title: Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector.
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.
authors.affiliation: Department of Pediatrics and Powell Gene Therapy Center, University of Florida, Gainesville, FL 32608, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Travis
authors.initials: T
authors.lastname: Cossette
authors.forename: Kirsten
authors.initials: K
authors.lastname: Erger
authors.forename: Young-Kook
authors.initials: YK
authors.lastname: Choi
authors.forename: Tracy
authors.initials: T
authors.lastname: Clarke
authors.forename: Marda
authors.initials: M
authors.lastname: Scott-Jorgensen
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: James
authors.initials: J
authors.lastname: Crawford
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D011169:Portal Vein; D019076:Transgenes; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics / Q000628:therapy*
chemical_list: D000515:alpha 1-Antitrypsin