We are upgrading the repository! A content freeze is in effect until December 6, 2024. New submissions or changes to existing items will not be allowed during this period. All content already published will remain publicly available for searching and downloading. Updates will be posted in the Website Upgrade 2024 FAQ in the sidebar Help menu. Reach out to escholarship@umassmed.edu with any questions.
Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles
Authors
Mueller, ChristianTang, Qiushi
Gruntman, Alisha M
Blomenkamp, Keith S.
Teckman, Jeffrey H.
Song, Lina
Zamore, Phillip D.
Flotte, Terence R.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDepartment of Pediatrics
Gene Therapy Center
Document Type
Journal ArticlePublication Date
2012-01-17Keywords
DependovirusGenetic Vectors
MicroRNAs
Transgenes
alpha 1-Antitrypsin Deficiency
Liver Diseases
Neurodegenerative Diseases
Allergy and Immunology
Digestive System Diseases
Genetics and Genomics
Pediatrics
Metadata
Show full item recordAbstract
Alpha-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently reduced by an average of 80%. Treated animals showed knockdown of Z-AAT in liver and serum with concomitant increased serum M-AAT as determined by allele-specific enzyme-linked immunosorbent assays (ELISAs). In addition, decreased globular accumulation of misfolded Z-AAT in hepatocytes and a reduction in inflammatory infiltrates in the liver was observed. Results from microarray studies demonstrate that endogenous miRNAs were minimally affected by this treatment. These data suggests that miRNA mediated knockdown does not saturate the miRNA pathway as has been seen with viral vector expression of short hairpin RNAs (shRNAs). This safe dual-therapy approach can be applied to other disorders such as amyotrophic lateral sclerosis, Huntington disease, cerebral ataxia, and optic atrophies.Source
Mueller C, Tang Q, Gruntman A, Blomenkamp K, Teckman J, Song L, Zamore PD, Flotte TR. Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles. Molecular Therapy (2012); doi:10.1038/mt.2011.292. Link to article on publisher's websiteDOI
10.1038/mt.2011.292Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43845Rights
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
ae974a485f413a2113503eed53cd6c53
10.1038/mt.2011.292