University of Massachusetts Medical School Faculty Publications


Gene-based therapy for alpha-1 antitrypsin deficiency

UMMS Affiliation

Gene Therapy Center; Department of Pediatrics

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alpha 1-Antitrypsin Deficiency; Genetic Therapy


Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Digestive System Diseases | Molecular Genetics | Respiratory Tract Diseases | Therapeutics


Alpha-1 antitrypsin Deficiency (AATD) has been an attractive target for the development of gene therapy because it is a common single gene disorder, for which there would appear to be significant benefit to be gained for lung disease patients by augmentation of plasma levels of wild-type (M) alpha-1 antitrypsin (AAT). While a significant proportion of patients also have liver disease, which is unlikely to be benefitted by augmentation, the potential to treat or prevent lung disease by replacement of plasma levels to at least 11 microMolar (571 mcg/ml) is the basis upon which several protein replacement therapies have been licensed for human use. Further enhancing the likelihood of success of gene therapy is the fact that the AAT coding sequence is relatively short and the protein appears to function primarily in the plasma and extracellular space. This means that AAT production from any cell or tissue capable of secreting it could be useful therapeutically for augmentation. Based on these considerations, attempts have been made to develop AAT therapies using nonviral gene transfer, gammaretrovirus, recombinant adenovirus (rAd), and recombinant adeno-associated virus (rAAV) vectors. These have resulted in three phase I clinical trials (one of cationic liposome, one of rAAV2, and one of rAAV1) and one phase II clinical trial (with rAAV1). The results of the latter trial, while promising, demonstrated levels were only 3 to 5% of the target range. This indicates the need to further increase the dose of the vector and/or to increase the levels to within the therapeutic range.

DOI of Published Version



COPD. 2013 Mar;10 Suppl 1:44-9. doi: 10.3109/15412555.2013.764978. Link to article on publisher's site

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