Therapeutic Potential of the Potassium Channel Inhibitor SHK-186 for Pediatric Lupus

DESCRIPTION provided by applicant Systemic lupus erythematosus SLE is a chronic multisystem autoimmune disease with poorly understood etiology and pathogenesis and for which adequate treatment options are limited Although dysregulated production of autoantibodies and immune complex deposition are considered hallmarks of SLE considerable evidence supports the hypothesis that auto reactive lymphocytes are implicated in disease SLE patients have several T cell defects including aberrant signaling suboptimal IL production lower regulatory T cell frequencies high CD CD Th T cells and sustained abnormally high intracellular calcium Effector memory T cells TEMs decrease in circulation and increase in the kidneys and urine of lupus nephritis patients suggesting that renal infiltration of this T ell subtype contributes to disease Activation and inflammatory cytokine production by effector memory T cells requires expression of Kv a potassium channel needed for sustained intracellular calcium levels in effector memory T cells that have been found to be autoreactive and pathogenic in several autoimmune diseases Here we propose to evaluate the levels of expression of Kv in SLE T cells in peripheral blood of inactive and active SLE patients compared to normal healthy controls and test the functional effect of blocking the Kv channels in these cells with Kinetaandapos s drug candidate Kv specific peptide blocker ShK dalazatide in terms of calcium flux and cytokine production ex vivo In addition we will evaluate Kv expression in kidney biopsies from patients with lupus nephritis and correlate expression to disease activity This study will inform our hypothesis that Kv expressing T cells are pathogenic in SLE and may support considering evaluation of ShK in SLE patient populations in clinical trials PUBLIC HEALTH RELEVANCE Lupus is an autoimmune disease that predominantly affects females early in life There is no cure and the uncontrolled inflammation of lupus can cause life threatening organ failure requiring chronic and intensive therapy Current therapies suppressing the immune system leave the patient open to severe side effects including infection and malignancy The proposed study will identify whether a protein channel required for the activation of immune cells that mount responses against self autoimmunity is expressed in cells in the kidney of lupus nephritis patients and will also test a novel therapeutic agent targeting this protein to evaluate if it can block the autoreactive inflammatory nature of these cells The results could have implications for the prevention and treatment of lupus as well as other autoimmune diseases