Human IPS Cells and Cerebral Palsy: Patient and Family Enrollment for Genetic and Biological Pathway Discovery and Insights into Novel Treatment Approaches
Tissue Collection for Disease Modeling
Cerebral palsy (CP) is a complex and debilitating childhood disorder that affects up to 4 in every 1000 children born in California and throughout the world. There are over 800,000 children in the US alone with CP, and this disorder crosses ethnic, racial and geographic lines. Children with CP suffer from weakness and impaired movement of the limbs and trunk. Beyond the significant motor disability, children with CP can also have seizures, intellectual impairment, hearing and vision loss, and autism. Caring for a child with CP is a complex process involving many medical and non-medical specialists, with enormous financial costs that average more than $1,000,000 over a lifetime. Currently there is no treatment that targets the underlying biology of CP; instead, there are only symptomatic treatments. Moreover, while there are clues that problems in brain development can cause CP, the exact nature of these abnormalities is not clearly delineated. This study will enroll patients with CP (and their families) into a longitudinal study in which white blood cells taken from a simple blood draw will be used to generate stem cells for research. In the laboratory these stem cells could be used to study how certain aspects of brain development are disrupted in these patients. In the future, these cells could also serve as “test tube” surrogates in which investigators can test the efficacy of new drugs that might eventually treat the core deficits in CP.
Statement of Benefit to California:
An estimated 100,000 individuals in the state of California have cerebral palsy. They require considerable medical assistance and their disability impairs that capacity to reach their full potential. If this proposal is funded, it would allow California residents with CP to contribute to our understanding of CP biology, which many families find an important and satisfying goal. We not only have patients in the Child Neurology practice at [REDACTED] with CP, we will also be receiving recruitment assistance from state agencies whose mandate it is to care for these patients, so we will reach out broadly to the CP population in California. This study will increase awareness of CP in California and holds the potential to improve treatment strategies. If this initial repository of stem cells is generated in California, it increases the chances that follow up studies will be done here (and funded by outside agencies in addition to CIRM). Not to be under-considered, this study if funded would provide additional medical research employment in California, which not only has immediate effects on the economy but also helps train the next generation of California scientists.
Cerebral palsy (CP) is an “umbrella term” for a group of disorders characterized by disorders of posture or movement resulting from brain lesions and cortical pathway disturbances incurred early in life; it is often accompanied by impaired cognition, communication, sensory perception and epilepsy. The most common forms of CP result from various forms of injury to the developing brain, but other forms may have underlying genetic/metabolic causes and may involve the white matter and/or cortex. In the latter cases, the underlying biology could be studied if there were available model systems. In this proposal, the applicant plans to collect blood lymphocytes from 250 CP patients comprising three cohorts including patients with white matter developmental abnormalities, patients with familial CP and patients with white matter injury. Impact and Significance - Cerebral palsy (CP) is a significant public health concern for which there is no cure. CP research suffers from the lack of reliable animal and cellular models. - Reviewers cautioned that the lack of information about the etiology of CP and about the contribution of genetics versus environment could represent a limitation for the effective use of the iPSC modeling. - Reviewers were unaware of a repository of banked iPSC CP lines and noted that a systematic collection of well-defined phenotype CP cases that do not have a clearly identifiable cause of their disease would be very valuable. Rationale - Although some reviewers believed that there is some evidence suggesting the influence of inherited modifiers, they all agreed the exact contribution of genetics to the forms of CP proposed for tissue collection is still under debate and more studies are required to reach a consensus on the exact etiology. - If environmental conditions play a major contributory role to the white matter injury forms of CP, then iPSC-based modeling could prove to be less informative. - The proposed numbers of samples to be collected from the different CP cohorts is not consistent with their representation in the CP patient population. Of the three proposed CP subgroups described by the investigator, only the third group, white matter injury, represents a large proportion of CP, and identifying biological factors that are associated with severity of white matter injury and developmental outcome could be an important goal; therefore, the proportion of patients in group 3 with white matter injury as compared to the first two groups should be significantly increased. - Reviewers considered the proposed number of control samples to be not justifiable. In addition, some reviewers felt that related controls may not be the best when trying to identify subtle differences associated with disease, since family members share at least part of the genetic background of the affected individual. - Some reviewers argued that it is unclear whether iPSCs generated from lymphocytes or lymphoblastoid cell lines will work as well as the fibroblast derived lines, and cautioned that this might make their comparison to previous cell lines using skin fibroblasts more difficult. Quality of the Proposed Protocols - The consenting procedure and patient follow-up is adequately described. The inclusion and exclusion criteria are well defined, and aims to maximize inclusion of cases with likely genetic components. Data storage, encryption and management allow for data harmonization, integration, data transfer and for project management. - The investigator has a prototype of a consent form, which includes all the conditions expressed by the CIRM guidelines. - A comprehensive plan has been provided for gathering clinical data that would help interpret later iPSC experiments Feasibility - The applicant has experience in organizing large research and clinical studies approved by the local IRB institution. - IRB approval already in place to collect clinical information and blood from a variety of subjects with brain malformations. - The principal investigator has access to well-characterized patients with disorders of corpus callosum and white matter development; however, it may be more appropriate to focus on term and premature infants with white matter injury and appropriate controls. - The protocol aims to use lymphocytes versus fibroblasts to generate iPSCs, which simplifies the recruitment process, however some reviewers argued that the lack of fibroblast derived cell lines would need to be discussed with the iPSC Deriver Budget - The budget seems reasonable for what was proposed although as noted reviewers thought there were too many control samples. - Some reviewers considered personnel costs high and inadequately justified. Qualifications of the Principal Investigator (PI) and Team Members, Resources - The applicant and the team are distinguished scientists and clinicians with extensive expertise in neurodevelopmental disorders. - The PI has assembled an excellent team of investigators. The Co-PI in particular has great expertise in clinical and epidemiological aspects of CP. Reviewers were confident that the investigators can successfully recruit/enroll patients and manage data and samples.
- Chad Cowan
- Jacob McCauley