Alpha-1-Antitrypsin Gene Replacement Therapy Cures Emphysema in Mouse Model

A virus-like vector loaded with the gene for production of the enzyme alpha-1-antitrypsin (AAT) successfully established production of the protein in the lungs of mice serving as a model for human emphysema.

Alpha-1-antitrypsin protects tissues from enzymes of inflammatory cells, especially neutrophil elastase. In its absence (such as in alpha 1-antitrypsin deficiency or AATD), neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema, or COPD (chronic obstructive pulmonary disease) in adults and cirrhosis in adults or children.


Gene therapy to reinstate AAT production in emphysema patients has been considered as an attractive alternative to the current therapy regime of weekly intravenous infusion of the normal AAT protein.

In one approach to developing gene therapy for treatment of emphysema, investigators at Boston Medical College (MA, USA) used a lung-targeted adeno-associated virus (AAV) vector to transport the AAT gene (SERPINA1) to the lungs of mice serving as a model for the human disease.

The investigators reported in the June 29, 2016, online edition of the journal Molecular Therapy - Methods & Clinical Development that the genes delivered in a single injection of lung-directed AAV2/8 were able to achieve therapeutic AAT protein levels within the lung epithelial lining fluid, and that gene expression persisted for at least 52 weeks. Enzyme levels reached after AAT gene delivery were sufficient to relieve the severity of experimental emphysema in the mice. They also found that the same injection of AAV2/8 efficiently transduced liver cells, a finding that may have significance for AAV-based human gene therapy studies.

"These results support direct transgene delivery to the lung as a potential alternative approach to achieve the goal of developing a gene therapy for AATD," said senior author Dr. Andrew Wilson, assistant professor of medicine at Boston Medical College.

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