AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

• Published in: Experimental neurology Vol. 211; no. 1; pp. 252 - 258
• Main Authors: Elsworth, J.D., Redmond, D.E., Leranth, C., Bjugstad, K.B., Sladek, J.R., Collier, T.J., Foti, S.B., Samulski, R.J., Vives, K.P., Roth, R.H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-05-2008; Elsevier
• Subjects: Adeno-associated virus 2; Animals; Associated adenoviral vector (AAV); Biological and medical sciences; Cercopithecus aethiops; Corpus Striatum - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dependovirus - physiology; Disease Models, Animal; Dopamine; Dopamine - metabolism; Embryo, Mammalian; Fetal tissue; Fetal Tissue Transplantation - methods; Gene Transfer Techniques; Glial Cell Line-Derived Neurotrophic Factor - biosynthesis; Glial Cell Line-Derived Neurotrophic Factor - physiology; Glial derived neurotrophic factor (GDNF); Graft; Male; Medical sciences; Monkey; MPTP; MPTP Poisoning - pathology; MPTP Poisoning - surgery; Neurology; Parkinson's disease; Striatum; Time Factors; Transplantation; Tyrosine 3-Monooxygenase - metabolism; Striatum; Glial derived neurotrophic factor (GDNF); Dopamine; Parkinson's disease; Associated adenoviral vector (AAV); Monkey; Graft; Transplantation; MPTP; Fetal tissue; Parkinson disease; Primates; Glial cell line derived neurotrophic factor; Degenerative disease; Vector; Nervous system diseases; Implant; Catecholamine; Survival; Cerebral disorder; Vertebrata; Mammalia; Neuron; Animal; Central nervous system disease; Neurotransmitter; Extrapyramidal syndrome
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2008.01.026

Neural transplantation offers the potential of treating Parkinson's disease by grafting fetal dopamine neurons to depleted regions of the brain. However, clinical studies of neural grafting in Parkinson's disease have produced only modest improvements. One of the main reasons for this is the low survival rate of transplanted neurons. The inadequate supply of critical neurotrophic factors in the adult brain is likely to be a major cause of early cell death and restricted outgrowth of fetal grafts placed into the mature striatum. Glial derived neurotrophic factor (GDNF) is a potent neurotrophic factor that is crucial to the survival, outgrowth and maintenance of dopamine neurons, and so is a candidate for protecting grafted fetal dopamine neurons in the adult brain. We found that implantation of adeno-associated virus type 2 encoding GDNF (AAV2-GDNF) in the normal monkey caudate nucleus induced overexpression of GDNF that persisted for at least 6 months after injection. In a 6-month within-animal controlled study, AAV2-GDNF enhanced the survival of fetal dopamine neurons by 4-fold, and increased the outgrowth of grafted fetal dopamine neurons by almost 3-fold in the caudate nucleus of MPTP-treated monkeys, compared with control grafts in the other caudate nucleus. Thus, the addition of GDNF gene therapy to neural transplantation may be a useful strategy to improve treatment for Parkinson's disease.