The failure of large clinical trials for Alzheimer’s disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis and Parkinson’s disease (PD) are forcing the field to consider more targeted treatments for genetically homogeneous cohorts. Precision medicine approaches to the diagnosis and treatment of patients offer huge opportunities to advance the dementia field. New trials for AD patients with presenilin-1 mutations and FTD patients with progranulin and tau mutations have already been started or are being considered.
Dr. Shinya Yamanaka brought a revolution to stem cell technology by delineating a method to convert skin cells to induced pluripotent stem cells (iPSCs). This approach has facilitated development of new models of neurodegeneration for patients with FTD-related mutations of progranulin (1,2) or C9orf72 (3). Similarly, iPSC-based modeling of the detrimental effects of apolipoprotein E4 and the tau polymorphism A152T (Yadong Huang, personal, communication) is facilitating a precision medicine approach to the determination of disease effects of specific genes. Via iPSC technology, large quantities of neurons can be produced allowing exploration of the pathological consequences of genetic polymorphisms while simultaneously allowing drug screening of neurons from patients with genetically caused forms of dementia. (4)
We propose to create through UCSF’s CTSI a national core of neurons from patients with both sporadic and genetic forms of Alzheimer’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson’s disease and other rare forms of dementia. Selected investigators will study and manipulate these neurons in order to develop model systems for the major mutations that cause AD, FTD, ALS and PD. Simultaneously, age-matched control neuronal lines would also be generated for comparison studies. Large numbers of these neurons would be created for and distributed to other CTSI sites investigators and scientists across the world, requesting the use of these valuable cells.
Comprehensive clinical phenotyping would be performed on the participants in this project that would include clinical characterization (demographics, cognitive, motor and imaging data), and family history. Whole genome sequencing of the cells would be performed at UCLA and transciptome analysis would be done at UCSB. The resulting multidimensional data would be incorporated into the UCSF Precision Medicine Knowledgebase, linking it with related neuroscientific datasets and analytic resources to maximize its value for the larger research community. The project would be led by UCSF’s Memory and Aging Center (Bruce Miller, Kate Rankin, Aimee Kao), the Gladstone Institute (Yadong Huang), the Broad Institute (Steve Haggarty), UCSD (Irene Litvan), and UCLA (Dan Geschwind and Giovanni Coppola). Partial support for the study will be supplied by three private foundations, the UCSF NIA supported by an Alzheimer Disease Research Center (Miller), and a grant supported by the NINDS (Huang).
1. Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot S, Tapper AR, Sellier C, Charlet-Berguerand N, Karydas A, Seeley WW, Boxer AL, Petrucelli L, Miller BL, Gao FB. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 2013 Jul 9.
2. Almeida S, Zhang Z, Coppola G, Mao W, Futai K, Karydas A, Geschwind MD, Tartaglia MC, Gao F, Gianni D, Sena-Esteves M, Geschwind DH, Miller BL, Farese RV Jr, Gao FB.
3. Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. Cell Rep. 2012 Oct 25;2(4):789-98.
4. Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, Niu W, Coppola G, Coughlin SE, Lee SE, Dries DR, Almeida S, Geschwind D, Gao FB, Miller BL, Farese RV Jr, Posner BA, Yu G, Herz J. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem. 2011 May 6;286(18):16101-8.
5. Zhao WN, Cheng C, Theriault KM, Sheridan SD, Tsai LH, Haggarty SJ. A high-throughput screen for Wnt/β-catenin signaling pathway modulators in human iPSC-derived neural progenitors. J Biomol Screen. 2012 Oct;17(9):1252-63.
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