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

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Abstract

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.

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Fig. 1: Long-term amelioration of MPTP-induced motor deficits by bone marrow hematopoietic stem cell transplant-derived macrophage/microglia-mediated GDNF gene therapy.
Fig. 2: Mitigation of MPTP-induced loss of dopaminergic neurons in the substantia nigra by macrophage/microglia-mediated GDNF gene therapy.
Fig. 3: Alleviation of degeneration of dopaminergic terminals in the striatum by macrophage/microglia-mediated GDNF gene therapy.
Fig. 4: Selective recruitment of transplant-derived macrophages/microglia to neurodegenerative regions of the substantia nigra.
Fig. 5: High levels of GDNF secretion by lentivirus-transduced bone marrow-derived macrophages.
Fig. 6: Time course of hGDNF concentration in plasma after bone marrow cell transplantation.
Fig. 7: Lack of effect of macrophage/microglia-mediated GDNF gene therapy on body weight and food intake.
Fig. 8: Absence of brain cerebellar morphological changes caused by macrophage/microglia-mediated GDNF gene therapy.
Fig. 9: Morphological analysis of the cerebral cortex and hippocampus.

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Data availability

The datasets generated and/or analyzed in the current study are accessible upon reasonable request from either the first author or the corresponding author.

References

  1. Aarsland D, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Prim. 2021;7:47.

    Article  PubMed  Google Scholar 

  2. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.

    Article  CAS  PubMed  Google Scholar 

  3. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448–58.

    Article  CAS  PubMed  Google Scholar 

  4. Liu B, et al. Effects of Eldepryl on glial cell proliferation and activation in the substantia nigra and striatum in a rat model of Parkinson’s disease. Neurol Res. 2017;39:459–67.

    Article  CAS  PubMed  Google Scholar 

  5. Henchcliffe C, Severt WL. Disease modification in Parkinson’s disease. Drugs Aging. 2011;28:605–15.

    Article  CAS  PubMed  Google Scholar 

  6. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260:1130–2.

    Article  CAS  PubMed  Google Scholar 

  7. Tomac A, et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature. 1995;373:335–9.

    Article  CAS  PubMed  Google Scholar 

  8. Henderson CE, et al. GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science. 1994;266:1062–4.

    Article  CAS  PubMed  Google Scholar 

  9. Kramer ER, Liss B. GDNF-Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease. FEBS Lett. 2015;589:3760–72.

    Article  CAS  PubMed  Google Scholar 

  10. Emborg ME, et al. Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF. Neurobiol Dis. 2009;36:303–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kells AP, et al. Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF. J Neurosci. 2010;30:9567–9577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Migliore MM, et al. Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson’s disease. Neuroscience. 2014;274:11–23.

    Article  CAS  PubMed  Google Scholar 

  13. Manfredsson FP, et al. The future of GDNF in Parkinson’s disease. Front Aging Neurosci. 2020;12:593572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tereshchenko J, Maddalena A, Bahr M, Kugler S. Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson’s disease. Neurobiol Dis. 2014;65:35–42.

    Article  CAS  PubMed  Google Scholar 

  15. Gill SS, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9:589–95.

    Article  CAS  PubMed  Google Scholar 

  16. Love S, et al. Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Nat Med. 2005;11:703–4.

    Article  CAS  PubMed  Google Scholar 

  17. Patel NK, et al. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol. 2005;57:298–302.

    Article  CAS  PubMed  Google Scholar 

  18. Slevin JT, et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg. 2005;102:216–22.

    Article  CAS  PubMed  Google Scholar 

  19. Kordower JH, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science. 2000;290:767–73.

    Article  CAS  PubMed  Google Scholar 

  20. Georgievska B, Kirik D, Rosenblad C, Lundberg C, Bjorklund A. Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector. Neuroreport. 2002;13:75–82.

    Article  CAS  PubMed  Google Scholar 

  21. Bauer M, et al. Lipid-mediated glial cell line-derived neurotrophic factor gene transfer to cultured porcine ventral mesencephalic tissue. Exp Neurol. 2002;177:40–9.

    Article  CAS  PubMed  Google Scholar 

  22. Chtarto A, et al. Controlled delivery of glial cell line-derived neurotrophic factor by a single tetracycline-inducible AAV vector. Exp Neurol. 2007;204:387–99.

    Article  CAS  PubMed  Google Scholar 

  23. Wang L, et al. Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson’s disease. Gene Ther. 2002;9:381–9.

    Article  CAS  PubMed  Google Scholar 

  24. McGrath J, et al. Adeno-associated viral delivery of GDNF promotes recovery of dopaminergic phenotype following a unilateral 6-hydroxydopamine lesion. Cell Transpl. 2002;11:215–27.

    Article  Google Scholar 

  25. Brundin P. GDNF treatment in Parkinson’s disease: time for controlled clinical trials? Brain. 2002;125:2149–51.

    Article  PubMed  Google Scholar 

  26. Sherer TB, Fiske BK, Svendsen CN, Lang AE, Langston JW. Crossroads in GDNF therapy for Parkinson’s disease. Mov Disord. 2006;21:136–41.

    Article  PubMed  Google Scholar 

  27. Salvatore MF, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol. 2006;202:497–505.

    Article  CAS  PubMed  Google Scholar 

  28. Kambey PA, et al. Failure of glial cell-line derived neurotrophic factor (GDNF) in clinical trials orchestrated by reduced NR4A2 (NURR1) transcription factor in Parkinson’s disease. A systematic review. Front Aging Neurosci. 2021;13:645583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Barker RA, et al. GDNF and Parkinson’s disease: where next? a summary from a recent workshop. J Parkinsons Dis. 2020;10:875–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rosenblad C, Georgievska B, Kirik D. Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system. Eur J Neurosci. 2003;17:260–70.

    Article  PubMed  Google Scholar 

  31. Georgievska B, Kirik D, Bjorklund A. Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system. J Neurosci. 2004;24:6437–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Barroso-Chinea P, et al. Long-term controlled GDNF over-expression reduces dopamine transporter activity without affecting tyrosine hydroxylase expression in the rat mesostriatal system. Neurobiol Dis. 2016;88:44–54.

    Article  CAS  PubMed  Google Scholar 

  33. Mesa-Infante V, Afonso-Oramas D, Salas-Hernandez J, Rodriguez-Nunez J, Barroso-Chinea P. Long-term exposure to GDNF induces dephosphorylation of Ret, AKT, and ERK1/2, and is ineffective at protecting midbrain dopaminergic neurons in cellular models of Parkinson’s disease. Mol Cell Neurosci. 2022;118:103684.

    Article  CAS  PubMed  Google Scholar 

  34. Lang AE, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59:459–66.

    Article  CAS  PubMed  Google Scholar 

  35. Luz M, Mohr E, Fibiger HC. GDNF-induced cerebellar toxicity: a brief review. Neurotoxicology. 2016;52:46–56.

    Article  CAS  PubMed  Google Scholar 

  36. Hovland DN Jr., et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys. Toxicol Pathol. 2007;35:676–92.

    Article  CAS  PubMed  Google Scholar 

  37. Hoane MR, et al. Differential in vivo effects of neurturin and glial cell-line-derived neurotrophic factor. Exp Neurol. 1999;160:235–43.

    Article  CAS  PubMed  Google Scholar 

  38. Su X, et al. Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum Gene Ther. 2009;20:1627–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen C, et al. Non-toxic HSC transplantation-based macrophage/microglia-mediated GDNF delivery for Parkinson’s disease. Mol Ther Methods Clin Dev. 2020;17:83–98.

    Article  CAS  PubMed  Google Scholar 

  40. He W, et al. Development of a synthetic promoter for macrophage gene therapy. Hum Gene Ther. 2006;17:949–59.

    Article  CAS  PubMed  Google Scholar 

  41. Biju K, et al. Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson’s disease. Mol Ther. 2010;18:1536–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhao Y, et al. GDNF-transfected macrophages produce potent neuroprotective effects in Parkinson’s disease mouse model. PLoS One. 2014;9:e106867.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Yokoi A, Ochiya T. Exosomes and extracellular vesicles: rethinking the essential values in cancer biology. Semin Cancer Biol. 2021;74:79–91.

    Article  CAS  PubMed  Google Scholar 

  44. Biju KC, et al. Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. Neurosci Lett. 2013;535:24–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen C, et al. GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice. Sci Rep. 2018;8:5460.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ge G, et al. Regulatable lentiviral hematopoietic stem cell gene therapy in a mouse model of Parkinson’s disease. Stem Cells Dev. 2018;27:995–1005.

    Article  CAS  PubMed  Google Scholar 

  47. Sterky FH, et al. Glial cell line-derived neurotrophic factor partially ameliorates motor symptoms without slowing neurodegeneration in mice with respiratory chain-deficient dopamine neurons. Cell Transpl. 2013;22:1529–39.

    Article  Google Scholar 

  48. Zhao Y, et al. GDNF-expressing macrophages restore motor functions at a severe late-stage, and produce long-term neuroprotective effects at an early-stage of Parkinson’s disease in transgenic Parkin Q311X(A) mice. J Control Release. 2019;315:139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Choi-Lundberg DL, et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science. 1997;275:838–41.

    Article  CAS  PubMed  Google Scholar 

  50. Connor B, et al. Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration. Exp Neurol. 2001;169:83–95.

    Article  CAS  PubMed  Google Scholar 

  51. Manfredsson FP, et al. Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector. Mol Ther. 2009;17:1857–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hudson J, et al. Glial cell line-derived neurotrophic factor augments midbrain dopaminergic circuits in vivo. Brain Res Bull. 1995;36:425–32.

    Article  CAS  PubMed  Google Scholar 

  53. Chu Y, Kordower JH. Post-mortem studies of neurturin gene therapy for Parkinson’s disease: two subjects with 10  years CERE120 delivery. Mov Disord. 2023;38:1728–36.

  54. Mueller KL, Hines PJ, Travis J. Neuroimmunology. Science. 2016;353:760–1.

    Article  CAS  PubMed  Google Scholar 

  55. Cartier N, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818–23.

    Article  CAS  PubMed  Google Scholar 

  56. Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc. 2007;2:141–51.

    Article  CAS  PubMed  Google Scholar 

  57. Huang D, et al. Long-term changes in the nigrostriatal pathway in the MPTP mouse model of Parkinson’s disease. Neuroscience. 2018;369:303–13.

    Article  CAS  PubMed  Google Scholar 

  58. Kanter J, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386:617–28.

    Article  CAS  PubMed  Google Scholar 

  59. Hayashi T, et al. Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects. FASEB J. 2012;26:4765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Paix A, et al. Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: a review. Crit Rev Oncol Hematol. 2018;123:138–48.

    Article  PubMed  Google Scholar 

  61. Sun L, et al. Dose-dependent decrease in anti-oxidant capacity of whole blood after irradiation: a novel potential marker for biodosimetry. Sci Rep. 2018;8:7425.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Sun L, et al. Total body irradiation causes a chronic decrease in antioxidant levels. Sci Rep. 2021;11:6716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Images were generated in the Core Optical Imaging Facility which is supported by UT Health San Antonio and NIH-NCI P30 CA54174. Flow cytometry data were generated in the Flow Cytometry Shared Resource at UT Health San Antonio which is supported by a grant from the National Cancer Institute (P30CA054174) to the Mays Cancer Center, a grant from the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210126), a grant from the National Institutes of Health (S10OD030432), and support from the Office of the Vice President for Research at UT Health San Antonio.

Funding

This study was supported by a Merit Review grant from the Department of Veterans Affairs Biomedical Laboratory Research & Development (5I01BX000737) and the Perry & Ruby Stevens Parkinson’s Disease Center of Excellence. Partial support was also provided by the Natural Science Foundation Project of Guizhou Provincial Science and Technology Department (Qiankehe Foundation-ZK 2024 General 182).

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Authors and Affiliations

  1. Audie L. Murphy VA Medical Center, 7400 Merton Minter Boulevard, San Antonio, TX, 78229, USA

    Guo Ge, Shujie Zhao, Qing Zhou, Jason C. O’Connor, Robert A. Clark & Senlin Li

  2. Department of Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA

    Guo Ge, Barath P. Sivasubramanian, Bill D. Geng, Shujie Zhao, Qing Zhou, Robert A. Clark & Senlin Li

  3. Department of Human Anatomy, School of Basic Medicine, Guizhou Medical University, Guian New Area, Guizhou, 550025, China

    Guo Ge

  4. Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Gang Huang

  5. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Jason C. O’Connor & Senlin Li

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  1. Guo Ge
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Contributions

Conceptualization: G.G. and S.L.; Investigation: G.G., B.P.S., B.D.G., S.Z. and Q.Z.; Formal Analysis: G.G., B.P.S., B.D.G., S.Z., Q.Z., G.H., J.C.O., R.A.C. and S.L.; Writing—Original Draft Preparation, G.G., B.P.S., B.D.G. and S.L.; Writing—Review & Editing, G.G., G.H., J.C.O., R.A.C. and S.L.; Supervision: S.L. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Senlin Li.

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This study was approved by the IACUC of the University of Texas Health Science Center at San Antonio (protocol 20140100AR).

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Ge, G., Sivasubramanian, B.P., Geng, B.D. et al. Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson’s disease. Gene Ther (2024). https://doi.org/10.1038/s41434-024-00451-3

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