Long-term stable correction of low-density lipoprotein receptor-deficient mice with a helper-dependent adenoviral vector expressing the very low-density lipoprotein receptor.
BACKGROUND
Familial hypercholesterolemia (FH) that results from LDL receptor (LDLR) deficiency affects approximately 1 in 500 persons in the heterozygous state and approximately 1 in 1 million persons in the homozygous state. We tested a novel gene therapy strategy for the treatment of FH in a mouse model.


RESULTS
We delivered the VLDL receptor (VLDLR) to the liver of LDLR-deficient mice and compared the effect of a helper-dependent adenoviral vector with all viral coding sequences deleted (HD-Ad-mVLDLR) with a first-generation vector (FG-Ad-mVLDLR), an HD-Ad (HD-Ad-0) that contained no expression cassette, and dialysis buffer (DB). A single intravenous injection of HD-Ad-mVLDLR led to a lowering of plasma cholesterol that lasted >/=6 months. Acute liver toxicity (as measured with liver enzyme elevation) occurred after FG-Ad-mVLDLR but not after HD-Ad-mVLDLR, HD-Ad-0, or DB treatment. At 6 months, VLDLR was detected in the liver with Western blotting and with immunofluorescence staining only in HD-Ad-mVLDLR-treated mice. Aortic atherosclerosis was almost completely prevented in these animals.


CONCLUSIONS
HD-Ad-mediated intravenous delivery of VLDLR to hepatocytes is well tolerated. It produces long-term lowering of plasma cholesterol and prevents atherosclerosis development in LDLR-deficient mice. These data provide support for the feasibility and safety of this approach for therapy of human subjects.
Oka
K
K
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Pastore
L
L
Kim
I H
IH
Merched
A
A
Nomura
S
S
Lee
H J
HJ
Merched-Sauvage
M
M
Arden-Riley
C
C
Lee
B
B
Finegold
M
M
Beaudet
A
A
Chan
L
L
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002784:Cholesterol / Q000097:blood; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D006378:Helper Viruses / Q000235:genetics; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes / Q000235:genetics
D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C036053:VLDL receptor; D002784:Cholesterol