Xenotransplantation of porcine CTLA4-Ig+/+ neural precursors enables recovery of the locomotor activity in parkinsonian primates

Background: Transplantation of neural precursors from human embryos can restore the locomotor activity in Parkinsonian (PD) patients. The use of human embryos however is precluded for ethical and technical reasons. In this study we have investigated the clinical effects of transplanting in PD primates CTLA4-Ig+/+ or wild-type embryonic neural precursors of porcine origin. Methods: PD was induced in 17 non-human primates by repeated exposure to MPTP. Once stable lesions were obtained, PD monkeys were unilaterally injected in the left putamen with neural precursors from CTLA4-Ig+/+ (n=14) or wild type pig embryos (n=3). All primates were immunosuppressed using a clinically applicable immunosuppressive regimen (cyclosporin A, mycophenolate sodium and steroids) and monitored for clinical parameters. Xenograft survival and function was determined by clinical neurological assessment, analysis of locomotor function (Ethovision software), brain imaging (18F-L-DOPA PET scan) and histological studies at the end of each experiment. Results: Xenografted animals have been monitored for up to 739 days. In primates receiving CTLA4- Ig+/+ neuronal embryonic xenografts a recovery of spontaneous locomotion was observed. Partial restoration of dopaminergic activity was detected by PET scans in at least 9 primates. Histological analysis of the brain from clinically improved animals revealed the existence of a large porcine xenograft composed of dopaminergic, serotoninergic and GABAergic differentiated neurons and various glial components that were not observed in the control animals. In this context, no activation of the classical or alternative pathway of the complement cascade was observed. Conclusions: In this model, CTLA4-Ig+/+ expression protects graft from immune response injury allowing longterm survival and differentiation of transplanted porcine neural precursors. In each case, the presence of the CTLA4-Ig+/+ porcine graft was associated with significant improvement of locomotor activity in PD xenografted primates.