HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsThomas J Conlon, Travis Cossette, Kirsten Erger, Young-Kook Choi, Tracy Clarke, Marda Scott-Jorgensen, Sihong Song, Martha Campbell-Thompson, James Crawford, Terence R Flotte
JournalMolecular 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
PMID16085464 (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.)
Chemical References
  • alpha 1-Antitrypsin
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: