Treatment of Multiple Sclerosis with Small Molecule IL-6/STAT3 Inhibitors

Small-molecule prodrugs that target IL-6/STAT3 signaling pathway.

The Need

Multiple Sclerosis (MS), an unpredictable and disabling autoimmune disease affecting the central nervous system, is the leading cause of non-traumatic neurological disability in young adults. There have been important advances in MS therapy, such as drugs that slow the progression of the disease and reduce attacks. But current treatments are only partially effective, with sometimes serious side effects. New strategies are still needed. MS has an array of symptoms and unique characteristics that make traditional drug therapy difficult. A new therapy targeting an element common to multiple pathways of MS pathogenesis may provide significant improvement over current strategies that target a single pathway. One such element that is a suitable candidate target is IL-6/STAT3, since dysregulation of IL-6 signaling plays a significant role in the pathogenesis of MS and other autoimmune diseases.

The Technology

Researchers at The Ohio State University, led by Drs. Chenglong Li, Yuhong Yang and Michael Racke, developed a family of small-molecule prodrugs targeting the IL-6/STAT3 pathway, an important and common conduit of pathogenicity in MS. A lead inhibitor compound (LLL12b) and its analogs have been shown to suppress the expression of pSTAT3 and production of IL-17 and other inflammatory cytokines in myelin-specific CD4 T cells, in a dose-dependent manner. Multiple in vivo experiments in mice where the disease was induced in different ways or the treatment regime varied demonstrate marked therapeutic benefit in suppressing disease progression: (1) disease was induced by adoptive transfer of activated myelin-specific T cells (figure 1A-C); (2) disease was induced in C57BL6 mice immunized with the myelin peptide MOG 35-55 (figure 1 D-E); (3) disease was evaluated in SJL/J mice immunized with the myelin peptide PLP 139-151, which develop a relapsing-remitting disease course resembling relapsing-remitting MS (RRMS) (RRMS being the major MS subtype affecting more than 85% of MS patients), permitting treatment assessment at various stages of disease, including administration during the acute phase (figure 1F); or (4) remission phase (days 25–35 after immunization) (figure 1G-H). As well, in LLL12b-treated groups, Foxp3+ T regulatory cells were increased (figure 1B) while Th17 cells suppressed (figure 1C, E, H). Additionally, the small-molecule prodrug shifts the balance of T cells from MS patients toward biennial regulatory T cells. These data suggest that selective inhibition of STAT3 by LLL12b may recalibrate the effector and regulatory arms of T response, representing a potentially clinically translatable therapeutic strategy for MS.

Commercial Applications

  • Potential for treatment of autoimmune diseases mediated by the IL-6/STAT3 signaling pathway
  • Potential for treatment of diseases with altered Teff/Treg balance

Benefits/Advantages

  • Small molecule drug with advantages over antibody-based therapeutics
  • Therapy adherence is improved when oral agents are used over the injectable drugs

Patent Filing

PCT/US2018/053085 nationalized in CA, EU, and US.

Publications

A STAT3 inhibitor ameliorates CNS autoimmunity by restoring Teff:Treg balance https://insight.jci.org/articles/view/142376

Loading icon