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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
K
K
Oka
L
L
Pastore
I H
IH
Kim
A
A
Merched
S
S
Nomura
H J
HJ
Lee
M
M
Merched-Sauvage
C
C
Arden-Riley
B
B
Lee
M
M
Finegold
A
A
Beaudet
L
L
Chan
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