GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice

• Published in: Scientific reports Vol. 8; no. 1; pp. 5460 - 16
• Main Authors: Chen, Cang, Li, Xiuhua, Ge, Guo, Liu, Jingwei, Biju, K. C., Laing, Suzette D., Qian, Yusheng, Ballard, Cori, He, Zhixu, Masliah, Eliezer, Clark, Robert A., O’Connor, Jason C., Li, Senlin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2018; Nature Publishing Group
• Subjects: 13/109; 13/44; 42; 42/100; 42/41; 631/378/1686; 64/60; 692/617/375/1718; Animal models; Animals; Basal ganglia; Blood-brain barrier; Bone marrow; Cell Line, Tumor; Cell Survival; Central nervous system; Central nervous system diseases; Dopamine; Dopaminergic Neurons - pathology; Gene Expression; Gene therapy; Genetic Therapy; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - genetics; Hematopoietic Stem Cell Transplantation; Humanities and Social Sciences; Humans; Hydroxylase; Inflammation; Irradiation; Macrophages; Macrophages - metabolism; Mice; Motor Activity - genetics; Movement disorders; multidisciplinary; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neuronal-glial interactions; Neurons; Neuroprotection; Neurotoxicity; Parkinson's disease; Parkinsonian Disorders - genetics; Parkinsonian Disorders - pathology; Parkinsonian Disorders - physiopathology; Parkinsonian Disorders - therapy; Radiation; Rodents; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Transplants & implants
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-23795-4

Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson’s disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model – the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD.