Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

Abstract

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 À/À 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 helperdependent 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.

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

“…142,143 Two problems with the early viral vectors were the limited duration and amplitude of expression of the candidate gene, but progress in viral vectors has greatly improved performance in these 2 areas. 144 One major benefit of this approach is that a gene of interest can be introduced without the need for crossbreeding; however, a limitation is that the regression factor must be effective on predominately hepatic expression.…”

Gene Therapy Targeting LDL Cholesterol but not HDL Cholesterol Induces Regression of Advanced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia

“…Two weeks after treatment, plasma cholesterol levels in the HDAd-E-E3 group were 71 ± 8 mg/dL, whereas those in the HDAd-EW-E3 were 145± 24 mg/dL (p<0.001). Despite our experience with HDAd based on genomic fragments [11,19], HDAd containing APOE gene was not better in lowering cholesterol than those containing cDNA (HDAd-E-E3 vs. HDAd-gE3, Figure 2C). Therefore, we constructed HDAd-gE3 on the pΔ21 backbone (HDAd-gE3-D21).…”

Candidate SNP Markers of Chronopathologies Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

“…A keyword search yielded some data on a knockout mouse model (APOA1 −/− ) regarding the risk of atherosclerosis [78] which develops in postprandial flare-ups in diabetes [79]. For this reason, we propose the SNP “APOA1: -31A→C” as a candidate marker of this chronopathology.…”