Glial cell-line-derived neurotrophic factor (
GDNF) is a potent
neuroprotective agent in cellular and animal models of
Parkinson's disease (PD). However, CNS delivery of
GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC)
transplantation-based macrophage-mediated gene delivery may provide a
solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven
GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with
granulocyte colony-stimulating factor (
G-CSF) and
AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven
transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased
GDNF levels in the midbrain. Macrophage
GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal
dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC
transplantation (HSCT)-based macrophage-mediated
GDNF gene delivery as a disease-modifying
therapy for PD.