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    In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA

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    Authors
    Cruz, Pedro E.
    Mueller, Christian
    Cossette, Travis L.
    Golant, Alexandra
    Tang, Qiushi
    Beattie, Stuart G.
    Brantly, Mark
    Campbell-Thompson, Martha
    Blomenkamp, Keith S.
    Teckman, Jeffrey H.
    Flotte, Terence R.
    Show allShow less
    UMass Chan Affiliations
    Department of Pediatrics
    Gene Therapy Center
    Document Type
    Journal Article
    Publication Date
    2007-09-27
    Keywords
    Animals
    Cell Line, Tumor
    Dependovirus
    Disease Models, Animal
    Down-Regulation
    *Gene Therapy
    Genetic Vectors
    Hepatocytes
    Humans
    Mice
    Mice, Transgenic
    Polymorphism, Single Nucleotide
    *RNA Interference
    RNA, Small Interfering
    alpha 1-Antitrypsin
    alpha 1-Antitrypsin Deficiency
    Allergy and Immunology
    Genetics and Genomics
    Pediatrics
    Respiratory Tract Diseases
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    Link to Full Text
    http://dx.doi.org/10.1038/labinvest.3700629
    Abstract
    alpha-1 Antitrypsin (AAT) deficiency is one of the most common genetic diseases in North America, with a carrier frequency of approximately 4% in the US population. Homozygosity for the most common mutation (Glu342Lys, PI(*)Z) leads to the synthesis of a mutant protein, which accumulates and polymerizes within hepatocytes rather than being efficiently secreted. This lack of secretion causes severe serum deficiency predisposing to chronic lung disease. Twelve to fifteen percent of patients with PI(*)ZZ also develop liver disease, which can be severe, even in infancy. This is thought to be due to toxic effects of the accumulated mutant Z-AAT within the hepatocyte. Thus, an approach to reduce AAT-deficient liver disease will likely require some mechanism to decrease the amount of Z-AAT within hepatocytes. In this report, we describe studies of small-interfering RNAs (siRNAs) designed to downregulate endogenous AAT within hepatocytes. Three different siRNA sequences were identified and cloned into a recombinant adeno-associated virus (rAAV) backbone, either singly or as a trifunctional (3X) construct. Each had activity independently, but the levels of AAT expression in cell culture models showed the greatest decrease with the 3X construct, resulting in levels that were five-fold lower than controls. The rAAV-3X-siRNA was then packaged into AAV8 capsids and used in vivo to transduce the livers of human Z-AAT overexpressing transgenic mice. Those studies showed a decrease in total human AAT, a clearing of Z-AAT accumulation by immunohistochemistry, and a decrease in monomer Z-AAT within the liver within 3 weeks after vector injection. The rAAV8-3X-siRNA vector may hold promise as a potential therapy for patients with AAT liver disease.
    Source
    Lab Invest. 2007 Sep;87(9):893-902. Epub 2007 Jun 25. Link to article on publisher's site
    DOI
    10.1038/labinvest.3700629
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43797
    PubMed ID
    17592477
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1038/labinvest.3700629
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