Hepatocyte-directed gene transfer in vivo leads to transient improvement of hypercholesterolemia in low density lipoprotein receptor-deficient rabbits.
Familial hypercholesterolemia is an inherited disease in humans, caused by a deficiency of low density lipoprotein (LDL) receptors, that we have used as a model for developing liver-directed gene therapies. Our strategy is to reconstitute hepatic LDL receptor expression in vivo by administering a DNA-protein complex that is capable of targeting the delivery of functional LDL receptor genes to hepatocytes. Infusion of this DNA-protein complex into the peripheral circulation of a rabbit animal model for familial hypercholesterolemia resulted in hepatocyte-specific gene transfer and a temporary amelioration of hypercholesterolemia. This noninvasive approach to gene therapy should have applications in the treatment of a wide spectrum of human diseases.
Department of Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor 48109-0650.
J M
JM
Wilson
M
M
Grossman
C H
CH
Wu
N R
NR
Chowdhury
G Y
GY
Wu
J R
JR
Chowdhury
D000818:Animals; D004247:DNA / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000628:therapy; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D010957:Plasmids; D012313:RNA / Q000032:analysis; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D004268:DNA-Binding Proteins; D011973:Receptors, LDL; D011994:Recombinant Proteins; D012313:RNA; D004247:DNA