TY - JOUR
T1 - Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson’s disease
AU - Ge, Guo
AU - Sivasubramanian, Barath P.
AU - Geng, Bill D.
AU - Zhao, Shujie
AU - Zhou, Qing
AU - Huang, Gang
AU - O’Connor, Jason C.
AU - Clark, Robert A.
AU - Li, Senlin
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/5
Y1 - 2024/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85190525288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85190525288&partnerID=8YFLogxK
U2 - 10.1038/s41434-024-00451-3
DO - 10.1038/s41434-024-00451-3
M3 - Article
C2 - 38627469
AN - SCOPUS:85190525288
SN - 0969-7128
VL - 31
SP - 324
EP - 334
JO - Gene Therapy
JF - Gene Therapy
IS - 5-6
ER -