In utero allotransplantation of retrovirally transduced fetal hepatocytes in primates: feasibility and short-term follow-up.
In utero allotransplantation of fetal hepatocytes into a preimmune fetus could be used in early treatment of many inherited hepatic metabolic diseases. This study was designed to assess the tolerance to hepatocyte transplantation and to test the feasability and toxicity of such an injection in a primate model. Fetal hepatocytes were obtained from two 120-day-old Macaca mulatta fetuses and cryopreserved. They were thawed, cultured in vitro, and transduced with a recombinant retrovirus expressing beta-galactosidase. Transduction efficiency was 75-85%. Three unrelated fetuses (90, 100, and 104 days old) were each given 1-2 x 10(7) transduced cells via the umbilical vein. This caused vasospasm and severe bradycardia. Two fetuses died in the 48 hours after transplantation; the third survived and was killed at the end of gestation. No evidence of the infused cells was found. Three fetuses (90 days old) were, therefore, given 3-4 10(7) hepatocytes by direct intrahepatic injection. All the fetuses survived without side effect. Donor cells were not apparent from histochemical staining and PCR reactions. There was no evidence of inflammatory reaction. These findings indicate that the protocole could be improved by increasing the number of transplanted cells and using specific hepatic promoters in the retroviral vectors to achieve an effective postnatal chimerism.
Andreoletti
M
M
U380 INSERM, Paris, France.
LePercq
J
J
Loux
N
N
Beaudoin
S
S
Sacquin
P
P
Borgnon
J
J
Nguyen
T
T
Mahieu
D
D
Toubas
F
F
Di Rico
V
V
Farge
D
D
Franco
D
D
Briand
P
P
Hamza
J
J
Capron
F
F
Bargy
F
F
Weber
A
A
D000818:Animals; D017690:Cell Transplantation; D002478:Cells, Cultured; D015925:Cryopreservation; D005333:Fetus / Q000601:surgery*; D018014:Gene Transfer Techniques; D005819:Genetic Markers; D008099:Liver / Q000166:cytology / Q000196:embryology*; D016031:Liver Transplantation; D008253:Macaca mulatta; D012190:Retroviridae / Q000235:genetics*; D014184:Transplantation, Homologous; D014471:Umbilical Veins; D001616:beta-Galactosidase / Q000235:genetics
D005819:Genetic Markers; D001616:beta-Galactosidase