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利用腺相关病毒和微RNA抑制SOD1治疗家族性肌萎缩侧索硬化
SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS


Christian Mueller ... 其他 • 2020.07.09
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• 反义寡核苷酸tofersen治疗SOD1突变所致肌萎缩侧索硬化的1~2期试验 • FDA批准依达拉奉用于治疗肌萎缩侧索硬化

摘要


有超氧化物歧化酶1编码基因(SOD1)突变的2例家族性肌萎缩侧索硬化(ALS)患者接受了腺相关病毒单次鞘内输入治疗,该腺相关病毒编码靶向SOD1的微RNA。患者1在尸检时测定的脊髓组织SOD1水平低于未接受治疗的SOD1 ALS患者和健康对照的相应水平。患者1的脑脊液SOD1水平只是一过性地略微降低,而患者2的脑脊液SOD1水平未受影响。患者1接受输入给药后发生了脑膜神经根炎;患者2预先接受了免疫抑制药物治疗,该患者未出现这一并发症。患者1的右腿力量有一过性改善(这一指标在该患者的病程中保持相对稳定),但肺活量无变化。患者2的ALS功能综合指标评分和肺活量在12个月期间保持稳定。本研究表明,微RNA鞘内给药有可能成为SOD1介导的ALS的治疗方案。

在肌萎缩侧索硬化(ALS)患者中,有10%是遗传性的,致病原因是单基因突变1。在超氧化物歧化酶1(SOD1)编码基因突变导致的家族性ALS动物模型中,抑制突变基因可改善动物生存2-5。在猴子中,鞘内输入含有抗SOD1微RNA的腺相关病毒rh10(AAV-miR-SOD1)已被证明能够降解SOD1信使RNA,从而抑制该基因在脊髓中的表达6,7。我们在SOD1突变导致的2例ALS患者中检验了输入AAV-miR-SOD1的安全性。临床疗效指标属于探索性指标。





作者信息

Christian Mueller, Ph.D., James D. Berry, M.D., Diane M. McKenna-Yasek, R.N., Gwladys Gernoux, Ph.D., Margaret A. Owegi, M.D., Lindsay M. Pothier, B.S., Catherine L. Douthwright, Ph.D., Dario Gelevski, B.S., Sarah D. Luppino, B.S.N., R.N., Meghan Blackwood, B.S., Nicholas S. Wightman, B.S., Derek H. Oakley, M.D., Ph.D., Matthew P. Frosch, M.D., Ph.D., Terrence R. Flotte, M.D., Merit E. Cudkowicz, M.D., and Robert H. Brown, Jr., D.Phil., M.D.
From the Horae Gene Therapy Center, Department of Pediatrics, University of Massachusetts Medical School (UMMS) (C.M., G.G., M.B., T.R.F.), and the Department of Neurology, UMMS and UMass Memorial Medical Center (D.M.M.-Y., M.A.O., C.L.D., N.S.W., R.H.B.), Worcester, and the Healey Center for ALS, Department of Neurology (J.D.B., L.M.P., D.G., S.D.L., M.P.F., M.E.C.), and the C.S. Kubik Laboratory for Neuropathology (D.H.O., M.P.F.), Massachusetts General Hospital and Harvard Medical School, Boston. Address reprint requests to Dr. Brown at the Department of Neurology, S5-753, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655, or at robert.brown@umassmed.edu.

 

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