Functional blockade or elimination of antigen-specific immune responses without impacting general immune function must be considered a holy grail in the quest to treat autoimmune disease. One approach to achieving this lofty goal is to suppress and/or eliminate effector memory (TEM) cells that have been implicated in the pathogenesis of many autoimmune diseases without affecting other immune cells. This proposal focuses on the voltage-gated Kv1.3 potassium channel in TEM cells as a therapeutic target for autoimmune diseases. Disease-associated autoreactive T cells in patients with multiple sclerosis (MS), type-1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA) are TEM cells with elevated expression of Kv1.3 channels. We have developed highly specific inhibitors of Kv1.3 and these selectively suppress calcium signaling, cytokine production, proliferation, and in vivo migration of TEM cells without affecting other T cell subsets. In proof-of-concept studies, Kv1.3 blockers prevent and/or treat disease in rat models of MS, T1DM, RA, contact dermatitis, delayed type hypersensitivity (DTH) and bone resorption associated with periodontitis. These blockers have excellent safety profiles in animal models. They do not compromise the acute protective immune response to viral and bacterial pathogens. Specific Kv1.3 blockers, provide an exciting new therapeutic approach to mute autoreactive responses without compromising the protective immune response. The studies outlined in this proposal will lay the groundwork for clinical trials in patients with MS with ShK-186, our lead candidate.
Aim 1 will define the mechanisms underlying ShK-186's therapeutic effect in chronic relapsing-remitting experimental autoimmune encephalomyelitis (CR-EAE) in DA rats, a model for human MS. We will test the hypothesis that ShK-186 eliminates disease-causing CNS autoantigen-specific TEM cells by a mechanism we term """"""""death by neglect"""""""" while other immune cells, particularly disease-suppressing regulatory T cells, proliferate unabated because they are protected by the ShK-186-resistant KCa3.1 channel.
Aim 2 will characterize the therapeutic dose, frequency and duration of ShK-186 treatment in CR-EAE to better predict human studies.
In Aim 3 we will use patch-clamp recording and flow cytometry to determine whether Kv1.3high expression is a reliable biomarker for MS, and whether it will be useful for tracking Kv1.3 blocker therapy. A second goal of aim 3 is to study channel expression in T cells from Cynomolgus monkeys because this species is widely used for toxicological evaluation of human immune modulating therapies and is our non-human primate choice for IND- enabling toxicological studies. We will define the K-channel phenotype of cynomolgus monkey T cell subsets, and we will evaluate ShK-186's effectiveness in suppressing monkey TEM cell-proliferation.
Our goal is to develop a therapy that suppresses or eliminates disease-causing immune cells in autoimmune diseases without compromising the protective immune response. Our strategy is to selectively target voltage-gated Kv1.3 potassium channels in effector memory T cells that are important mediators of autoimmune diseases.
|Galea, Charles A; Nguyen, Hai M; George Chandy, K et al. (2014) Domain structure and function of matrix metalloprotease 23 (MMP23): role in potassium channel trafficking. Cell Mol Life Sci 71:1191-210|
|Nguyen, Hai M; Galea, Charles A; Schmunk, Galina et al. (2013) Intracellular trafficking of the KV1.3 potassium channel is regulated by the prodomain of a matrix metalloprotease. J Biol Chem 288:6451-64|
|Lioudyno, Maria I; Birch, Alexandra M; Tanaka, Brian S et al. (2013) Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci 33:16310-22|
|Upadhyay, Sanjeev Kumar; Eckel-Mahan, Kristin L; Mirbolooki, M Reza et al. (2013) Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. Proc Natl Acad Sci U S A 110:E2239-48|
|Nguyen, Hai M; Miyazaki, Haruko; Hoshi, Naoto et al. (2012) Modulation of voltage-gated K+ channels by the sodium channel ?1 subunit. Proc Natl Acad Sci U S A 109:18577-82|
|Chi, Victor; Pennington, Michael W; Norton, Raymond S et al. (2012) Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases. Toxicon 59:529-46|
|Tarcha, Eric J; Chi, Victor; Munoz-Elias, Ernesto J et al. (2012) Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease. J Pharmacol Exp Ther 342:642-53|
|Garcia, Adriana; Mirbolooki, Mohammad Reza; Constantinescu, Cristian et al. (2011) 18F-Fallypride PET of pancreatic islets: in vitro and in vivo rodent studies. J Nucl Med 52:1125-32|
|Rangaraju, Srikant; Khoo, Keith K; Feng, Zhi-Ping et al. (2010) Potassium channel modulation by a toxin domain in matrix metalloprotease 23. J Biol Chem 285:9124-36|
|Pennington, M W; Beeton, C; Galea, C A et al. (2009) Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Mol Pharmacol 75:762-73|
Showing the most recent 10 out of 18 publications