Multiple sclerosis (MS) is an autoimmune disease in which the myelin sheath that insulates neurons is destroyed, resulting in loss of proper neuronal function. Existing treatments for MS are based on strategies that suppress the immune response. While these drugs do provide benefit by reducing relapses and delaying progression (but have significant side effects), the disease invariably progresses. We are pursuing an alternative therapy aimed at regeneration of the myelin sheath through drugs that act on an endogenous stem cell population in the central nervous system termed oligodendrocyte precursor cells (OPCs). Remission in MS is largely dependent upon OPCs migrating to sites of injury and subsequently differentiating into oligodendrocytes – the cells that synthesize myelin and are capable of neuronal repair. Previous studies indicate that in progressive MS, OPCs are abundantly present at sites of damage but fail to differentiate to oligodendrocytes. As such, drug-like molecules capable of inducing OPC differentiation should have significant potential, used alone or in combination with existing immunomodulatory agents, for the treatment of MS. The objective of this project is to identify a development candidate (DC) for the treatment of multiple sclerosis (MS) that functions by directly stimulating the differentiation of the adult stem cells required for remyelination.
Multiple Sclerosis (MS) is a painful, neurodegenerative disease that leads to an impairment of physical and cognitive abilities. Patients with MS are often forced to stop working because their condition becomes so limiting. MS can interfere with a patient's ability to even perform simple routine daily activities, resulting in a decreased quality of life. Existing treatments for MS delay disease progression and minimize symptoms, however, the disease invariably progresses to a state of chronic demyelination. The goal of this project is to identify novel promyelinating drugs, based on differentiation of an endogenous stem cell population. Such drugs would be used in combination with existing immunosuppressive drugs to prevent disease progression and restore proper neuronal activity. More effective MS treatment strategies represent a major unmet medical need that could impact the roughly 50,000 Californians suffering from this disease. Clearly the development of a promyelinating therapeutic would have a significant impact on the well-being of Californians and reduce the negative economic impact on the state resulting from this degenerative disease.
This application for a Development Candidate Award is focused on identifying small molecule drugs to treat 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 identify small molecule drugs that remyelinate axons by stimulating the differentiation of oligodendrocyte precursor cells (OPCs) to oligodendrocytes, the myelin-producing cells. There are six Milestones proposed: 1) to identify novel compounds that selectively and potently induce OPC differentiation; 2) to determine the efficacy and biological mechanism of previously identified remyelinating compounds; 3) to demonstrate dose dependent disease modifying activity of these previously identified compounds in animal models of MS; 4) to identify the biological target of a novel compound; 5) to conduct lead optimization of this novel compound and demonstrate dose dependent activity in animal models of MS with this optimized lead; and 6) to develop a clinical plan for the best development candidate identified.
Objective and Milestones
- The objective of identifying novel OPC differentiating compounds is not well justified. The applicant has already identified known compound(s) with OPC differentiating activity and good pharmaceutical properties, including at least one known drug. Any novel compounds would be years behind this compound and it is not clear what criteria would be used to establish that they are superior.
- The applicant provides a detailed scheme that supports a drug development strategy from high throughput screening to lead generation, lead optimization and finally development of a candidate. The milestones are well thought through and are well defined.
Rationale and Significance
- The rationale for developing drugs that stimulate OPC differentiation is not well justified. This approach is likely to move OPCs out of the progenitor pool into differentiation to oligodendrocytes, without affecting the cause of the disease and where it is not clear how autoimmune attack against newly created myelin would be avoided or mitigated. Reviewers also cautioned that treating MS with a drug that depletes the OPC pool is a potentially dangerous strategy, as it could deplete the progenitors necessary for differentiation to oligodendrocytes that effect lesion repair. They suggested that drugs that enhance OPC proliferation might be better targets.
- Improving treatment for this debilitating disease is an important goal. While progress is being made, no therapies are available that can reverse the disabilities associated with MS.
Research Project Feasibility and Design
- The preliminary data presented for an FDA approved compound are promising and worth pursuing.
- Drug screening and testing is proposed in tissue culture conditions that do not resemble the in vivo setting of MS, where scarring and inflammation may limit OPC differentiation.
- The proposed animal models poorly recapitulate MS. However, this issue is a known bottleneck in the field and is not limited to this application.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The team is very strong, particularly in small molecule drug discovery and medicinal chemistry. The PI is excellent and experienced in translational research.
- The team lacks a clinical MS expert. While the Co-PI is an experienced autoimmunity researcher, reviewers highlighted that specific expertise in MS would be required for successful execution of this project.
- The budget is very high for such a speculative project.
Collaborations, Assets, Resources and Environment
- The environment at the applicant institution is excellent.
Responsiveness to the RFA
- The proposal is responsive to the RFA. It targets endogenous stem cells to treat MS.
- A motion was made to move this application into Tier 1, Recommended for Funding. The programmatic reason provided was that CIRM investment in MS research is low. There was a brief recap of the concerns expressed in the scientific review. The motion failed.
- A second motion was made to convert this application to a DCF and move it into Tier 1, Recommended for Funding. The goal of the DCF award would be to team up with MS investigators to do the full range of preclinical studies proposed for the FDA approved compound, but without the activities focused on the novel compounds. Some reviewers believed that pursuing this more focused program was warranted given the lack of therapeutic options for MS. Other reviewers were reluctant to rewrite the proposal. They noted that the PI is an expert in drug discovery and medicinal chemistry and that asking him/her to focus on developing an approved compound might not be the best use of his/her talents. CIRM staff questioned whether a DCF award is the proper mechanism given that feasibility for the FDA approved compound has largely been established. CIRM staff noted that converting to a DCF would eliminate the Co-PI position and reduce the budget to $1.2 million in direct costs. The motion carried.