Early Translational III
Multiple Sclerosis (MS) is a disease of the central nervous system (CNS) caused by inflammation and loss of cells that produce myelin, which normally insulates and protects nerve cells. MS is a leading cause of neurological disability among young adults in North America. Current treatments for MS include drugs such as interferons and corticosteroids that modulate the ability of immune system cells to invade the CNS. These therapies often have unsatisfactory outcomes, with continued progression of neurologic disability over time. This is most likely due to irreversible tissue injury resulting from permanent loss of myelin and nerve destruction. The limited ability of the body to repair damaged nerve tissue highlights a critically important and unmet need for MS patients. The long-term goal of our research is to develop a stem cell-based therapy that will not only halt ongoing loss of myelin but also lead to remyelination and repair of damaged nerve tissue. Our preliminary data in animal models of human MS are very promising and suggest that this goal is possible. Research efforts will concentrate on refining techniques for production and rigorous quality control of clinically-compatible transplantable cells generated from high-quality human pluripotent stem cell lines, and to verify the therapeutic activity of these cells. We will emphasize safety and development of the most therapeutically beneficial cell type for eventual use in patients with MS.
Statement of Benefit to California:
One in seven Americans lives in California, and these people make up the single largest health care market in the United States. The diseases and injuries that affect Californians affect the rest of the US and the world. Many of these diseases involve degeneration of healthy cells and tissues, including neuronal tissue in diseases such as Multiple Sclerosis (MS). The best estimates indicate that there are 400,000 people diagnosed with MS in the USA and 2.2 million worldwide. In California, there are approximately 160,000 people with MS – roughly half of MS patients in the US live in California. MS is a life-long, chronic disease diagnosed primarily in young adults who have a virtually normal life expectancy but suffer from progressive loss of motor and cognitive function. Consequently, the economic, social and medical costs associated with the disease are significant. Estimates place the annual cost of MS in the United States in the billions of dollars. The development of a stem cell therapy for treatment of MS patients will not only alleviate ongoing suffering but also allow people afflicted with this disease to return to work and contribute to the economic stabilization of California. Moreover, a stem cell-based therapy that will provide sustained recovery will reduce recurrence and the ever-growing cost burden to the California medical community.
This application for a Development Candidate Award is focused on a human pluripotent stem cell (hPSC) derived neural progenitor cell (NPC) therapy for multiple sclerosis (MS). MS is an autoimmune disease of the central nervous system characterized by demyelination and axonal loss resulting in motor and cognitive disability. The applicant proposes to transplant NPCs that could potentially slow, arrest or reverse demyelination. There are five Milestones proposed: 1) to derive and bank Good Manufacturing Practices (GMP) compatible hPSC lines; 2) to develop methods for NPC production; 3) to confirm therapeutic activity of NPCs in animal models of MS and optimize route/dosing; 4) to compare the therapeutic activity of NPCs derived from different hPSC lines; and 5) to demonstrate therapeutic activity in animals models of MS with NPCs produced at clinically appropriate scale. Objective and Milestones - This proposal is likely to result in a development candidate ready for IND-enabling studies. Even if it does not, the data generated will provide important, clinically meaningful information that will inform the translational path. - The milestones are logical, clearly presented and have clear outcome measures. - The Target Product Profile is mainly focused on specific functional improvement in a mouse model of MS and lacks detail on cell biologic attributes. Reviewers raised concerns about the target level proposed for contaminants in the final product and suggested that the FDA may require lower levels of detection. - Reviewers suggested that patient selection criteria be articulated to eliminate patients with other treatment options available. Rationale and Significance - Although progress is being made in the treatment of MS, there are no therapies available that can reverse demyelination. The proposed development candidate has the potential to do so and thus could have a significant impact on the disease. - The preliminary data strongly support the scientific rationale. Research Project Feasibility and Design - The preliminary data in two animal models are impressive. The use of these two complementary MS models is a strength of the proposal. - The research plan is well thought out and comprehensive. The projected timeline appears feasible. - Studies designed to evaluate in vivo stability and potential tumorigenicity of hPSC-derived NPCs were not adequately described. More effort should be devoted to these issues as the longevity of a therapeutic effect will likely depend on survival of transplanted cells, and hPSC safety is relatively uncharted territory. - Reviewers suggested that the team consider including immunosuppressant drugs in the research plan, as many MS patients may be taking them. They also noted that the MS patient population is enriched with women of childbearing age, and therefore the FDA may require preclinical assessment of reproductive safety. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI, Co-PI and Partner PI all have outstanding and complementary expertise. All three have strong track records. - There is a clear plan for communication between research groups. - The inclusion of a flow cytometer in the budget is not adequately justified. There is no supporting documentation describing currently available equipment and the research plan does not require a full-time flow cytometer. Collaborations, Assets, Resources and Environment - No relevant concerns were highlighted by the reviewers under this review criterion. Responsiveness to the RFA - This proposal is responsive to the RFA. It uses human stem cells to target MS.