Using antisense technology to develop a novel therapy for α-1 antitrypsin deficient (AATD) liver disease and to model AATD lung disease.

Rare Dis 2014 12;2:e28511. Epub 2014 Mar 12.

Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.

Alpha-1 antitrypsin (AAT) is a serum protease inhibitor that belongs to the serpin superfamily. Mutations in AAT are associated with α-1 antitrypsin deficiency (AATD), a rare genetic disease with two distinct manifestations: AATD lung disease and AATD liver disease. AATD lung disease is caused by loss-of-function of AAT and can be treated with plasma-derived AAT. AATD liver disease is due to the aggregation and retention of mutant AAT protein in the liver; the only treatment available for AATD liver disease is liver transplantation. Here we demonstrate that antisense oligonucleotides (ASOs) targeting human AAT efficiently reduce levels of both short and long human AAT transcript in vitro and in transgenic mice, providing a novel therapy for AATD liver disease. In addition, ASO-mediated depletion of mouse AAT may offer a useful animal model for the investigation of AATD lung disease.

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Source
http://www.tandfonline.com/doi/abs/10.4161/rdis.28511
Publisher Site
http://dx.doi.org/10.4161/rdis.28511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091453PMC
July 2014
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