Complications of a trophic xenotransplant approach in parkinsonian monkeys.
Various restorative cell transplantation strategies have been investigated to substitute for lost dopamine (DA) neurons or to enhance DA synthesis in Parkinson's disease. Intracerebral implantation of engineered cells encapsulated in a semipermeable polymer membrane constitutes one way to deliver bioactive substances unable to cross the blood-brain barrier while avoiding the need for long-term immunosuppression. Glial cell line-derived neurotrophic factor (GDNF) has shown trophic effects on DA neurons but effective and sustained delivery within the brain parenchyma remains problematic. The long-term efficacy and late complications of a xenotransplant approach utilizing GDNF-expressing encapsulated baby hamster kidney (BHK) cells were examined. Each of five MPTP-lesioned parkinsonian cynomolgus monkeys received five devices containing active or inert cells grafted bilaterally in the striatum in a two-stage procedure 9 months apart and animals were sacrificed 4 months later for analyses. No definite motor benefit was observed, DA levels were comparable between GDNF- and control cell-implanted striata, and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra showed no consistent recovery. Cell viability and GDNF synthesis in the explanted devices were negligible. The brain tissue surrounding all implants showed an intense immune reaction with prominent "foreign body" inflammatory infiltrates. Membrane biophysics, the cell type used, and the extended period of time the devices remained in situ may have contributed to the negative outcome and should be addressed in future investigations using this approach.
Blanchet
Pierre J
PJ
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Konitsiotis
Spiros
S
Mochizuki
Hideki
H
Pluta
Ryszard
R
Emerich
Dwaine F
DF
Chase
Thomas N
TN
Mouradian
M Maral
MM
D000818:Animals; D001812:Blood-Brain Barrier; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D005260:Female; D005549:Foreign-Body Reaction; D005818:Genetic Engineering; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007249:Inflammation; D007668:Kidney / Q000166:cytology; D008252:Macaca fascicularis; D008297:Male; D008567:Membranes, Artificial; D009043:Motor Activity; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010300:Parkinson Disease / Q000628:therapy* / Q000662:veterinary; D010539:Permeability; D011108:Polymers; D014183:Transplantation, Heterologous / Q000009:adverse effects*
D051100:Glial Cell Line-Derived Neurotrophic Factor; D008567:Membranes, Artificial; D009414:Nerve Growth Factors; D011108:Polymers; D004298:Dopamine