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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2006-09-07

AUTHORS

K Oka, L M Belalcazar, C Dieker, E A Nour, P Nuno-Gonzalez, A Paul, S Cormier, J-K Shin, M Finegold, L Chan

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−/− 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. More... »

PAGES

191-202

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.gt.3302819

DOI

http://dx.doi.org/10.1038/sj.gt.3302819

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1039263353

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16957769


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62 effect
63 efficacy
64 expression
65 first-generation vectors
66 gene delivery
67 genes
68 helper-dependent adenovirus vector
69 helper-dependent vectors
70 host response
71 human apolipoprotein A
72 human level
73 humoral response
74 hypoalphalipoproteinemia
75 investigation
76 levels
77 liver
78 long-term phenotypic correction
79 mRNA levels
80 mice
81 model
82 mouse model
83 normal human levels
84 number
85 phenotypic correction
86 plasma
87 plasma ApoA1 levels
88 plasma cholesterol levels
89 principles
90 promoter
91 proof
92 proof of principle
93 response
94 results
95 single treatment
96 titers
97 transgene cassette
98 transient appearance
99 treatment
100 vector
101 vector copy number
102 years
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