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

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

  • EMBO Mol Med. 2025 Sep 29. doi: 10.1038/s44321-025-00307-2.
Beatrice Angi # 1,  Tatiana Varanita # 1,  Marco Puthenparampil 2,  Valentina Scattolini 1,  Michael Donadon 1,  Mitra Tavakoli 1,  Marta Favero 1,  Maguie El Boustani 1,  Matthias Soddemann 3,  Lucia Biasutto 4,  Diletta Arcidiacono 5,  Alberto Ongaro 6,  Andrea Mattarei 6,  Livio Trentin 7,  Gregory Wilson 8,  Erich Gulbins 9 10,  Paolo Gallo 2,  Ildiko Szabo 11
Affiliations

Affiliations

  • 1 Department of Biology, University of Padova, Padova, Italy.
  • 2 Department of Neurology, University Hospital of Padova, Padova, Italy.
  • 3 Department of Molecular Biology, University Hospital Essen, Essen, Germany.
  • 4 CNR Institute of Neurosciences, Padova, Italy.
  • 5 Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
  • 6 Department of Pharmacological Sciences, University of Padova, Padova, Italy.
  • 7 Hematology Unit, University Hospital of Padova, Padova, Italy.
  • 8 Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 9 Department of Molecular Biology, University Hospital Essen, Essen, Germany. erich.gulbins@uni-due.de.
  • 10 Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA. erich.gulbins@uni-due.de.
  • 11 Department of Biology, University of Padova, Padova, Italy. ildiko.szabo@unipd.it.
  • # Contributed equally.
PMID: 41023199 DOI: 10.1038/s44321-025-00307-2
Abstract

Multiple sclerosis (MS) is characterized by invasion of the brain by effector memory T (TEM) 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 TEMs, we investigated whether specific targeting of mitochondrial Kv1.3 using the pharmacological inhibitor PAPTP could selectively kill these TEMs in patients and mice with MS. 1 µM PAPTP targeted and reduced the number of autoreactive TEMs 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 TEMs and completely prevented disease onset in this mouse model. Moreover, PAPTP selectively eliminated activated TEMs 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.

Keywords

Effector Memory T Cell; Experimental Autoimmune Encephalomyelitis; Mitochondrial Kv1.3 Channel Inhibition; Multiple Sclerosis.

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