Abstract |
alpha1-Antitrypsin (AAT) deficiency is a single-gene disorder in which a mutation in the AAT (approved symbol SERPINA1) gene (PI*Z) leads to misfolding of the protein, loss of the protective antiprotease effect of AAT for the lungs, and a toxic effect on hepatocytes. Optimal therapy for AAT deficiency will require a high percentage of hepatocyte transduction to be effective for liver and lung disease. Recently, rAAV genomes pseudotyped with capsids from serotypes 7 and 8 showed efficient hepatic transduction. We hypothesized that upon portal vein injection to target hepatocytes, serotype 8 would better transduce target cells and therefore express hAAT in both a greater percentage of cells and greater amounts. AAV2 and pseudotyped vectors for serotypes 1, 5, and 8 carrying the human AAT transgene were injected at 1 x 10(10) particle doses into C57Bl/6 mice. Circulating hAAT from AAV2/8-injected animals showed a 2-log advantage over AAV2 and 3-log increase over AAV2/1 and 5 for the 24-week study. Most significantly, up to 40% of total liver cells stained positive for the transgene in AAV2/8 subjects while remaining primarily episomal. Therefore, pseudotyped AAV8 provides a vehicle to infect a high percentage of hepatocytes stably and thereby express therapeutic molecules to modify AAT PiZ transcripts.
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Authors | Thomas J Conlon, Travis Cossette, Kirsten Erger, Young-Kook Choi, Tracy Clarke, Marda Scott-Jorgensen, Sihong Song, Martha Campbell-Thompson, James Crawford, Terence R Flotte |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 12
Issue 5
Pg. 867-75
(Nov 2005)
ISSN: 1525-0016 [Print] United States |
PMID | 16085464
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
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Topics |
- Animals
- Dependovirus
(genetics)
- Disease Models, Animal
- Female
- Gene Expression
- Genetic Therapy
- Genetic Vectors
(administration & dosage)
- Hepatocytes
(metabolism)
- Humans
- Injections, Intravenous
- Mice
- Mice, Inbred C57BL
(genetics)
- Portal Vein
- Transgenes
- alpha 1-Antitrypsin
(genetics, metabolism)
- alpha 1-Antitrypsin Deficiency
(genetics, therapy)
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