Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice.
Mol Ther Methods Clin Dev
; 25: 425-438, 2022 Jun 09.
Article
em En
| MEDLINE
| ID: mdl-35592360
ABSTRACT
α1-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 α1-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 α1-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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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Mol Ther Methods Clin Dev
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos