. Reviewers found the research plan to be strongly supported by these preliminary data and entirely feasible. They did note that the applicant has not developed a robust differentiation protocol for specific neuronal subtypes, but were confident that the research team could overcome this obstacle. Reviewers praised the plan for a sophisticated in vitro assay system with multiple phenotypic readouts. They found the milestones to be clearly described and the timeline realistic. Well-considered alternative approaches are presented. One reviewer noted that a clinical trial of dextromethorphan and donezepil is currently ongoing for an ASD prototype disease and suggested that using these compounds in the applicant’s cellular model could generate important supporting data. Reviewers were enthusiastic about the Principal Investigator (PI) and assembled research team. They noted that the PI is relatively junior, but has been extremely productive and has substantial expertise in this field. In addition, the PI has established impressive collaborations with co-investigators who are experts in neurogenesis and autism. The reviewers appreciated the strong letters of support from collaborators as well as the resources available to the applicant, which include interesting chemical libraries for screens. Overall, reviewers found this proposal to be truly outstanding. They were excited by the preliminary data, the well-designed research plan and the highly qualified research team. The reviewers expressed confidence that this project will lead to significant advances in the understanding of ASD and recommended this DCF award for funding.