Nontoxic hematopoietic stem cell transplantation-based macrophage/microglia-mediated GDNF delivery for Parkinson’s disease

Abstract 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 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 HSCT-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.