Autism spectrum disorders (ASD) are a family of disabling disorders of the developing brain that affect about 1% of the population. Studying the biology of these conditions has been difficult as they have been challenging to represent in animal models. The core symptoms of ASD, including deficits in social communication, imagination and curiosity are intrinsically human and difficult to model in organisms commonly studied in the laboratory. Ideally, the mechanisms underlying ASDs need to be studied in human patients and in their cells. Since they maintain the genetic profile of an individual, studying neurons derived from human induced pluripotent stem cells (hiPSC) is attractive as a method for studying neurons from ASD patients. hiPSC based studies of ASDs hold promise to uncover deficits in cellular development and function, to evaluate susceptibility to environmental insults, and for screening of novel therapeutics. In this project our goal is to contribute blood and skin samples for hiPSC research from 200 children with an ASD and 100 control subjects to the CIRM repository. To maximize the value of the collected tissue, all subjects will have undergone comprehensive clinical evaluation of their ASD. The cells collected through this project will be made available to the wider research community and should result in a resource that will enable research on hiPSC-derived neurons on a scale and depth that is unmatched anywhere else in the world.
The prevalence and impact of Autism Spectrum Disorders (ASD) in California is staggering. California has experienced 13% new ASD cases each year since 2002. ASD are a highly heritable family of complex neurodevelopmental conditions affecting the brain, with core symptoms of impaired social skills, language, behavior and intellectual abilities. The majority with an ASD experience lifelong disability that requires intensive parental, school, and social support. The result has been a 12-fold increase in the number of people receiving ASD services in California since 1987, with over 50,000 people with ASDs served by developmental and regional centers. Within the school system, the number of special education students with ASD in California has more than tripled between 2002 and 2010. The economic, social and psychological toll is enormous.
It is critical to both prevent and develop effective treatments for ASD. While rare genetic mutations account for a minority of cases, our understanding of idiopathic ASD (>85% of cases) is extremely limited. Mechanisms underlying ASDs need to be studied in human patients and in cells that share the genetic background of these patients. Since they maintain the complete genetic background of an individual, hiPSCs represent a very practical and direct method for investigating neurons from ASD patients to uncover cellular deficits in their development and function, and for screening of novel therapeutics.
Autism Spectrum Disorders (ASD) are a family of prevalent and complex genetic neurodevelopmental disorders that affect the development of proper communication, social, and cognitive abilities. These disorders are difficult to model since many of the core disabilities (impairments in imagination, curiosity, or proper human social interaction) observed in those afflicted with ASDs are intrinsically human and difficult to recapitulate in an animal system. Given the genetic component of ASDs, human induced pluripotent stem cells (hiPSCs) represent an opportunity to study neurons differentiated from individuals with ASDs. Study of hiPSC-derived neurons may allow researchers to begin to understand deficits in cellular development and function, evaluate responses to environmental insults, and screen for drug candidates that may attenuate ASD phenotypes. The applicants intend to collect blood and skin samples from 200 patients with ASDs and 100 control subjects and provide these samples to the recipient of the CIRM hiPSC Derivation Awards. All samples will be tied to extensive demographic, medical, and diagnostic information including results from a comprehensive medical and cognitive assessment.
Impact and Significance
- ASDs are a debilitating and poorly understood family of disorders with significant incidence that requires life-long support for the patient. Currently, there are no reliable biomarkers or biologically based treatments. ASDs account for a major medical, sociological and financial burden for the family of those afflicted and the national health system, so research advancements using this resource could have substantial impact.
- The existing cellular repositories for ASD have focused on rare patients with known monogenic causes and a cellular repository for idiopathic autism could be a unique resource.
- Animal models are inadequate for recapitulating the language and social defects of this genetically complex family of diseases and can primarily be used to understand monogenic ASDs. The use of hiPSCs offers a renewable source of patient-derived neurons and allows study of the more genetically complex ASDs that represent the majority of ASDs.
- Cellular phenotypes in hiSPC-derived neurons have been demonstrated so it is likely a phenotype could be observed in neurons derived from this cohort, though the diversity of causes of ASDs may make identifying underlying mechanisms difficult.
Quality of the Proposed Protocols
- The proposed cohort should reflect the genetic diversity of the disease and the controls are well matched in terms of diversity. However, some reviewers thought the investigators should consider whether to over-sample minority population in their catchment area to increase the genetic diversity of the cohort.
- No rationale is provided for the proposed number of cell lines, though the review panel recognizes the difficulty in making predictions regarding how many lines might be required to identify a biomarker or understand the underlying mechanisms of the disorder.
- The proposal includes exemplary characterization of the cohort and good exclusion criteria, and the team is experienced in managing this type of clinical data.
- The investigators have a robust system for collecting and managing patient information in a HIPAA compliant manner.
- The consent form provides for broad use, including potential commercial use of derived iPSC lines from patient samples.
- Some reviewers advised that the applicant should consider pushing to collect skin from as many subjects as possible; performing cognitive and diagnostic evaluation only on those subjects who have consented for skin biopsy; and collecting blood or saliva from family members for future use.
- The team is strong and experienced in recruiting patients and managing data for this type of study and already has IRB approval for a similar protocol.
- Although challenging, the proposed rates of recruitment and sample collection appear feasible based on the expertise and experience of the team.
- The study does not include enrollment outside of CA and the investigators should consider including samples from cohorts that have been subjected to intensive genetic analysis, such as the Simons Simplex Collection.
- The budget appears reasonable.
Qualifications of the Principal Investigator (PI) and Team Members, Resources
- The PI is knowledgeable, has appropriate experience, and has assembled a strong team that increases the likelihood the proposed project will be successfully executed.
- The team has extensive experience assessing patients with autism and has previously collected samples and data for these types of genetic studies.