Gene augmentation therapy could restore a beneficial lung protease-antiprotease balance in alpha-1 antitrypsin deficiency (AATD), according to a new study published in Molecular Therapy: Methods & Clinical Development.

There is currently no cure for AATD. The disease is caused by a mutation in the SERPINA1 gene leading to a disruption in the normal production of alpha-1 antitrypsin (AAT) protein. AAT is essential for the protection of lung tissue from the damaging effect of neutrophil elastase, and the progression of the disease may be slowed with plasma-purified AAT but this requires repeated infusions, which can have a negative impact on patients’ quality of life.

Gene therapy for AATD involves the transfer of the gene encoding AAT to the body using a recombinant adeno-associated virus (rAAV).

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Here, a team of researchers led by Christian Mueller, PhD, treated a Serpina1a-e knockout mouse with gene therapy to see whether this approach could have an impact on disease course whether it is caused by aging or exposure to cigarette smoke.

Read more about gene therapy and other experimental therapies for AATD

They found that gene therapy directed to the liver resulted in biologically active human AAT protein being expressed in the liver of the animals in a dose-dependent manner. Not only that, gene therapy led to a decrease in lung compliance and an increase in elastic recoil.

This indicates that the treatment preserved the elasticity of the animals’ lung tissue and the integrity of their alveolar walls, the researchers said. “rAAV-mediated gene augmentation is therefore able to compensate for the loss of function.”

“This work constitutes preclinical study report of a disease-modifying treatment in Serpina1a-e knockout mouse model using liver-specific rAAV serotype 8 capsid,” they concluded.


Zieger M, Borel F, Greer C, et al. Liver-directed SERPINA1 gene augmentation therapy attenuates progression of spontaneous and tobacco smoke induced emphysema in alpha1-antitrypsin null mice. Mol Ther Methods Clin Dev. Published online April 13, 2022. doi:10.1016/j.omtm.2022.04.003