Controllable neurotrophic expression offers hope for PD gene therapy

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Researchers at the University of Texas Health Science Center at San Antonio have demonstrated the potential of lentiviral hematopoietic stem cell gene therapy in modulating the expression of neurotrophic factor in Parkinson’s disease mice models.

Lentiviral delivery of glial cell line-derived neurotrophic factor (GDNF) has been reported to have neuroprotective effects in preclinical models of Parkinson’s disease (PD). However, evidences also show that long-term overexpression of GDNF is associated with side effects. Regulating gene expression is one of the major challenges for gene therapy in clinical trials.

To overcome this problem, Prof. Senlin Li and colleagues at the University of Texas Health Science Center at San Antonio developed a regulatable platform for controlled GDNF delivery in PD mice. They used a hematopoietic stem cell transplantation-based GDNF therapy platform to introduce a regulatable lentiviral vector (Tet-Off-hGDNF) in order to allow the expression of human GDNF to be increased or decreased by oral administration of doxycycline (Dox).

Healthy and PD mice were transplanted with bone marrow cells transduced with either the hGDNF-expressing vector or a corresponding GFP-expressing vector (control vector). MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection was used to create PD mice that showed nigral cell/striatal dopamine loss and behavioral deficits. Suppression of vector gene expression was achieved through administration of Dox in drinking water.

Results published in Stem Cells and Development showed basal plasma GDNF levels when Dox was administered in drinking water and elevated plasma GDNF levels during the absence of Dox, indicating the successful regulation of therapeutic gene expression. Motor activities of PD mice transduced with hGDNF-expressing vector were comparable to those of the healthy control mice group but was significantly better than those of the PD mice transduced with GFP-expressing vector. The improvement in motor activities and neuroprotection was sustained when Dox was withdrawn from PD mice transduced with hGDNF-expressing vector.

Together, these findings show that GDNF expression could be regulated; upregulated to achieve efficacy or downregulated to avoid off-target effects or adverse events. By adding this ‘regulatable’ feature to lentivirus-mediated hGDNF gene delivery system, the team is hopeful that the approach be used for PD therapy eventually.

Source: Ge G et al., Regulatable Lentiviral Hematopoietic Stem Cell Gene Therapy in a Mouse Model of Parkinson’s Disease. Stem Cells and Development, March 2018. DOI