Regulation of JAK/STAT pathways in the eye

National Eye Institute

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Abstract

Experimental Autoimmune Encephalomyelitis (EAE) is the mouse model of multiple sclerosis (MS) commonly used to understand what causes MS and for evaluating potential drugs or biologics for MS. Proinflammatory Th1 and Th17 lymphocytes that are recruited into the brain or spinal cord EAE are implicated in MS. The disease in spinal cord is caused by IFN-γ-producing Th1 cells that require STAT1 protein while IL-17-producing Th17 cells that cause MS symptoms in the brain require STAT3. Although simultaneous inhibition of STAT1 and STAT3 pathways is an attractive therapeutic strategy for MS, pharmacological targeting of STAT1 or STAT3 presents significant challenges because of their intracellular localization. We have developed a pan-STAT-specific single-domain nanobody (SBT-100) from camelids that penetrates cells. The SBT-100 camelid nanobody targets conserved residues in Src homolog 2 (SH2) domains shared by all STAT proteins and is effective in suppressing each of the 6 STAT proteins in nature. We therefore used it to simultaneously inhibit STAT1 and STAT3 pathways. SBT-100 ameliorates encephalomyelitis by simultaneously suppressing Th17 and Th1 in the brain and spinal cord. The small size of SBT-100 nanobody makes this pan-STAT-specific nanobody capable of targeting undruggable intracellular proteins and transcription factors and is a promising immunotherapy for CNS autoimmune diseases, including MS, chronic uveitis and age-related macular degeneration (AMD)