Yee Karen Kar Lye, Kumamoto Junichi, Inomata Daijiro, Suzuki Naoki, Harada Ryuhei, Yumoto Norihiro
Jiksak Bioengineering, Inc., Cybernics Medical Innovation Base-A room 322, 3-25-16 Tonomachi, Kawasaki-ku Kawasaki-shi, Kanagawa 210-0821, Japan.
Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku Sendai, Miyagi 980-8574, Japan.
Mol Ther Methods Clin Dev. 2025 Apr 19;33(2):101476. doi: 10.1016/j.omtm.2025.101476. eCollection 2025 Jun 12.
The effective delivery of therapeutic molecules to neurons are mainly limited by the presence of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), leading to suboptimal therapeutic outcomes in neurodegenerative diseases treatment. This study introduces a neuron-selective drug delivery system that utilizes the synaptic vesicle release and recycling mechanism (SVRM) to overcome these barriers. This delivery system consists of an antibody shuttle that targets SV transmembrane proteins, which enables selective molecule delivery to neurons. We demonstrated that intravenously administered antibodies raised against the luminal domain of synaptotagmin-2 (SYT2) selectively localize to neuromuscular junctions. They were taken up and retrogradely transported to CHAT-positive motor neurons in both the spinal cord and brainstem. Anti-SYT2 antibody delivery of anti-microtubule agent and gapmer antisense oligonucleotides (ASOs) induces axonal degeneration and RNA downregulation , respectively. Additionally, intravenous administration of anti-SYT2 conjugated with gapmer ASOs in mice resulted in the reduction of RNA in targeted cells. This approach circumvents the BSCB, enabling the neuron-selective delivery of therapeutic agents to increase neuronal drug concentrations while minimizing off-target effects in non-targeted cells. Thus, harnessing the SVRM offers a promising strategy to enhance the therapeutic index for neurodegenerative diseases treatment.
治疗分子向神经元的有效递送主要受到血脑屏障（BBB）和血脊髓屏障（BSCB）的限制，导致神经退行性疾病治疗的疗效欠佳。本研究引入了一种神经元选择性药物递送系统，该系统利用突触小泡释放和循环机制（SVRM）来克服这些障碍。该递送系统由靶向突触小泡跨膜蛋白的抗体穿梭体组成，可实现分子向神经元的选择性递送。我们证明，静脉注射针对突触结合蛋白-2（SYT2）腔内结构域产生的抗体可选择性定位于神经肌肉接头。这些抗体被摄取并逆行运输至脊髓和脑干中表达胆碱乙酰转移酶（CHAT）的运动神经元。抗微管药物和缺口mer反义寡核苷酸（ASO）通过抗SYT2抗体递送分别诱导轴突变性和RNA下调。此外，在小鼠中静脉注射与缺口mer ASO偶联的抗SYT2可导致靶细胞中RNA减少。这种方法绕过了BSCB，能够实现治疗剂向神经元的选择性递送，从而提高神经元药物浓度，同时将非靶细胞中的脱靶效应降至最低。因此，利用SVRM为提高神经退行性疾病治疗的治疗指数提供了一种有前景的策略。
