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RL1-00650-1: Establishment of Frontotemporal Dementia Patient-Specific Induced Pluripotent Stem (iPS) Cell Lines with Defined Genetic Mutations

Recommendation: Recommended for funding
Scientific Score: 85

First Year Funds Requested: $569,520
Total Funds Requested: $1,708,560

Public Abstract (provided by applicant)

We propose to generate induced pluripotent stem (iPS) cells from skin cells derived from human subjects with frontotemporal dementia (FTD). FTD accounts for 15–20% of all dementia cases and, with newly identified genetic causes, is now recognized as the most common dementia in patients under 65 years of age. FTD patients suffer progressive neurodegeneration in the frontal and temporal lobes and other brain regions, resulting in behavioral changes and memory and motor neuron deficits. The median age of onset for this devastating disease is 58 years, and disease progression is rapid, with death in 3–8 years. Compared with other age-dependent neurodegenerative diseases, the molecular, cellular, and genetic bases of FTD remain poorly understood. Genetic causes are estimated to account for ~40% of FTD. In addition to tau identified in 1998, mutations in three causative genes have been identified during the last three years. The identification of FTD mutations opens exciting new avenues for understanding the causes of FTD. Research on these mutations will help to identify effective therapies. However, the ability to study the functions of these factors is severely limited due to the lack of available human neurons from FTD patients. To address the need for disease– and patient–specific neurons, we will use the powerful new technique of iPS cells. iPS cells are derived from skin cells and can be used to generate any cell types in the body, including neurons. We will obtain human skin cells from FTD patients with disease-causing mutations and generate many FTD mutation–specific iPS cell lines. We will then use these iPS cells to generate FTD mutation–specific neurons to study disease mechanisms. The bank of iPS cell lines we generate will also enable the development of sensitive assays for drug screening and testing of therapeutic agents for treating FTD. All cell lines will be made available to the global FTD research community. The generation of human neurons from FTD patients will be a tremendous advance toward finding a cure for this disease.

Statement of Benefit to California (provided by applicant)

California is the U.S. leader in basic research into stem cell–based therapies for disease. To help California remain at the forefront of research on neurological disease, we propose to use induced pluripotent stem (iPS) cells—a revolutionary new technique developed recently by Dr. Shinya Yamanaka—to target frontotemporal dementia (FTD). FTD is a devastating and common form of dementia. {REDACTED} The proposed research will establish California as the leader in generating human patient–specific neurons from iPS cells. The potential long-term benefits to California include growth of the clinical enterprise in the diagnosis and treatment of FTD, the establishment of biotechnology to generate new drugs for FTD, and potential intellectual properties for driving private enterprises to develop therapies.

Review

The goal of this proposal is to establish multiple induced pluripotent stem (iPS) cell lines from patients with many forms of frontotemporal dementia (FTD) and differentiate these into neurons, in order to study underlying molecular defects and potentially develop therapies. In Specific Aim 1, fibroblasts from patients with FTD with different mutations and from control will be reprogrammed to generate iPS cells. The applicant will use published protocols, and will collaborate with a leader in the field of somatic cell reprogramming. Microarray analyses will be used to compare patient and control stem cells. In Specific Aim 2, the iPS cells from FTD patients will be assessed for their pluripotent potential, and then differentiated into forebrain neurons. This will allow the applicant to study the effects of FTD mutations on the formation of dendritic spines, and to identify potential biochemical defects in these cells.

FTD accounts for 15-20% of all dementia cases and there are no reliable animal or cell-based models of the disease. Thus, the generation of human neurons and a reliable cell-based model of FTD would be a significant advance. Overall, reviewers commented that this proposal is extremely clear, coherent and ultimately appears quite feasible. By looking at a relevant and measurable cellular phenotype, namely the formation and maintenance of dendritic spines, the applicant is very likely to uncover important differences between normal and affected neurons. By combining cellular phenotyping with a biochemical dissection of the disease process, the work may even yield some insight into the pathological mechanism(s) of FTD. Finally, the team that will be collaborating on this project is outstanding, and reviewers were impressed with the clinical aspect of this project as the applicant carefully considers the genetics of the disorder and proposes multiple cell lines for each mutation. If successful, this project would provide the first definitive proof of the hypothesis that dendritic spine abnormalities contribute to FTD. Applicants have clear plans to share their cell lines, which will increase the impact of this work.

Reviewers identified weaknesses in the proposal, although overall they were not important enough to outweigh the potential significance of the work. One concern was whether it will be feasible to study late-onset diseases using in vitro culture models. One reviewer questioned whether differentiating iPS cells into generic post-mitotic neurons would be a sufficiently sensitive assay to detect defects in dendrite formation or biochemical changes, or whether it would be necessary to focus on a particular subtype of neurons. Minor concerns over grantsmanship were raised regarding the presentation of preliminary data in the grant application itself, which made it difficult for reviewers to assess some of the data. Finally, the evaluation of gene expression in the FTD patient iPS cells compared to controls was not considered well justified.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• None