VP Science and Innovation NIMML Inst., United States
Disclosure(s):
Andrew Leber, PhD: No financial relationships to disclose
Introduction/Rationale: Multiple sclerosis (MS) is a complex autoimmune disease involving myriad cell types with varied baseline immunological profiles across patients. Treatment of MS remains a challenge with substantial annual relapse rates and disability progression. Absent combination therapies, new mechanisms bridging innate and adaptive immunity to provide protection from neurodegeneration need further exploration.
Methods: Efficacy of a novel treatment was tested in passive experimental autoimmune encephalomyelitis (EAE) and a demyelinating cuprizone model. For EAE, a MOG35-55 emulsion was injected to donors. After 10 days, harvested splenocytes were incubated with IL-12, MOG35-55, and anti-IFNy for three days after which they were injected into recipients. For the cuprizone model, mice were fed powdered cuprizone diets for 5 weeks. Spinal cords and brains were collected for histology, gene expression and flow cytometry. Differentiation, cytokine production and cell survival were studied in cultures of CD4+ T cells, microglia and neurons.
Results: In cultures of primary CD4+ T cells, treatment provided a greater than 50% reduction in IFNy+ and IL17+ cells at 100 nM. Similarly, microglia treated ex vivo produce less IL-6, IL-1β and TNF. Meanwhile, a 4-fold increase in neuronal cell viability in oxidative stress conditions after treatment. In EAE, treatment reduced IFNy+ and IL17+ CD4+ cells by 2-fold, along with reduction of GFAP+ cells histologically and decreased expression of Il1b and Tnf in the spinal cord. In the cuprizone model, treatment provided a near complete protection against oligodendrocyte precursor cell (Olig2+ Pdgfr+) loss while preventing the generation of TNF+ microglia (CD11b+ Iba1+). Histologically, this resulted in a 70% reduction in demyelination.
Conclusion: NIMML has developed a novel oral, once-daily treatment for MS and other neuroinflammatory diseases that provides therapeutic efficacy by directly impacting CD4+ T cells, microglia and neurons implicated in these diseases.
