期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 25, 期 -, 页码 425-438出版社
CELL PRESS
DOI: 10.1016/j.omtm.2022.04.003
关键词
-
资金
- Alpha-1 Foundation
- National Institutes of Health grant [PO1H2131471]
This study demonstrates that gene therapy can be used to treat alpha(1)-antitrypsin deficiency, improving lung disease progression and restoring lung tissue elasticity and alveolar wall integrity.
alpha(1)-antitrypsin deficiency is a rare genetic condition that can cause liver and/or lung disease. There is currently no cure for this disorder, although repeated infusions of plasma-purified protein may slow down emphysema progression. Gene therapy in which a single recombinant adeno-associated viral vector (rAAV) administration would lead to sustained protein expression could therefore similarly affect disease progression, and provide the added benefits of reducing treatment burden and thereby improving the patient's quality of life. The study presented here tests whether treating the Serpina1a-e knockout mouse model of alpha(1)-antitrypsin-deficiency lung disease with gene therapy would have an impact on the disease course, either on spontaneous disease caused by aging or on accelerated disease caused by exposure to cigarette smoke. Liver-directed gene therapy led to dose-dependent levels of biologically active human alpha(1)-antitrypsin protein. Furthermore, decreased lung compliance and increased elastic recoil indicate that treated mice had largely preserved lung tissue elasticity and alveolar wall integrity compared with untreated mice. rAAV-mediated gene augmentation is therefore able to compensate for the loss of function and restore a beneficial lung protease-antiprotease balance. This work constitutes a preclinical study report of a disease-modifying treatment in the Serpina1a-e knockout mouse model using a liver-specific rAAV serotype 8 capsid.
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