Tissue Collection for Disease Modeling
Autism is a common disorder with a prevalence of 1 in 88 worldwide (Centers for Disease Control 2008). 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. Thus far, the iPSC approach was used for syndromeic forms of ASD, such as Rett syndrome. Our preliminary data shows that one can actually model for idiopathic autism and provide evidence for an unexplored developmental window in ASD wherein potential therapies could be successfully employed. The current proposal uses human somatic cells converted into iPSC-derived neurons. 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 study neurons and other cell types derived from induced pluripotent stem cells generated from patients with ASD. If successful, our model will bring novel insights on the identification of potential diagnostics for early detection of ASD risk, or ability to predict severity of particular symptoms. In addition, we plan to use this resource for a drug-screening platform, aiming to rescue defect in ASD-derived cells. 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 in California with consequent economic benefit.
Autism Spectrum Disorders (ASDs) are a family of prevalent neurodevelopmental disorders characterized by impairments in communication and social interaction and by abnormal behaviors such as repetitive interests and actions. Different combinations of genetic mutations contribute to the pathology observed in ASD patients. Given the nature of the impairments and the likely complex genetics, ASD animal models are limited in terms of relevance to the human disease state. The use of human induced pluripotent stem cells (hiPSCs) derived from individuals with ASDs to investigate the molecular and cellular underpinnings of the disease and identify potential biomarkers and therapeutic targets is an attractive alternative. In this proposal, the applicant proposes to collect tissue samples from 150 ASD and 150 control subjects with diverse clinical histories from both California and outside California and from 60 ASD and 60 control subjects from an existing cohort where whole-genome sequencing data is available. Impact and Significance - ASD patients require life-long support and these disorders have enormous medical, social, and financial impacts. The biologic basis of ASDs is poorly understood and currently, reliable biomarkers and biologically-based treatments do not exist. As hiPSC-based studies have the potential to improve the understanding of the molecular basis of disease or lead to identification of biomarkers or therapeutic targets, a collection of hiPSC lines derived from ASD patients’ cells could be impactful. - The proposal lacks a clear description of what information will be associated with the hiPSC lines that are ultimately banked as a resource for the community. As the primary value and utility of the banked cells lies in the clinical data associated with the cell lines, this weakness limits the potential impact of this proposal. Rationale - Animal models are inadequate for recapitulating ASD disease phenotype, and the applicant has provided compelling data that neuronal phenotypes can be modeled using hiPSCs from patients with a single-gene cause of autism. Moreover, there is preliminary evidence that a phenotype can be observed in hiPSC-derived neurons generated from patients with more genetically complex ASDs. - ASDs are appropriate for study using hiPSCs, though the diversity of causes may make it difficult to identify the underlying disease mechanisms. Quality of the Proposed Protocols - The proposal has numerous failings in that the applicant does not properly describe how subjects will be diagnosed, recruited, or clinically assessed. - Tissue and data collection and storage protocols are not adequately described and there is little attention paid to how clinical data will be organized and made available to the Repository. Additionally, it is unclear what clinical data will be associated with each sample. - The inclusion/exclusion criteria are lacking. - The applicant proposes to collect a novel tissue source from many of the tissue donors, and provides preliminary data that hiPSCs can be derived from this source. When considering the patient population, this is an excellent choice, as it would likely enable inclusion of individuals who may be excluded if tissue is collected from skin punch biopsies. However, it is unclear how the viability of that tissue will be ensured, and it is not certain the Deriver will be able to utilize it in the derivation protocol. - The samples collected outside of California will add considerable genetic diversity to the cohort. Feasibility - It is crucial for the utility of the hiPSC lines that extensive and appropriate clinical data is associated with each tissue sample and that the data are provided to the Repository in a usable format. Reviewers expressed concern that the applicant did not allocate appropriate resources for successful organization and transfer of clinical data to the Repository. - Inadequate and/or inappropriate resources are devoted to subject recruitment, assessments, and data management. Budget - Per patient tissue collection costs are not particularly competitive, and there are some differences in costs associated with different cohorts that are not properly explained. - The budget is unbalanced. There are insufficient personnel and costs allocated to data management, communication with the tissue donor families and clinicians, and interacting with the Deriver, while other costs, for e.g. cell handling, seem high. Qualifications of the Principal Investigator (PI) and Team Members, Resources - Though the team is excellent in terms of investigating the genetics of autism, the proposal lacked sufficient detail in the tissue collection aspect of the proposal; it appears this applicant would be better suited as a recipient of hiPSC lines from the Repository than as a Tissue Collector. - The PI has done excellent work on hiPSCs and is an active investigator in the field and is a strength of the proposal in terms of stem cell expertise. - The team has proposed collaborations but does not have letters of support from these collaborators.