This is a revised application, modified to fully respond to reviewers? comments and FDA interactions since the application (FDA pre-IND meeting held on Sept. 25, 2018). The proposed work will complete IND-enabling studies to progress cell replacement paradigms into the clinic using induced pluripotent stem cell (iPSC)- derived dopamine (DA) neurons, and a first-in-man clinical trial for autologous transplantation in Parkinson?s disease (PD). Cell replacement therapy with midbrain dopamine (mDA) neurons provides cellular and synaptic repair in the parkinsonian brain, and addresses both the motor symptoms of PD as well as levodopa-induced dyskinesias. Our previous fetal cell transplantation work shows that in PD patients transplanted mDA neurons remain healthy and can provide remarkable therapeutic benefit for decades. While fetal cell transplantations are not scalable for a larger patient population and require immunosuppression, iPSCs are a promising alternative cell source. iPSCs generated from PD patients can be differentiated into midbrain dopaminergic cells, frozen and used for autologous transplantation. The NINDS CREATE Bio Development Track U01 proposal over 5 years consists of milestones within four Specific Aims, that includes a Phase I clinical trial in human patients with PD.
In Specific Aim 1 we will transfer the remaining mDA neuron product quality control assays for qualification in the cGMP facility, perform FDA- guided quality control of excipients for the clinical product, and produce mDA neurons to be used in IND- enabling studies.
In Specific Aim 2, definitive IND-enabling studies will be performed to test the safety (tumorigenicity and biodistribution) and efficacy of human iPSC-derived frozen-thawed mDA neurons in rodents, as well as testing of the planned clinical delivery device in non-human primates.
Specific Aim 3 will include IND package preparation and filing for an Investigator-initiated Phase I clinical trial, recruitment of patients with PD and generation of autologous cGMP iPSCs and mDA neurons as well as release criteria testing of the cryopreserved clinical product. Finally, Specific Aim 4 is a first-in-human clinical Phase I interventional, open-label clinical trial in 6 patients with sporadic PD, to test the safety and efficacy of autologous transplantation of frozen-thawed mDA neurons. This highly innovative autologous CMC iPS cell technology U01 proposal for cell replacement clinical trials in PD patients provides a necessary step and exploration for the development of successful cell therapy for PD and several neurological disorders.

Public Health Relevance

Parkinson?s disease lacks a therapy that could restore dopaminergic neurons permanently lost to the disease process. With a completed development of all steps required for initiating IND-enabling studies, this U01 project in the CREATE Bio Development Track program will accomplish the first cell therapy clinical trials with cGMP frozen autologous midbrain dopaminergic neurons to restore function in patients with Parkinson?s disease. The results from this U01 project will provide necessary information about the safety and feasibility of autologous cell therapy for Parkinson?s disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Boshoff, Chris
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Mclean Hospital
United States
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