Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: A strategy for broad clinical application

Journal Article (Journal Article)

Delivery of genes that are larger than the wild-type adeno-associated virus (AAV) 4,681 nucleotide genome is inefficient using AAV vectors. We previously demonstrated in vitro that concurrent proteasome inhibitor (PI) treatment improves transduction by AAV vectors encoding oversized transgenes. In this study, an AAV vector with a 5.6 kilobase (kb) factor VIII expression cassette was used to test the effect of an US Food and Drug Administration-approved PI (bortezomib) treatment concurrent with vector delivery in vivo. Intrahepatic vector delivery resulted in factor VIII expression that persisted for 1 year in hemophilia mice. Single-dose bortezomib given with AAV2 or AAV8 factor VIII vector enhanced expression on average ∼600 and ∼300%, respectively. Moreover, coadministration of AAV8.canineFVIII (1 × 10 13 vg/kg) and bortezomib in hemophilia A dogs (n = 4) resulted in normalization of the whole blood clotting time (WBCT) and 90% reduction in hemorrhages for 32 months compared to untreated hemophilia A dogs (n = 3) or dogs administered vector alone (n = 3). Demonstration of long-term phenotypic correction of hemophilia A dogs with combination adjuvant bortezomib and AAV vector expressing the oversized transgene establishes preclinical studies that support testing in humans and provides a working paradigm to facilitate a significant expansion of therapeutic targets for human gene therapy. © 2010 The American Society of Gene & Cell Therapy.

Full Text

Duke Authors

Cited Authors

  • Monahan, PE; Lothrop, CD; Sun, J; Hirsch, ML; Kafri, T; Kantor, B; Sarkar, R; Tillson, DM; Elia, JR; Samulski, RJ

Published Date

  • January 1, 2010

Published In

Volume / Issue

  • 18 / 11

Start / End Page

  • 1907 - 1916

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1038/mt.2010.170

Citation Source

  • Scopus