Selective inhibition of mitochondrial Kv1.3 prevents and alleviates multiple sclerosis in vivo

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Abstract Multiple sclerosis (MS) is characterized by invasion of the brain by effector memory T (T EM ) lymphocytes that have been activated by repeated auto-antigen stimulation. Existing therapies target these and other autoreactive lymphocytes but their side effects include general immunosuppression and toxicity. Because the Kv1.3 potassium channel is highly expressed by chronically activated autoreactive T EM s, we investigated whether specific targeting of mitochondrial Kv1.3 using the pharmacological inhibitor PAPTP could selectively kill these T EM s in patients and mice with MS. 1 µM PAPTP targeted and reduced the number of autoreactive T EM s in blood samples from relapsing-remitting MS (RRMS) patients, leaving other T cell populations unaffected. Remarkably, pre-treatment of the entire T cell population with PAPTP during adoptive transfer of experimental autoimmune encephalomyelitis (EAE) killed T EM s and completely prevented disease onset in this mouse model. Moreover, PAPTP selectively eliminated activated T EM s and halted EAE progression when administered following disease onset. Our findings reveal the potential of PAPTP as an effective treatment for MS without adverse side effects.

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