Chen Cang, Guderyon Michael J, Li Yang, Ge Guo, Bhattacharjee Anindita, Ballard Cori, He Zhixu, Masliah Eliezer, Clark Robert A, O'Connor Jason C, Li Senlin
Department of Medicine, The University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Ther Methods Clin Dev. 2019 Nov 26;17:83-98. doi: 10.1016/j.omtm.2019.11.013. eCollection 2020 Jun 12.
Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.
胶质细胞源性神经营养因子（GDNF）在帕金森病（PD）的细胞和动物模型中是一种有效的神经保护剂。然而，在临床试验中，由于血脑屏障（BBB）的不透性、在脑组织内的扩散性差以及大脑体积大，GDNF的中枢神经系统递送已被证明具有挑战性。我们报告，使用无毒的动员预处理，基于造血干细胞（HSC）移植的巨噬细胞介导的基因递送可能提供一种克服这些障碍的解决方案。将表达巨噬细胞启动子驱动的GDNF的慢病毒载体转导同基因骨髓造血干细胞，并将其移植到表现出类似PD损伤的14周龄MitoPark小鼠体内。用粒细胞集落刺激因子（G-CSF）和AMD3100进行移植预处理，以腾空骨髓干细胞龛。经过七个移植周期后，嵌合率达到约80%。表达转基因的巨噬细胞浸润到MitoPark小鼠（而非野生型同窝对照）的退化中枢神经系统区域，导致中脑GDNF水平升高。巨噬细胞递送GDNF不仅显著改善了运动和非运动功能障碍，还显著减轻了黑质和腹侧被盖区多巴胺能神经元的损失，并保留了纹状体中的轴突终末。纹状体多巴胺水平几乎完全恢复。我们的数据支持进一步开发基于动员的造血干细胞移植（HSCT）的巨噬细胞介导的GDNF基因递送，作为一种用于PD的疾病修饰疗法。
