Nucleoside analog kamuvudine-9 показывает защитную и терапевтическую эффективность в мышиной модели множественного склероза.
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Yerramothu Praveen, Ambati Kameshwari, Magagnoli Joseph, Ambati Meenakshi, Velmurugan Thendral, Yu Dijing, Zhang Jing, Zhang Jingjing, Cummings Tammy, Nguyen Joseph, Thomas Claire C, Ambati Vidya L, Cheng Kaitlyn, Juraev Maksud, Dholkawala Roshni, Pereira Felipe, Huang Peirong, Nagasaka Ayami, Nagasaka Yosuke, Rudraraju Madhuri, Ban Ashley, Apicella Ivana, Cai Xiaoyu, Konduri Ranjith, Zahir Rhea, Frost Elizabeth, Lukens John, Yin Ruwen, Brøndsted Frederick, Stains Cliff I, Ono Makoto, Delisle Brian P, Horn Jamie, Leggas Markos, Dupree Jeffrey L, Sutton S Scott, Gelfand Bradley D, Wang Shao-Bin, Ambati Jayakrishna
Аннотация
Оригинал публикации
The nucleoside analog kamuvudine-9 shows protective and therapeutic efficacy in a mouse model of multiple sclerosis.
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.