Portal branch occlusion safely facilitates in vivo retroviral vector transduction of rat liver.
Hepatic gene therapy might correct the clinical manifestations of several genetic disorders in patients. Although retroviral vectors with a strong liver-specific promoter can result in stable and therapeutic levels of expression of genes from the liver, application of these techniques in humans is limited by the need to perform one or more invasive procedures to achieve ex vivo or in vivo transduction of hepatocytes. In vivo delivery involves injection of retrovirus into the portal vein during liver regeneration. Although transduction is efficient and specific for the liver, induction of hepatocyte replication requires a 70% partial hepatectomy or administration of a liver toxin. An alternative method for inducing hepatocyte replication is to occlude branches of the portal vein. This results in apoptosis of hepatocytes in the occluded lobes and compensatory replication of the hepatocytes in the nonoccluded lobes. We demonstrate here that portal branch occlusion is nearly as effective as partial hepatectomy at facilitating retroviral vector transduction in vivo and has a lower morbidity. Portal branch occlusion could be performed in larger animals by minimally invasive techniques and has been used safely to treat human patients with liver cancer. Portal branch occlusion might ultimately be used in humans to facilitate retroviral vector transduction in vivo for the treatment of genetic diseases.
Bowling
W M
WM
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kennedy
S C
SC
Cai
S R
SR
Duncan
J R
JR
Gao
C
C
Flye
M W
MW
Ponder
K P
KP
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics*; D006498:Hepatectomy; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000098:blood supply* / Q000166:cytology / Q000821:virology; D008115:Liver Regeneration / Q000235:genetics; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D012190:Retroviridae / Q000235:genetics*; D014118:Toxins, Biological / Q000494:pharmacology; D014162:Transfection / Q000379:methods*
D014118:Toxins, Biological; D000410:Alanine Transaminase