Superoxide dismutase1 (SOD 1) mutation is a leading cause of familial amyotrophic lateral sclerosis (ALS). Growing evidence suggests that antibody therapy against misfolded SOD1 protein can be therapeutic. However, the therapeutic effects are limited, partly because of the delivery system. Therefore, we investigated the efficacy of oligodendrocyte precursor cells (OPCs) as a drug delivery vehicle of single-chain variable fragments (scFv). Using a Borna disease virus vector that is pharmacologically removable and episomally replicable in the recipient cells, we successfully transformed wild-type OPCs to secrete scFv of a novel monoclonal antibody (D3-1), specific for misfolded SOD1. Single intrathecal injection of OPCs scFvD3-1, but not OPCs alone, significantly delayed disease onset and prolonged the lifespan of ALS rat models expressing SOD1 ^H46R. The effect of OPC scFvD3-1 surpassed that of a 1 month intrathecal infusion of full-length D3-1 antibody alone. scFv-secreting OPCs suppressed neuronal loss and gliosis, reduced levels of misfolded SOD1 in the spinal cord, and suppressed the transcription of inflammatory genes, including Olr1, an oxidized low-density lipoprotein receptor 1. The use of OPCs as a delivery vehicle for therapeutic antibodies is a new option for ALS in which misfolded protein and oligodendrocyte dysfunction are implicated in the pathogenesis.

超氧化物歧化酶 1 ( SOD 1) 突变是家族性肌萎缩侧索硬化症 (ALS) 的主要原因。越来越多的证据表明，针对错误折叠的 SOD1 蛋白的抗体疗法可能具有治疗作用。然而，治疗效果是有限的，部分原因在于递送系统。因此，我们研究了少突胶质细胞前体细胞 (OPC) 作为单链可变片段 (scFv) 药物递送载体的功效。使用可在受体细胞中药理学去除和游离复制的博尔纳病病毒载体，我们成功地将野生型 OPCs 转化为分泌一种新型单克隆抗体 (D3-1) 的 scFv，该单克隆抗体对错误折叠的 SOD1 具有特异性。单次鞘内注射 OPCs scFvD3-1，而非单独的 OPCs，可显着延迟疾病发作并延长表达SOD1的 ALS 大鼠模型的寿命 ^H46R。OPC scFvD3-1 的效果超过了单独全长 D3-1 抗体鞘内输注 1 个月的效果。分泌 scFv 的 OPC 抑制神经元丢失和神经胶质增生，降低脊髓中错误折叠的 SOD1 水平，并抑制炎症基因的转录，包括 Olr1，一种氧化的低密度脂蛋白受体 1。使用 OPC 作为治疗性药物的递送载体抗体是 ALS 的新选择，其中错误折叠的蛋白质和少突胶质细胞功能障碍与发病机制有关。