Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson’s disease

• Published in: Gene therapy Vol. 31; no. 5-6; pp. 324 - 334
• Main Authors: Ge, Guo, Sivasubramanian, Barath P., Geng, Bill D., Zhao, Shujie, Zhou, Qing, Huang, Gang, O’Connor, Jason C., Clark, Robert A., Li, Senlin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2024; Nature Publishing Group
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 13; 13/51; 42/100; 42/109; 42/44; 631/378/1934; 64; 64/60; 692/699/375; Animal models; Animals; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cerebellum; Clinical outcomes; Clinical trials; Disease Models, Animal; Dopamine; Dopamine receptors; Dopaminergic Neurons - metabolism; Exosomes; Exosomes - metabolism; Food intake; Gene Expression; Gene Therapy; Gene transfer; Genetic Therapy - methods; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Glial Cell Line-Derived Neurotrophic Factor - therapeutic use; Glial cells; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Human Genetics; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Microglia - metabolism; Motor ability; Movement disorders; MPTP; Nanotechnology; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neuronal-glial interactions; Neurotrophic factors; Parkinson Disease - metabolism; Parkinson Disease - therapy; Parkinson's disease; Side effects; Stem cells; Substantia nigra; Substantia Nigra - metabolism
• ISSN: 0969-7128; 1476-5462; 1476-5462
• DOI: 10.1038/s41434-024-00451-3

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.