Translating SOD1 Gene Silencing toward the Clinic: A Highly Efficacious, Off-Target-free, and Biomarker-Supported Strategy for fALS.
Translating SOD1 Gene Silencing toward the Clinic: A Highly Efficacious, Off-Target-free, and Biomarker-Supported Strategy for fALS.
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DOI：
10.1016/j.omtn.2018.04.015
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发表时间：
2018-09-07
期刊：
影响因子：
--
通讯作者：
Azzouz M
中科院分区：
文献类型：
--
作者：
Iannitti T;Scarrott JM;Likhite S;Coldicott IRP;Lewis KE;Heath PR;Higginbottom A;Myszczynska MA;Milo M;Hautbergue GM;Meyer K;Kaspar BK;Ferraiuolo L;Shaw PJ;Azzouz M
在家族性肌萎缩侧索硬化（fALS）病例中，20%是由编码人胞质Cu/Zn超氧化物歧化酶（hSOD 1）的基因突变引起的。RNAi用于治疗SOD 1-ALS患者的治疗潜力的有效转化需要开发无显著脱靶效应且具有可靠生物标志物的载体，以辨别足够的靶标接合和正确给药。在SOD 1G 93 A小鼠模型中使用腺相关病毒血清型9递送针对hSOD 1的RNAi，我们发现通过小脑延髓池鞘内注射治疗载体延迟了疾病的发作，使终末期运动神经元死亡减少高达88%，并使SOD 1G 93 A小鼠的中位生存期延长高达42%。据我们所知，这是第一份证明没有与hSOD 1沉默相关的显著脱靶效应的报告，为这种方法的特异性提供了进一步的信心。我们还报告了脑脊液（CSF）hSOD 1蛋白水平的测量作为hSOD 1敲低的有效剂量和功效的生物标志物。总之，这些数据为临床治疗载体的安全性提供了进一步的信心。CSF生物标志物将是用于转化为人类临床试验的生物活性的有用量度。在ALS小鼠模型中开发无脱靶效应的AAV 9-shRNA介导的SOD 1沉默，使用可靠的生物标志物来辨别足够的靶标接合和正确的给药。
Of familial amyotrophic lateral sclerosis (fALS) cases, 20% are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of the therapeutic potential of RNAi for the treatment of SOD1-ALS patients requires the development of vectors that are free of significant off-target effects and with reliable biomarkers to discern sufficient target engagement and correct dosing. Using adeno-associated virus serotype 9 to deliver RNAi against hSOD1 in the SOD1G93A mouse model, we found that intrathecal injection of the therapeutic vector via the cisterna magna delayed onset of disease, decreased motor neuron death at end stage by up to 88%, and prolonged the median survival of SOD1G93A mice by up to 42%. To our knowledge, this is the first report to demonstrate no significant off-target effects linked to hSOD1 silencing, providing further confidence in the specificity of this approach. We also report the measurement of cerebrospinal fluid (CSF) hSOD1 protein levels as a biomarker of effective dosing and efficacy of hSOD1 knockdown. Together, these data provide further confidence in the safety of the clinical therapeutic vector. The CSF biomarker will be a useful measure of biological activity for translation into human clinical trials. Development of off-target effect-free AAV9-shRNA-mediated SOD1 silencing in an ALS mouse model, with reliable biomarkers to discern sufficient target engagement and correct dosing.
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影响因子：
46.9
作者：
Jackson, AL;Bartz, SR;Linsley, PS
通讯作者：
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