Tissue Collection for Disease Modeling
Multiple sclerosis (MS) is a disease of the central nervous system; it is the most common cause of non-traumatic neurological disability in young adults, affecting approximately 2 million people worldwide. The incidence of MS appears to have increased considerably over the last century. In most cases, MS starts out as a relapsing-remitting disease with episodes during which neurological symptoms occur and persist for days to months and are followed by symptom-free intervals. After 10 to 15 years, a large percentage of patients begin to accumulate neurological disability and follow a progressively worsening disease course. Together with tissue changes observed in the brain and spinal cord of MS patients, this suggests inflammation and neurodegeneration to participate in MS pathology. MS is a prototypical complex genetic disease as multiple so-called "susceptibility loci" have been identified. The ensuing challenge is to design effective functional studies that link genetic variation to the underlying pathophysiology of MS. Such knowledge might translate into clinically useful genetic biomarkers and reveal novel targets for therapy. The availability of a representative panel of MS hiPSCs will undoubtedly aid in this effort. We plan to recruit tissue donors from a cohort of MS patients followed at[REDACTED]. These patients are extremely well studied and extensive clinical, imaging, laboratory, and genetic data information is available for each study participant
Statement of Benefit to California:
Multiple sclerosis (MS) is a debilitating disease leading to significant neurological disability in about about 80% of patients within 15 years after diagnosis. MS mainly affects young adults aged 20 to 30 years-old; there are more than 50,000 MS patients living in California. MS symptoms are caused by inflammatory myelin destruction and neurodegenerative mechanisms. Our understanding of inflammatory activity in MS has led to the development of numerous treatments that reduce disease activity. However, our understanding of neurodegenerative processes occurring in MS patients and why in these patients the brain's ability to self-repair ultimately fails and permits accumulating neurological deficitis and disability, remains very limited. MS is a disease with a complex genetic background. As more-and-more genes are being identified that may be involved in the disease process, we begin to learn about genes that may be particularly important to the neurodengenerative aspect of the disease. The availability of a large cohort of clinically, genetically, and by imaging studies well-studied MS patients in [REDACTED], directly permits selection of patients carrying specific genetic markers. This study will obtain tissues from 100 MS patients based disease-course and genetic data to generate hiPSC which can then be used to better model MS. Understanding how to better repair brain or prevent lasting damage and disability will ultimately improve the lives and ability to work of many.
The goal of the proposed project is to produce starting materials for generating human induced pluripotent stem cells (hiPSC) from a cohort of patients with multiple sclerosis (MS). MS is a serious, debilitating disease of the central nervous system. It is the most common cause of non-traumatic neurological disability in young adults, affecting approximately 2 million people worldwide. Histopathological characteristics of MS suggest that both autoimmune and neurodegenerative pathologies occur in this disease. In addition, MS is a complex genetic disease and the ability to study the link between the genetic variation and the manifestations of MS could help identify potential biomarkers and new targets for drug development. The hiPSC lines, ultimately resulting from this proposal, are intended to aid with this effort. Impact and Significance - The use of differentiated hiPSC cells to study MS disease mechanisms is innovative but may be less likely to succeed than work in disorders with a stronger genetic component. - One drawback is that the genetic background of MS is so diverse, that it is unlikely that a small number of cell lines, as proposed here, would be sufficient to study MS in a meaningful way. - In support of future studies, a bank of MS hiPSC cells would be valuable. Rationale - Reviewers debated whether MS could be modeled in hiPSC-derived cells. Although the applicants do not cite prior work or preliminary data supporting any specific phenotypic assays, reviewers did think that the potential for hiPSC-based discoveries for MS is visionary and exciting. - The number of cell lines to be generated is quite low with no samples proposed from age- and gender-matched controls. - The application proposes to collect cells from patients already participating in a large MS study at the applicant’s institution. The link to this on-going study, which has generated a well-characterized patient cohort, is considered a strength of the proposal. This collection could provide significant advantages, e.g. a long follow-up and an over-representation of young age MS cases. - The investigators propose to collect samples from a diverse, yet representative, patient cohort and reviewers found the process for identifying prospective subjects to be well thought out. Quality of the Proposed Protocols - Much of the tissue procurement protocol appears to have been written for an alternative funding application, suggesting that insufficient focus may have been given to the nuances of this RFA. Reviewers discussed that several protocols were not well developed and were lacking in detail. - Additionally, the informed consent and patient information brochure are written for a number of different studies and it would seem appropriate to have a form that is customized solely for this project. - The investigators mention that control hiPSCs will be important, but do not propose to collect samples from a control population. - Although the project seems to have a secure and flexible data management system, the description of the data management structure is relatively superficial. It would have been helpful if more information had been provided to explain how the management of project-specific data relates to that of existing clinical data. Feasibility No relevant concerns were highlighted by reviewers under this review criterion. Budget - Based on the total direct costs, reviewers thought that the cost per sample was disproportionally high. - Most of the costs are associated with personnel and the application was found to be somewhat heavy on faculty FTEs, given the scope of the proposed work. Qualifications of the Principal Investigator (PI) and Team Members, Resources - Both the PI and the co-investigator are established and well respected researchers in the field. They have experience in patient-related research and are well qualified for the project. - The team has deep clinical experience with MS and has been one of the leading research groups in this area. They have extensive experience with enrolling subjects, collecting/managing clinical data and collecting/banking biological specimens. - There are no identified biostatisticians in the team. Moreover, there is only 10% effort for data management personnel.
- Jacob McCauley