Estrogen Receptor Beta agonist stimulates oligodendrocyte progenitor cell survival/differentiation, endogenous remyelination, and improves neuronal function in animal models of Multiple Sclerosis.
Early Translational IV
$2 851 954
Multiple sclerosis (MS) is an autoimmune degenerative disease characterized by motor, sensory, and/or cognitive deficits. These deficits result from demyelination, a process in which the conductive myelin sheath that surrounds axons is compromised, leading to impaired communication between neurons. Normally, oligodendrocyte progenitor cells (OPCs) can differentiate and contribute to myelin formation. However, OPCs present in and around MS lesions appear to exist quiescently and remyelination is limited. While most available MS drugs address the immune component of the disease, effective neuroprotective and restorative agents are lacking. Our proposed research aims to provide proof of principle for a preclinical development candidate that has the potential to drive differentiation of endogenous OPCs to ultimately protect and restore neurons, and improve axon function. This strategy addresses a key unmet medical need in MS by reversing disability and/or preventing disease progression, as is supported by our reproducible preliminary data. Because these data suggest that treatment with this drug stimulates endogenous cells, short-duration dosing regimens will be thoroughly explored. Such a treatment is expected to prevent/improve disability progression by upholding endogenous cells, and the proposed non-continual dosing regimen promises to limit the already intense life style disruption experienced by MS patients
Statement of Benefit to California:
Multiple sclerosis (MS) is a chronic, central nervous system-attacking disease that primarily affects young adults. While MS patients have a virtually normal life expectancy, they suffer from progressive loss of motor and cognitive function, ranging from limb numbness to blindness and paralysis. These symptoms have devastating effects on quality of life, careers, and self-esteem of MS patients and their families. Consequently, economic, social, and medical costs associated with MS are significant. Approximately 800,000 and 450,000 people worldwide and in the US, respectively, are diagnosed with MS. The 160,000 people living with MS in California comprise roughly half the MS patients in the US. Currently, no available MS treatments prevent or reverse underlying progressive degeneration, leaving considerable unmet need for novel, disease-modifying drugs. Our aim is to establish a MS treatment capable of encouraging effective remyelination via stimulation of endogenous oligodendrocyte progenitor cells (OPCs) present in and around MS lesions. Such a drug could be paired with existing immunomodulatory treatments to prevent neurodegeneration and disability progression in MS patients. The development of a treatment that takes advantage of endogenous cells to improve disease will significantly benefit California in many aspects, including cutting the non-negligible MS-associated costs and, most importantly, improving the quality of life of MS patients.
This Development Candidate application is focused on a therapeutic agent that will promote remyelination in patients with multiple sclerosis (MS). MS is an autoimmune degenerative disease in which motor, sensory and cognitive deficits may occur subsequent to demyelination of the brain and spinal cord. The applicant proposes to develop a candidate drug that will stimulate endogenous oligodendrocyte precursor cells (OPCs) to improve the function of neurons in the area of an MS lesion, with the goals of limiting disability and slowing disease progression. Milestones include: determining the optimal dosing regimen to show functional and anatomical efficacy in animal models of disease; confirming the cellular pathways through which the drug acts; and looking for biomarkers of disease modification by the drug. Objective and Milestones - Reviewers stated that development of a therapeutic candidate that can promote remyelination in MS patients would be of great clinical importance. - Proposed milestones were viewed as well designed and appropriate for the development of a therapeutic candidate. Rationale and Significance - Reviewers expressed concern that preliminary data did not allow distinction between generalized anti-inflammatory effects of the candidate drug and a direct effect of the candidate on the target endogenous progenitor cells. - A number of anti-inflammatory agents have shown similar effects in the proposed MS disease model and the application does not provide evidence that the present approach would be superior to other therapeutics that are active in this model. - The rationale for developing a compound to stimulate endogenous OPCs to promote remyelination in MS and other demyelinating diseases is sound, and this proposal would be a novel approach in the field. Feasibility and Design - The reviewers expressed concern that the candidate molecule has poor solubility and could be clinically difficult to use without reformulation, which could require some of the proposed studies to be repeated with the new compound. - Reviewers questioned whether the proposed animal models of acute demyelination would adequately predict effects of the therapeutic candidate for the target clinical population of patients with chronic progressive MS. - The research plan was viewed as logical and feasible within the three year award term. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - Reviewers felt this was a very strong research team. The PI is viewed as a recognized expert in the study of MS using in vivo and in vitro models. Collaborations, Assets, Resources and Environment - Reviewers considered the proposed collaborations to be strong. The institutional support is excellent. - The budget was thought to be appropriate for the proposed studies. - It was not clear how intellectual property would be shared between collaborating parties if the therapeutic candidate moves forward to clinical development. Responsiveness to the RFA - Without more conclusive evidence that the candidate compound acts directly on endogenous progenitor cells, reviewers found it difficult to evaluate the degree to which this proposal is responsive to the RFA.