The nucleoside analog kamuvudine-9 shows protective and therapeutic efficacy in a mouse model of multiple sclerosis.

Authors

Praveen Yerramothu, Kameshwari Ambati, Joseph Magagnoli, Meenakshi Ambati, Thendral Velmurugan, Dijing Yu, Jing Zhang, Jingjing Zhang, Tammy Cummings, Joseph Nguyen, Claire C Thomas, Vidya L Ambati, Kaitlyn Cheng, Maksud Juraev, Roshni Dholkawala, Felipe Pereira, Peirong Huang, Ayami Nagasaka, Yosuke Nagasaka, Madhuri Rudraraju, Ashley Ban, Ivana Apicella, Xiaoyu Cai, Ranjith Konduri, Rhea Zahir, Elizabeth Frost, John Lukens, Ruwen Yin, Frederick Brøndsted, Cliff I Stains, Makoto Ono, Brian P Delisle, Jamie Horn, Markos Leggas, Jeffrey L Dupree, S Scott Sutton, Bradley D Gelfand, Shao-Bin Wang, Jayakrishna Ambati

Published in

Science translational medicine. Volume 18. Issue 868. Pages eaei2870. Sep 23, 2026. Epub Sep 23, 2026.

Abstract

Innate immune signaling through inflammasome activation has been implicated in the pathogenesis of multiple sclerosis (MS). We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat HIV and hepatitis B virus infections, and kamuvudines, safer NRTI derivatives, both inhibit inflammasome activation. Here, we report that in the experimental autoimmune encephalitis mouse model of MS, treatment with kamuvudine-9 (K-9), an NRTI derivative with an enhanced safety profile, prevented further neurological deficits and reversed preexisting paralysis and vision loss. K-9 promoted myelin and axonal preservation in the mouse spinal cord and abolished the increase in serum neurofilament light (NfL) chain. K-9 disrupted interactions between nucleotide-binding domain leucine-rich repeat (NLR) pyrin domain-containing protein 3 (NLRP3) and NIMA-related kinase 7 (NEK7) and between NLRP3 and NLR CARD domain containing 4 (NLRC4), inhibiting dual inflammasome activation. K-9 also exhibited appropriate safety and pharmacokinetic characteristics and biodistribution. In three distinct human cohorts, there was a lower incidence of MS in those individuals receiving NRTIs for HIV infection, preexposure prophylaxis for HIV, or hepatitis B virus infection. NRTI use was also associated with a reduction in relapse rate in individuals with MS. These findings provide a rationale for further investigating K-9 for treating MS.

PMID:
42777081
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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