Therapeutic approach to familial hypercholesterolemia by HVJ-liposomes in LDL receptor knockout mouse.
Familial hypercholesterolemia (FH) is an inherited disease in humans, which we have used as a model to develop a new strategy of gene therapy. This disease, which is due to mutation in the low density lipoprotein (LDL) receptor gene and results in deficiency of the LDL receptor, is associated with hypercholesterolemia and premature development of coronary heart disease. This disease has been identified as one of the target diseases for gene therapy, because a 50% reduction of cholesterol level would be beneficial in such patients. In this study, we examined the feasibility of gene therapy by the delivery of the human LDL receptor plasmid into the liver via the portal vein. For gene transfer we utilized HVJ-liposome method with which many successful gene transfers have been reported. Administration of the human LDL receptor plasmid by the HVJ-liposome method into the liver resulted in a decrease of total cholesterol level. Moreover, second administration of this gene two weeks after the first administration resulted in sustained lowering of total cholesterol level. Although single administration of plasmid by the HVJ-liposome method induced antibodies against HVJ, this antibody production did not affect gene expression following second administration. These results suggest the possibility of a novel repetitive gene therapy for FH, using human LDL receptor plasmid transfer directly into the liver by the HVJ-liposome method.
Department of General Medicine, Osaka University Hospital, Suita 565-0871, Japan. tomita@hp-gm.med.osaka-u.ac.jp
Naruya
N
Tomita
Ryuichi
R
Morishita
Hiromi
H
Koike
Masahide
M
Hashizume
Mitsue
M
Notake
Buichi
B
Fujitani
Yasufumi
Y
Kaneda
Masatsugu
M
Horiuchi
Toshio
T
Ogihara
D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000032:analysis / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D003673:Defective Viruses / Q000235:genetics*; D004334:Drug Administration Schedule; D004337:Drug Carriers; D005240:Feasibility Studies; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000235:genetics; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics / Q000628:therapy*; D007275:Injections, Intravenous; D008081:Liposomes; D008099:Liver; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011169:Portal Vein; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D029082:Sendai virus / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D004337:Drug Carriers; D024243:HMGB1 Protein; D008081:Liposomes; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D002784:Cholesterol; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase