Multiple Sclerosis (MS) is the leading cause of neurologic disability in the United States in young adults after trauma, thus most patients suffer from the effects of MS for most of their adult life. The current MS treatments are partially effective, making it necessary to develop innovative strategies. Interleukin-6 (IL-6), signaling through transcription factor STAT3, shares a central role in multiple pathways of MS pathogenesis and dysregulated IL-6/STAT3 signaling has been shown in MS patients. First, IL-6, signaling through STAT3, induces the generation of highly encephalitogenic IL-17, producing Th17 cells that transfers severe disease in the EAE model of MS. Meanwhile, IL-6 suppresses the generation of inducible T regulatory cells (iTreg), which is critical for dampening pathogenic inflammatory T cell responses. As a result, the Teff/Treg balance is skewed towards excessive T effector responses, favoring the development of autoimmunity. Furthermore, IL-6/STAT3 signaling contributes to the resistance of Teff cells to Treg-mediated suppression in MS patients, which further impairs Teff/Treg balance. Altogether, these studies suggest that the IL-6/STAT3 signaling pathway may serve as an innovative target for reversing pathogenesis in MS patients. In addition, orally available small molecule compounds usually offer improved bioavailability and manufacturing features over commonly used peptide/protein-based drugs. Moreover, therapy adherence is improved when oral agents are used. To this end, we intend to develop small molecule drug candidates targeting IL- 6/STAT3 pathway. We have developed four novel small molecule compounds, MDL-5 and MDL-16 targeting IL-6; LLL-12 and LY-5 targeting STAT3. MDL-5/16 bind to the D1 domain of GP130, preventing the IL-6/GP130 interaction during the hexamerization step of IL-6/IL- 6R/GP130 signaling complex formation; LLL-12/LY-5 bind to the SH2 domain of STAT3, preventing STAT3 phosphorylation and dimerization. When added into cell culture, all four lead compounds significantly inhibit IL-6 induced IL-17 production in myelin-specific CD4 T cells. Based on these previous studies and our preliminary data, we hypothesize that novel small molecule IL-6/STAT3 inhibitors repair the Teff/Treg imbalance of CD4 T responses and suppress disease development and progression in the EAE model of MS. The following aims will address this hypothesis.
Aim 1. Optimize the compounds as drug candidates.
Aim 2. Determine the effects of novel small molecule IL-6/STAT3 inhibitors on repairing the Teff/Treg imbalance of myelin-specific CD4 T responses and on suppressing disease development in the EAE model of MS.
Aim 3. Determine the effects of novel small molecular IL-6/STAT3 inhibitors on repairing Teff/Treg balance in CD4 T cells from MS patients. This study is the first attempt to modulate IL-6/STAT3 signaling using novel small molecules and will elucidate the mechanisms through which IL-6 signaling regulates murine and human CD4 T responses and disease development in vivo in the EAE model of MS. This study will establish the basis for future clinical studies using novel pharmacological compounds that target IL-6/STAT3 signaling, with the ultimate goal of treatment of multiple sclerosis.
Multiple Sclerosis (MS) is the leading cause of neurologic disability in the United States in young adults after trauma, thus most patients suffer from the effects of MS for most of their adult life. The inflammatory cytokine, IL-6, signaling through protein transcription factor STAT3, is dysregulated and plays a critical role in the pathogenesis of MS. Lots of research and clinic findings strongly suggest that IL-6/STAT3 blockade may serve as an innovative strategy for reversing pathogenesis in MS and other autoimmune diseases. In fact, an anti-IL-6 receptor antibody has been tested and approved for the treatment of several autoimmune diseases, but its therapeutic effects in MS have not been established. The objective of this proposal is to develop novel small molecules targeting IL-6/STAT3 for MS therapy by using a mouse model of MS and to confirm their effects with T cells from MS patients. Small molecule compounds offer manufacturing and delivery advantages over protein-based drugs, such as monoclonal antibodies. Most patients prefer an orally available small molecule (e.g., a tablet or capsule) over an injectable protein or antibody therapeutic, which is common in MS therapies, especially for long-term usage in autoimmune diseases. This study is the first attempt to target IL-6/STAT3 signaling pathway using novel small molecules in MS and will establish the basis for future drug development and clinical studies using novel pharmacological compounds that target IL- 6/STAT3 signaling, with the ultimate goal of treatment of MS.
|Nuro-Gyina, Patrick K; Rieser, Elizabeth L; Granitto, Marissa C et al. (2016) Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7R?. J Neuroinflammation 13:302|