Single chain variable fragment antibodies directed against SOD1 ameliorate disease in mutant SOD1 transgenic mice
Single chain variable fragment antibodies directed against SOD1 ameliorate disease in mutant SOD1 transgenic mice
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DOI：
10.1016/j.nbd.2018.08.021
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发表时间：
2019-01-01
影响因子：
6.1
通讯作者：
Roos, Raymond P.
中科院分区：
文献类型：
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作者：
Ghadge, Ghanashyam D.;Kay, Brian K.;Roos, Raymond P.
大约20%的家族性ALS （FALS）病例是由Cu/Zn超氧化物歧化酶（SOD1）突变引起的，FALS约占ALS总病例数的10%。突变体（mt） SOD1被认为是通过功能的增加而不是丧失导致FALS，这可能是突变蛋白错误折叠和聚集的结果。此前，我们利用噬菌体展示文库培养了针对SOD1的单链可变片段抗体（scFvs），发现该抗体能降低mtSODl的聚集和体外毒性。在本研究中，我们发现两种靶向SOD1的scFvs可以改善G93A mtSOD1转基因小鼠的疾病，并减少运动神经元丢失、小胶质细胞增生、星形细胞增生以及SOD1负担和聚集。结果表明，使用针对SOD1的抗体或抗体模拟物可能是mtsod1诱导的FALS的有效治疗方向。由于研究表明野生型SOD1可能与mtSODl相似出现错误折叠，因此这种治疗方向可能对散发性als和FALS都有效。
Mutations in Cu/Zn superoxide dismutase (SOD1) are the cause of similar to 20% of cases of familial ALS (FALS), which comprise similar to 10% of the overall total number of cases of ALS. Mutant (mt) SOD1 is thought to cause FALS through a gain and not loss in function, perhaps as a result of the mutant protein's misfolding and aggregation. Previously we used a phage display library to raise single chain variable fragment antibodies (scFvs) against SOD1, which were found to decrease aggregation of mtSODl and toxicity in vitro. In the present study, we show that two scFvs directed against SOD1 ameliorate disease in G93A mtSOD1 transgenic mice and also decrease motor neuron loss, microgliosis, astrocytosis, as well as SOD1 burden and aggregation. The results suggest that the use of antibodies or antibody mimetics directed against SOD1 may be a useful therapeutic direction in mtSOD1-induced FALS. Since studies suggest that wild type SOD1 may be misfolded similar to that seen with mtSODl, this therapeutic direction may be effective in sporadic as well as FALS.