Devinsky Orrin, Coller Jeff, Ahrens-Nicklas Rebecca, Liu X Shawn, Ahituv Nadav, Davidson Beverly L, Bishop Kathie M, Weiss Yael, Mingorance Ana
Department of Neurology, NYU Langone Medical Center, New York, NY, USA; Grossman School of Medicine, New York University, New York, NY, USA.
Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, USA; Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
Trends Mol Med. 2025 Sep;31(9):814-826. doi: 10.1016/j.molmed.2025.01.015. Epub 2025 Feb 17.
Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.
超过1700个基因中的致病变异可导致神经遗传性疾病。单基因疾病是基因治疗的理想靶点；然而，血脑屏障（BBB）、有丝分裂后神经元以及低效的递送平台使得神经遗传性疾病的基因治疗具有挑战性。自2016年nusinersen获批以来，神经遗传性疾病的基因治疗发展迅速，出现了新的递送载体（如穿越血脑屏障的衣壳、工程化病毒样蛋白、脂质纳米颗粒（LNP））和新的治疗策略（如调控元件、新型RNA疗法、tRNA疗法、表观遗传学和基因编辑）。患者主导的疾病基金会通过解决试验准备工作和支持转化研究，加速了治疗的开发。我们综述了神经遗传性疾病基因治疗的当前现状和未来方向。
