Patient-tailored approach to reprogram human subventricular zone neural stem cells for the development of cell-based therapies to treat motor deficits after stroke
New Faculty Physician Scientist
$2 955 324
Stroke is a common disease in the United States which leaves many patients with permanent disability. So far there is no treatment available to recover function after stroke except for physical and occupational therapy. After a recovery period of up to two years, patients do not have any hope of making any further progress. The proposed research will aim to solve this problem by using stem cells from patients to recover function after stroke. Tissue containing stem cells will be obtained from patients during a routine neurosurgical operation. These stem cells will be reprogrammed in the lab so they can be expanded in vast numbers and then directed to make a subset of neurons which have been lost after stroke. Derived cells first will be tested in mice to make sure that they do not form cancer or contribute to other adverse events after transplantation. If the safety of the transplantation has been confirmed, derived cells will be tested in animal models for their capacity to recover motor function after injury. The proposed experiments will give us data to apply for IND approval from the Food and Drug Administration to test these cells in stroke patients. Successful integration of the derived cells after transplantation and recovery of motor function would have a major impact on the lives of patients and the research community. So far the deficits after stroke cannot be restored, but we hope to change this with our research and to make a difference in the lives of our patients.
Statement of Benefit to California:
The proposed research will benefit the State of California on two levels: First, if the grant is awarded, it will create jobs since I am planning on hiring at least one postdoctoral associate and one technical associate. This is thought to be the start of a larger research group which I am planning on building at UC Davis over the next several years. Since California has excellent medical schools and neurobiology programs, I will pay special attention to applications from graduates within the state. Second, the proposed research is going to benefit the citizens of the State of California if I can show that transplantation of reprogammed neural stem cells can enhance functional recovery after stroke. More than 50% of people with severe stroke are in a nursing home 90 days and 1 year after a stroke, and 70% of patients will have spent some time in a nursing home by 1 year. The proposed reseach is aimed at helping patients who are permanently required to stay in a nursing home to regain motor function after stroke so that they may progress to live more independently and possibly be discharged to a lower level of care. Nursing home stays create a large economic burden in California. Therefore, reducing the number of stays would have a significant impact on the health care system in the state. It would also help citizens taking care of family members to regain hope that the condition of their loved ones is not permanent but in fact amenable to treatment.
Executive Summary This application is focused on the development of an autologous stem cell therapy for stroke. The applicant proposes to obtain neural progenitor cells from patients during a neurosurgical procedure and reprogram them in the lab to allow expansion and differentiation into a type of neuron that is commonly lost after stroke. There are three Specific Aims: 1) to develop protocols for harvest and expansion of human neural progenitor cells; 2) to reprogram these cells, differentiate them into the appropriate neuron subtype and test the safety of transplantation in a rodent model; and 3) to test the effectiveness of this cell transplant in animal models of stroke and brain injury. Research Plan - The preliminary data were insufficient to support the feasibility of the project. Data were not provided demonstrating the applicant’s ability to harvest, culture or reprogram human neural progenitor cells. - Behavioral assessments in the rodent model were not well described. Reviewers viewed this as a significant weakness, since there are many potential pitfalls in this area. - There is a compelling rationale for autologous cell therapy for stroke; infections are a leading cause of death following stroke, and autologous therapy could eliminate the need for immunosuppressive drugs that would put patients at greater risk of infection. - The proposed patient population was not well described, and the incidence of stroke requiring the neurosurgical procedure was not provided. - There was little discussion of potential pitfalls or alternative approaches. - The inclusion of a suicide gene in the reprogramming vector was considered conceptually sound, but reviewers were concerned that this vector may be silenced in pluripotent cells. Principal Investigator (PI) - The PI has trained in excellent clinical neurosurgery programs and performed post-doctoral research in a neural stem cell lab. - Reviewers were concerned that the PI percent effort proposed, while meeting the RFA minimum requirement, would not be sufficient to meet the goals of the proposal. They noted that between planned coursework, training programs and surgical harvest of cells, there seemed to be little time left for the research aims. - The PI has a number of first-author publications, some relevant to this proposal, but reviewers did not feel that these put him/her in the top tier of applicants. - The PI’s mentors are appropriate. They are established investigators with strong track records. The mentoring plan was judged to be sufficiently detailed and should contribute to the PI’s career development. Institutional Commitment - The institution has an excellent track record of promoting the career development of physician-scientist faculty and provided a strong letter of support for the PI. Responsiveness - The application is responsive to the RFA in its use of human stem cells and its translational focus.