Gomes-Duarte Andreia, Pascoal Sofia, Haselberg Rob, Sogorb-Gonzalez Marina, van Deventer Sander
VectorY Therapeutics, Matrix Innovation Center VI, Amsterdam, Netherlands.
Front Neurosci. 2025 Jul 8;19:1620181. doi: 10.3389/fnins.2025.1620181. eCollection 2025.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for a significant fraction of familial ALS (fALS) cases. Oxidative stress and oxidized phosphatidylcholines (PC-OxPL) contribute to neuroinflammation and neuronal damage, and to motor neuron degeneration in ALS. We previously demonstrated the therapeutic efficacy of an AAV-delivered anti-PC-OxPL single-chain variable fragment (PC-OxPL-VecTab) in neutralizing PC-OxPL toxicity in the periphery and central nervous system (CNS), but the therapeutic potential of PC-OxPL-VecTab has not been investigated in the context of fALS and SOD1-associated ALS. We report that PC-OxPL accumulation contributes to the pathological phenotypes associated with SOD1 iPSC-derived motor neurons and the corresponding mouse model. The current findings further demonstrate that PC-OxPL-VecTab is efficacious in neutralizing the downstream effects of SOD1-associated PC-OxPL accumulation, such as altered gene expression and axonal health in SOD1 motor neurons, as well as a pathological lipid profile in the SOD1 mouse model. Collectively, the present study underscores the significance of PC-OxPL dysfunction in the context of SOD1 genotypes and sheds light on the potential of PC-OxPL-VecTab® for therapeutically targeting ALS.
肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，其特征为进行性运动神经元变性。超氧化物歧化酶1（SOD1）基因突变在家族性ALS（fALS）病例中占很大比例。氧化应激和氧化磷脂酰胆碱（PC-OxPL）会导致神经炎症和神经元损伤，并在ALS中导致运动神经元变性。我们之前证明了通过腺相关病毒（AAV）递送的抗PC-OxPL单链可变片段（PC-OxPL-VecTab）在中和外周和中枢神经系统（CNS）中PC-OxPL毒性方面的治疗效果，但尚未在fALS和SOD1相关ALS的背景下研究PC-OxPL-VecTab的治疗潜力。我们报告称，PC-OxPL的积累促成了与SOD1诱导多能干细胞（iPSC）衍生的运动神经元及相应小鼠模型相关的病理表型。目前的研究结果进一步证明，PC-OxPL-VecTab在中和SOD1相关PC-OxPL积累的下游效应方面是有效的，如SOD1运动神经元中基因表达改变和轴突健康问题，以及SOD1小鼠模型中的病理性脂质谱。总的来说，本研究强调了在SOD1基因型背景下PC-OxPL功能障碍的重要性，并揭示了PC-OxPL-VecTab®在治疗ALS方面的潜力。
