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dc.contributor.authorRhee, Joonwoo-
dc.contributor.authorKang, Jong-Seol-
dc.contributor.authorJo, Young-Woo-
dc.contributor.authorYoo, Kyusang-
dc.contributor.authorKim, Ye Lynne-
dc.contributor.authorHann, Sang-Hyeon-
dc.contributor.authorKim, Yea-Eun-
dc.contributor.authorKim, Hyun-
dc.contributor.authorKim, Ji-Hoon-
dc.contributor.authorKong, Young-Yun-
dc.date.accessioned2024-05-02T02:30:16Z-
dc.date.available2024-05-02T02:30:16Z-
dc.date.created2024-05-02-
dc.date.issued2024-08-
dc.identifier.issn2190-5991-
dc.identifier.urihttps://pubs.kist.re.kr/handle/201004/149777-
dc.description.abstractBackground Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). 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-symptomatic 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-resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild-type SMN (SMNWT). Methods A severe SMA mouse model, SMA type 1.5 (Smn(-/-); SMN2+/+; SMN triangle 7(+/-)) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMNWT and AAV9-SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle. Results AAV9-SMNK186R-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMNWT-treated mice. Lifespan increased by more than 10-fold in AAV9-SMNK186R-treated mice (144.8 +/- 26.11 days) as compared with AAV9-SMNWT-treated mice (26.8 +/- 1.41 days). AAV9-SMNK186R-treated mice showed an ascending weight pattern, unlike AAV9-SMNWT-treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9-SMNK186R-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMNWT-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMNK186R-treated mice, unlike AAV9-SMNWT-treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMNK186R-treated mice compared with AAV9-SMNWT-treated mice without prominent neurotoxicity. AAV9-SMNK186R had fewer liver defects compared with AAV9-SMNWT, as judged by increased proliferation of hepatocytes (P < 0.0001) and insulin-like growth factor-1 production (P < 0.0001). Especially, low-dose AAV9-SMNK186R (nine-fold) also reduced clasping time compared with SMNWT. Conclusions SMNK186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMNK186R can reduce the adverse events of Zolgensma. Collectively, SMNK186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.-
dc.languageEnglish-
dc.publisherSpringer Verlag-
dc.titleImproved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant-
dc.typeArticle-
dc.identifier.doi10.1002/jcsm.13486-
dc.description.journalClass1-
dc.identifier.bibliographicCitationJournal of Cachexia, Sarcopenia and Muscle, v.15, no.4, pp.1404 - 1417-
dc.citation.titleJournal of Cachexia, Sarcopenia and Muscle-
dc.citation.volume15-
dc.citation.number4-
dc.citation.startPage1404-
dc.citation.endPage1417-
dc.description.isOpenAccessY-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.identifier.wosid001206966500001-
dc.identifier.scopusid2-s2.0-85191074410-
dc.relation.journalWebOfScienceCategoryGeriatrics & Gerontology-
dc.relation.journalWebOfScienceCategoryMedicine, General & Internal-
dc.relation.journalResearchAreaGeriatrics & Gerontology-
dc.relation.journalResearchAreaGeneral & Internal Medicine-
dc.type.docTypeArticle-
dc.subject.keywordPlusGENE-THERAPY-
dc.subject.keywordPlusMOUSE MODEL-
dc.subject.keywordPlusEFFICIENT TRANSDUCTION-
dc.subject.keywordPlusSMN PROTEIN-
dc.subject.keywordPlusPHENOTYPE-
dc.subject.keywordPlusREQUIREMENT-
dc.subject.keywordPlusEXPRESSION-
dc.subject.keywordPlusSAFETY-
dc.subject.keywordAuthorAAV-
dc.subject.keywordAuthormotor neuron-
dc.subject.keywordAuthorneuromuscular disease-
dc.subject.keywordAuthorneurotoxicity-
dc.subject.keywordAuthorSMA-
dc.subject.keywordAuthorSMN-
dc.subject.keywordAuthorspinal muscular atrophy-
dc.subject.keywordAuthorsurvival motor neuron-
dc.subject.keywordAuthorZolgensma-
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