Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector.
We examined the efficacy and host response to the adenovirus (Ad)-mediated delivery of human apolipoprotein A-I (APOA1) gene to the liver of APOA1(-/-) mice. Administration of a first-generation vector (FGAd-AI) resulted in a transient appearance of APOA1 in plasma and induced an anti-APOA1 antibody titer, whereas treatment with a helper-dependent vector (HDAd-AI) resulted in sustained APOA1 expression without inducing an antibody titer. With these results, we studied the effects of FGAd vectors on APOAI expression by HDAd-AI vector. Co-treatment with an FGAd vector inhibited HDAd-AI- mediated APOA1 expression independent of transgene cassettes, but only FGAd-AI induced a humoral response. Furthermore, APOA1 mRNA levels in mice co-treated with FGAd vectors were much lower than those expected from the vector copy number, suggesting that DNA of FGAd vectors interferes with the HDAd-AI vector's APOA1 promoter. A single treatment with an HDAd-AI vector produced a supraphysiological plasma APOA1 level that gradually declined to about half the normal human level over the course of 2 years, associated with a plasma cholesterol level that is persistently higher than that in controls. This investigation provides the proof of principle that liver-directed HDAd gene delivery is effective for the long-term phenotypic correction of monogenic hypoalphalipoproteinemia.
Oka
K
K
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. kazuhiro@bcm.tmc.edu
Belalcazar
L M
LM
Dieker
C
C
Nour
E A
EA
Nuno-Gonzalez
P
P
Paul
A
A
Cormier
S
S
Shin
J-K
JK
Finegold
M
M
Chan
L
L
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D016632:Apolipoprotein A-I / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D002784:Cholesterol / Q000097:blood; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D006378:Helper Viruses / Q000235:genetics*; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D007267:Injections; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010641:Phenotype; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes; D019562:Viral Load
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D001323:Autoantibodies; D002784:Cholesterol