Validation of the disease-protective effects of pristimerin in EAE models with complementary characteristics

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by demyelination of the axons, leading to weakness and paralysis of the limbs and other symptoms. Many potent drugs are currently in use for MS, but drawbacks such as limited efficacy, reduced responsiveness, severe adverse effects and high expense create an urgent need for new MS therapeutic agents. Over decades, natural plant products have served as an invaluable source for new drugs. However, this potential resource has not been fully exploited for MS treatment. In a recent study using the myelin oligodendrocyte glycoprotein-induced murine experimental autoimmune encephalomyelitis (MOG-EAE) model of human MS, we observed that pristimerin, a natural plant-derived triterpenoid, is highly effective in suppressing the development (early therapy) and progression (late therapy) of the disease. Pristimerin targeted key mediators of disease pathology (e.g., pro-inflammatory cytokines and a neurotrophic factor) in the spinal cord of MOG- EAE mice. Based on these significant results, Veterans Affairs (VA) has filed a patent application on the use of pristimerin as a novel therapeutic for MS. We now propose validating our preliminary findings in a second mouse model of EAE via this BLR&D pilot funding mechanism, in response to Validation RFA BX24-044. Objectives: To further strengthen and de-risk the translation of these novel pre-clinical findings to MS therapy, [we plan to test pristimerin in a relapsing-remitting EAE model in SJL/mice, whose genetics, antigen specificity, and clinical features are complementary to that of chronic progressive MOG-EAE model in C57BL/6 mice. The relapsing-remitting disease represents the most common (85%) type of human MS.] Hypothesis: Based on our initial study in the MOG-EAE model, we anticipate that [pristimerin will inhibit disease progression and controls relapses in the relapsing-remitting EAE model.] We further suggest that pristimerin inhibits EAE by reducing T helper 17 (Th17) activity/ differentiation (and altering the Th17/regulatory T cell balance) and [by reducing the activity of disease-associated microglia (DAM) (and restoring the balance in favor of homeostatic microglia (hMG)).] Finally, by suppressing the pro-inflammatory effects of cytokines and chemokines on these cells, pristimerin may have profound effects on disease management/ progression. We will use state-of-the-art methodology to address these propositions, including sc-RNA-Seq and proteomics. Specific Aims: Aim 1. Validate the disease-protective effect of pristimerin [administered either intraperitoneally or orally in relapsing-remitting EAE model] and determine its pharmacokinetics (PK) and multiorgan toxicity in both EAE models. Aim 2. Define the mechanisms by which pristimerin induces changes in the activity of Th17 and microglia in both EAE models. [In collaboration with experts in MS (H. Rus), neuro- inflammation (B. Stoica), and PK (R. Lapidus), we are well positioned to rigorously validate pristimerin in EAE mice, to further advance it for investigational new drug (IND)-enabling studies for eventual use in human MS.] Project Number: 1I21BX006831-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: KAMAL MOUDGIL | Institution: BALTIMORE VA MEDICAL CENTER, BALTIMORE, MD | Activity Code: I21 | Study Section: Special Emphasis Panel[ZRD1 NURB-H (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11189232