Regulatable lentiviral hematopoietic stem cell gene therapy in a mouse model of Parkinson's disease

Guo Ge, Cang Chen, Michael J. Guderyon, Jingwei Liu, Zhixu He, Yanni Yu, Robert A Clark, Senlin Li

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Glial cell line-derived neurotrophic factor (GDNF) exhibits potent neuroprotective properties in preclinical models of Parkinson's disease (PD), but challenges in GDNF delivery have been reported from clinical trials. To address this barrier, we developed a hematopoietic stem cell transplantation-based macrophage-mediated GDNF therapy platform. Here, we introduced a regulatable lentiviral vector (LV-MSP-Tet-Off-hGDNF) to allow the expression of human GDNF (hGDNF) to be adjusted or stopped by oral administration of doxycycline (Dox). C57BL/6J mice were lethally irradiated with head protection and then transplanted with syngeneic bone marrow cells transduced with either the hGDNF-expressing vector or a corresponding GFP-expressing vector, LV-MSP-Tet-Off-GFP. Suppression of vector gene expression was achieved through administration of Dox in drinking water. To create a toxin-induced Parkinsonian model, mice were injected in two cycles with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to yield nigral cell/striatal dopamine loss and behavioral deficits. During the presence of Dox in the drinking water, plasma GDNF was at a basal level, whereas during the absence of Dox, plasma GDNF was significantly elevated, indicating reliable regulation of therapeutic gene expression. Midbrain GDNF levels were altered in parallel, although these did not return completely to basal levels during the periods of Dox withdrawal. Motor activities of the MPTP-Tet-off-hGDNF group were comparable to those of the Tet-off-GFP (subject to no MPTP treatment) group, but substantially better than those of the MPTP-Tet-off-GFP group. Interestingly, the improvement in motor activities was sustained during the Dox-withdrawn periods in MPTP-Tet-off-hGDNF animals. Neuroprotection by therapeutic GDNF expression was further evidenced by significant amelioration of nigral tyrosine hydroxylase loss after both the first and second MPTP treatment cycles. These data suggest that neurotrophic factor expression can be upregulated to achieve efficacy or downregulated in case of off-target effects or adverse events, a feature that may eventually increase the acceptance of this potentially neuroprotective/disease-modifying PD therapy.

Original languageEnglish (US)
Pages (from-to)995-1005
Number of pages11
JournalStem Cells and Development
Volume27
Issue number14
DOIs
StatePublished - Jul 15 2018

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Glial Cell Line-Derived Neurotrophic Factor
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Therapy
Parkinson Disease
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Doxycycline
Substantia Nigra
Drinking Water
Motor Activity
Therapeutics
Corpus Striatum
Hematopoietic Stem Cell Transplantation
Nerve Growth Factors
Gene Expression Regulation
Tyrosine 3-Monooxygenase
Mesencephalon
Inbred C57BL Mouse
Bone Marrow Cells
Oral Administration

Keywords

  • doxycycline
  • GDNF
  • hematopoietic stem cell
  • neurodegeneration
  • Parkinson's disease

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Regulatable lentiviral hematopoietic stem cell gene therapy in a mouse model of Parkinson's disease. / Ge, Guo; Chen, Cang; Guderyon, Michael J.; Liu, Jingwei; He, Zhixu; Yu, Yanni; Clark, Robert A; Li, Senlin.

In: Stem Cells and Development, Vol. 27, No. 14, 15.07.2018, p. 995-1005.

Research output: Contribution to journalArticle

Ge, Guo ; Chen, Cang ; Guderyon, Michael J. ; Liu, Jingwei ; He, Zhixu ; Yu, Yanni ; Clark, Robert A ; Li, Senlin. / Regulatable lentiviral hematopoietic stem cell gene therapy in a mouse model of Parkinson's disease. In: Stem Cells and Development. 2018 ; Vol. 27, No. 14. pp. 995-1005.
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