Most children who go to the clinic with brain disorders have symptoms combining autism, cerebral palsy and epilepsy, suggesting underlying and shared mechanisms of brain dysfunction in these conditions. Such disorders affect 4-6% of the population with life-long disease, and account for about 10% of health care expenditures in the US. Genetic studies have pointed to frequent low-penetrant or low-frequency genetic alterations, but there is no clear way to use this information to make gene-specific diagnosis, to predict short- or long-term prognosis or to develop disease-specific therapy. We propose to recruit about 500 patients with these disorders mostly from our Children’s Hospital, through a dedicated on-site collaborative approach. Extracting from existing medical records, taking advantage of years of experience in recruitment and stem cell generation, and already existing or planned whole exome or genome sequencing on most patients, we propose a safe, anonymous database linked to meaningful biological, medical, radiographic and genetic data. Because team members will be at the hospital, we can adjust future disease-specific recruitment goals depending upon scientific priorities, and re-contact patients if necessary. The clinical data, coupled with the proposed hiPSC lines, represents a platform for cell-based disease investigation and therapeutic discovery, with benefits to the children of California.
This project can benefit Californians both in financial and non-financial terms. NeuroDevelopmental Disabilities (NDDs) affect 4-6% of Californians, create a huge disease burden estimated to account for 10% of California health care costs, and have no definitive treatments. Because we cannot study brain tissue directly, it is extraordinarily difficult to arrive at a specific diagnosis for affected children, so doctors are left ordering costly and low-yield tests, which limit prognostic information, counseling, prevention strategies, quality of life, and impede initiation of potentially beneficial therapies. Easily obtainable skin cells from Californians will be the basis of this project, so the study results will have maximal relevance to our own population. By combining “disease in a dish” platforms with cutting edge genomics, we can improve diagnosis and treatments for Californians and their families suffering from neurodevelopmental disorders.
Additionally, this project, more than others, will help Californians financially because: 1] The ongoing evaluations of this group of patients utilizes medical diagnostics and genetic sequencing tools developed and manufactured in California, increasing our state revenues. 2] The strategy to develop “disease in a dish” projects centered on Neurodevelopmental Disabilities supports opportunities for ongoing efforts of California-based pharmaceutical and life sciences companies to leverage these discoveries for future therapies.
Childhood neurodevelopmental disorders (NDD) continue to represent a significant and unmet medical challenge. They are understudied, in part, due to the inaccessibility of the neurons in the central nervous system affected by each of the pathologies. The recent development and use of human induced pluripotent stem cells (hiPSCs) to generate these affected neurons in a dish have opened promising new opportunities for therapeutic drug screening and enabled the study of the pathology and mechanisms of action contributing to these disorders. In this proposal, the applicant seeks to collect skin tissue samples from children with neurodevelopmental disorders comprising three broad categories representing infantile epilepsy, autism and cerebral palsy. There are shared comorbidities among these disorders and thus studying them collectively might, at least in part, reveal some shared genetic characteristics. Accordingly, the applicant is committed to obtaining whole exome or whole genome sequences from collected samples using other funds, and linking that data to the hiPSC in the CIRM Repository. Healthy population cohorts as well as healthy family members of affected individuals will serve as the control group in the study.
Impact and Significance
- The target disease group is of utmost importance in terms of unmet clinical need.
- Reviewers believed that the proposed hiPSC lines would be of exceptional scientific value, providing a wealth of opportunities for disease modeling and high throughput drug screens.
- Reviewers concurred that the relatively large number of samples to be collected would prove sufficient to enable compelling studies towards understanding some of the shared features and disease mechanisms underlying NDDs.
- Some reviewers felt that the reliance on skin fibroblasts to derive new lines is a minor weakness and the use of peripheral blood should have been considered. However, given that the applicants have already derived and banked a significant number of lines using skin tissue, reviewers agreed this was not a significant barrier to the success of this study.
- Reviewers agreed that the rationale for using hiPSC models to increase our understanding of the pathogenicity of NDDs is very strong.
- The commitment to generate whole genome or whole exome sequences for all patient samples adds considerable value to this study and was viewed as a major strength of the application.
- The applicants will collect a significant number of biological samples from patients recruited in well-renowned clinical centers of the state.
Quality of the Proposed Protocols
- Collection of the human tissues and their delivery to the CIRM hiPSC Derivation center is well described, and the overall quality of protocols is high.
- Reviewers agreed that the applicant and the collaborators have extensive experience in recruiting patients for their studies and have established a well functional workflow for consenting and re-contacting patients as well as clinical data management. Also, patients enrolled to this program will have a clear diagnosis supported by a large clinical assessment.
- Reviewers pointed out that although the PI has all assurances and patient consents in compliance with CIRM guidelines, the collaborator’s consent is limited to certain studies and therefore some patients will need to be re-consented for hiPSC research.
- The investigators’ experience with research protocols, clinical data collection, and skin collection convinced reviewers that the proposed number of patients to be recruited is feasible.
- Reviewers agreed that the team’s experience with all aspects of tissue procurement and database tracking adds confidence that the ambitious goal of performing the high number of proposed skin biopsies could be achieved.
- Reviewers were impressed with the investigators’ experience with Institutional Review Board approval.
- That the applicant has already procured and banked a significant number of patient samples representing NDD and controls speaks to the overall feasibility of the proposed endeavor.
- The proposed budget is judicious and well justified.
Qualifications of the Principal Investigator (PI) and Team Members, Resources
- The applicant and the co-investigators are leading scientists in the field of NDD and have made major contributions to the field over the past decade.
- Given their well established laboratories, multitude of collaborations and fruitful connections to large clinical centers in the state, the applicant team is extremely well positioned to successfully complete the proposed project.
- The research environment is excellent, and all of the necessary resources, facility and infrastructure are available to the applicant team.
- Daniel Doherty