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However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre\u2010symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination\u2010resistant variant of survival motor neuron (SMN), SMN<jats:sup>K186R<\/jats:sup>, has improved therapeutic effects for SMA compared with wild\u2010type SMN (SMN<jats:sup>WT<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A severe SMA mouse model, SMA type 1.5 (<jats:italic>Smn<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>; <jats:italic>SMN2<\/jats:italic><jats:sup>+\/+<\/jats:sup>; <jats:italic>SMN\u22067<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) mice, was used to compare the differences in therapeutic efficacy between AAV9\u2010SMN<jats:sup>WT<\/jats:sup> and AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>\u2010treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9\u2010SMN<jats:sup>WT<\/jats:sup>\u2010treated mice. Lifespan increased by more than 10\u2010fold in AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>\u2010treated mice (144.8\u00a0\u00b1\u00a026.11\u00a0days) as compared with AAV9\u2010SMN<jats:sup>WT<\/jats:sup>\u2010treated mice (26.8\u00a0\u00b1\u00a01.41\u00a0days). AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>\u2010treated mice showed an ascending weight pattern, unlike AAV9\u2010SMN<jats:sup>WT<\/jats:sup>\u2010treated mice, which only gained weight until P20 up to 5\u00a0g on average. Several motor function tests showed the improved therapeutic efficacy of SMN<jats:sup>K186R<\/jats:sup>. In the negative geotaxis test, AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>\u2010treated mice turned their bodies in an upward direction successfully, unlike AAV9\u2010SMN<jats:sup>WT<\/jats:sup>\u2010treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>\u2010treated mice, unlike AAV9\u2010SMN<jats:sup>WT<\/jats:sup>\u2010treated mice that showed clasping phenotype for more than 20 out of 30\u00a0s. At this point, the number of motor neurons (1.5\u2010fold) and the size of myofibers (2.1\u2010fold) were significantly increased in AAV9\u2010SMN<jats:sup>K186R<\/jats:sup>\u2010treated mice compared with AAV9\u2010SMN<jats:sup>WT<\/jats:sup>\u2010treated mice without prominent neurotoxicity. AAV9\u2010SMN<jats:sup>K186R<\/jats:sup> had fewer liver defects compared with AAV9\u2010SMN<jats:sup>WT<\/jats:sup>, as judged by increased proliferation of hepatocytes (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and insulin\u2010like growth factor\u20101 production (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001). Especially, low\u2010dose AAV9\u2010SMN<jats:sup>K186R<\/jats:sup> (nine\u2010fold) also reduced clasping time compared with SMN<jats:sup>WT<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>SMN<jats:sup>K186R<\/jats:sup> will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low\u2010dose treatment of SMA patients with AAV9\u2010SMN<jats:sup>K186R<\/jats:sup> can reduce the adverse events of Zolgensma. Collectively, SMN<jats:sup>K186R<\/jats:sup> has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13486","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T04:15:21Z","timestamp":1713845721000},"page":"1404-1417","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Improved therapeutic approach for spinal muscular atrophy via ubiquitination\u2010resistant survival motor neuron variant"],"prefix":"10.1002","volume":"15","author":[{"given":"Joonwoo","family":"Rhee","sequence":"first","affiliation":[{"name":"School of Biological Sciences Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong\u2010Seol","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Seoul National University  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