Audie L. Murphy VA Medical Center, 7400 Merton Minter Boulevard, San Antonio, TX, 78229, USA.
Department of Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
Gene Ther. 2024 May;31(5-6):324-334. doi: 10.1038/s41434-024-00451-3. Epub 2024 Apr 16.
Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.
胶质细胞源性神经营养因子（GDNF）可保护多种帕金森病（PD）模型中的多巴胺能神经元。基于细胞的 GDNF 基因传递可减轻 PD 小鼠的神经退行性变，并改善其运动和非运动功能。由于 PD 是一种慢性疾病，因此本研究旨在调查基于造血干细胞（HSC）的巨噬细胞/小胶质细胞介导的中枢神经系统 GDNF（MMC-GDNF）传递在 MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）小鼠模型中的长期益处。结果表明，GDNF 治疗可有效改善 MPTP 诱导的运动缺陷长达 12 个月，这与黑质多巴胺能神经元及其纹状体末端的保护作用一致。此外，HSC 衍生的巨噬细胞/小胶质细胞被选择性募集到黑质的神经退行性区域。治疗益处似乎涉及两种机制：（1）巨噬细胞/小胶质细胞释放含有 GDNF 的外泌体，这些外泌体被转移到靶神经元；（2）巨噬细胞/小胶质细胞直接释放 GDNF，GDNF 扩散到靶神经元。此外，该研究发现，血浆 GDNF 水平从基线开始显著升高并保持稳定，这可能成为未来临床试验的一个便利生物标志物。值得注意的是，未观察到体重减轻、食物摄入改变、小脑病理或其他不良反应。总体而言，这项研究为基于 HSC 的 MMC-GDNF 传递在 PD 治疗中的长期治疗效果和安全性提供了有力证据。
