Non-toxic HSC Transplantation-Based Macrophage/Microglia-Mediated GDNF Delivery for Parkinson’s Disease

著者: Cang Chen, Michael J. Guderyon, Yang Li, Guo Ge, Anindita Bhattacharjee, Cori Ballard, Zhixu He, Eliezer Masliah, Robert A. Clark, Jason C. O’Connor, Senlin Li - Molecular Therapy — Methods & Clinical Development 2019 被引用: 32

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.