Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia

肌萎缩侧索硬化症和额颞部的靶向免疫治疗 痴呆症 摘要 额颞叶痴呆(FTD)和肌萎缩侧索硬化症(ALS)是进行性和致命性的 神经退行性疾病。C9orf72中的六核苷酸重复扩增占所有病例的10%。 非AUG依赖的扩展重复序列的翻译导致几个二肽重复序列(DPR)的积累 蛋白质，其中多聚GA似乎在C9orf72病的病理中起中心作用。聚-GA的聚集抑制作用 蛋白酶体，并导致TDP-43聚集。尽管Poly-GA在C9orf72小鼠中广泛表达 模型中，特定的疾病相关神经元群体对多聚GA毒性特别敏感。反义 针对C9orf72的寡核苷酸在小鼠中是有效的，显性负蛋白激酶R(PKR)也是如此 减少多聚-GA的积累。初步数据表明，主动疫苗接种可诱导高抗体滴度。 并几乎完全防止小鼠的运动障碍和小胶质细胞激活，这表明多聚GA是一种 C9orf72 FTD/ALS治疗的可行靶点Poly-GA抗体阻断PolyGA和 在体外减弱TDP-43下游的病理，并改善小鼠模型的运动和行为缺陷。 这些数据表明，免疫疗法是目前减少以下集合体毒性的最佳方法 即使在有症状的携带者身上也能发现。我们的团队已经发现了有效的小鼠抗体，可以证明 在C9orf72小鼠模型中的活动。在这项第一阶段的研究中，我们建议人源化我们的主要抗GA抗体 并在几个与疾病相关的小鼠模型上进行抗GA抗体治疗的临床前验证。

Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia Abstract Frontotemporal dementias (FTD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative diseases. A hexanucleotide repeat expansion in C9orf72 accounts for >10% of all cases. Non-AUG dependent translation of expanded repeats results in accumulation of several dipeptide repeat (DPR) proteins, of which poly-GA appears central to the pathology of C9orf72 disease. Aggregation of poly-GA inhibits the proteasome and leads to TDP-43 aggregation. Despite widespread poly-GA expression in C9orf72 mouse models, specific disease-relevant neuron populations are especially sensitive to poly-GA toxicity. Antisense oligonucleotides directed to C9orf72 are effective in mice, as is a dominant negative protein kinase R (PKR) that attenuates poly-GA accumulation. Preliminary data indicate that active vaccination induces high antibody titers and nearly complete prevention of motor deficits and microglia activation in mice, suggesting poly-GA as a feasible target to treat C9orf72 FTD/ALS. Poly-GA antibodies block aggregation and spreading of poly-GA and attenuate downstream TDP-43 pathology in vitro, and improve motor and behavioral deficits in mouse models. These data suggest that immunotherapy is currently the best approach to reduce toxicity of aggregates that are found even in pre-symptomatic carriers. Our team has identified potent murine antibodies that demonstrate activity in a C9orf72 mouse model. During this Phase 1 study, we propose to humanize our lead anti-GA antibody and conduct preclinical validation of anti-GA antibody therapy in several disease-relevant mouse models.