Show simple item record

dc.contributor.authorMueller, Christian
dc.contributor.authorTang, Qiushi
dc.contributor.authorGruntman, Alisha M
dc.contributor.authorBlomenkamp, Keith S.
dc.contributor.authorTeckman, Jeffrey H.
dc.contributor.authorSong, Lina
dc.contributor.authorZamore, Phillip D.
dc.contributor.authorFlotte, Terence R.
dc.date2022-08-11T08:10:14.000
dc.date.accessioned2022-08-23T17:00:41Z
dc.date.available2022-08-23T17:00:41Z
dc.date.issued2012-01-17
dc.date.submitted2012-01-17
dc.identifier.citationMueller 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. <a href="http://dx.doi.org/10.1038/mt.2011.292">Link to article on publisher's website</a>
dc.identifier.doi10.1038/mt.2011.292
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43845
dc.description.abstractAlpha-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.
dc.language.isoen_US
dc.rights<p>This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy of this license, visit <a href="http://creativecommons.org/licenses/by-nc-nd/3.0/">http://creativecommons.org/licenses/by-nc-nd/3.0/</a></p>
dc.subjectDependovirus
dc.subjectGenetic Vectors
dc.subjectMicroRNAs
dc.subjectTransgenes
dc.subjectalpha 1-Antitrypsin Deficiency
dc.subjectLiver Diseases
dc.subjectNeurodegenerative Diseases
dc.subjectAllergy and Immunology
dc.subjectDigestive System Diseases
dc.subjectGenetics and Genomics
dc.subjectPediatrics
dc.titleSustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles
dc.typeJournal Article
dc.source.journaltitleMolecular Therapy
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1060&amp;context=peds_pulmonary&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_pulmonary/58
dc.identifier.contextkey2450614
refterms.dateFOA2022-08-23T17:00:41Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathpeds_pulmonary/58
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentDepartment of Pediatrics
dc.contributor.departmentGene Therapy Center


Files in this item

Thumbnail
Name:
mt2011292a.pdf
Size:
4.161Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record