The goal of the proposal is to identify the factors that limit in vivo survival and function of human ES (hES) derived dopamine (DA) neurons in preclinical models of Parkinson's disease (PD). Preliminary work in our lab has provided high-yield protocols for the derivation of midbrain DA neurons from hES cells. However, pilot transplantation studies of hES cell derived DA neurons in rodent and non-human primates suggest poor in vivo survival and maintenance of DA fate. Poor in vivo survival is in contrast to work with mouse ES derived DA neurons that showed robust survival in both allo- and xenograft PD models. This suggests that hES cell derived DA neurons exhibit a particular vulnerability that needs to be resolved before the clinical use of these cells can be envisaged. Here we propose to systematically address whether cell or host-based parameters or a combination of the two are responsible for the limited in vivo DA neuron survival and function in rodent and monkey models of PD. These studies should provide the basic foundation for our long-term efforts to translate hES cell based DA neuron differentiation strategies for clinical application. The Study has two major aims: ? ? 1. To address whether low numbers of surviving DA neurons in vivo are due to incomplete midbrain DA neuron differentiation in vitro ? ? 1.1. Improving patterning of hES derived neural rosettes towards midbrain DA neuron identity ? ? 1.2. Timing of patterning in neural rosettes: Early vs. late rosettes as a source of DA neurons. ? ? 2. To address whether low numbers of surviving DA neurons in vivo are due to selective cell death of the grafted hES-derived DA neuron population. ? ? 2.1. Intrinsic vulnerability of hES derived DA neurons ? ? 2.2. Lack of sufficient trophic support in vivo ? ? 2.3. Host immunological/inflammatory response interferes with DA neuron survival ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS052671-01A2
Application #
7213861
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2007-01-24
Project End
2010-12-31
Budget Start
2007-01-24
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$399,438
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Steinbeck, Julius A; Jaiswal, Manoj K; Calder, Elizabeth L et al. (2016) Functional Connectivity under Optogenetic Control Allows Modeling of Human Neuromuscular Disease. Cell Stem Cell 18:134-43
Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R et al. (2016) Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and ?-Synuclein Accumulation. Stem Cell Reports 7:664-677
Steinbeck, Julius A; Choi, Se Joon; Mrejeru, Ana et al. (2015) Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model. Nat Biotechnol 33:204-9
Steinbeck, Julius A; Studer, Lorenz (2015) Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86:187-206
Battista, Daniela; Ganat, Yosif; El Maarouf, Abderrahman et al. (2014) Enhancement of polysialic acid expression improves function of embryonic stem-derived dopamine neuron grafts in Parkinsonian mice. Stem Cells Transl Med 3:108-13
Tabar, Viviane; Studer, Lorenz (2014) Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet 15:82-92
Miller, Justine D; Ganat, Yosif M; Kishinevsky, Sarah et al. (2013) Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13:691-705
Ganat, Yosif M; Calder, Elizabeth L; Kriks, Sonja et al. (2012) Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment. J Clin Invest 122:2928-39
Ming, Guo-Li; Brustle, Oliver; Muotri, Alysson et al. (2011) Cellular reprogramming: recent advances in modeling neurological diseases. J Neurosci 31:16070-5
Kriks, Sonja; Shim, Jae-Won; Piao, Jinghua et al. (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480:547-51

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