Proteasome Inhibitors Enhance Gene Delivery by AAV Virus Vectors Expressing Large Genomes in Hemophilia Mouse and Dog Models: A Strategy for Broad Clinical Application

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 t...

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Bibliographic Details
Published in:	Molecular therapy Vol. 18; no. 11; pp. 1907 - 1916
Main Authors:	Monahan, Paul E, Lothrop, Clinton D, Sun, Junjiang, Hirsch, Matthew L, Kafri, Tal, Kantor, Boris, Sarkar, Rita, Tillson, D Michael, Elia, Joseph R, Samulski, R Jude
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2010 Elsevier Limited Nature Publishing Group
Subjects:	Animals Blood Coagulation - drug effects Boronic Acids - pharmacology Bortezomib Cell Nucleus - metabolism Combined Modality Therapy Dependovirus - genetics Disease Models, Animal Dogs Drug dosages Efficiency Factor IX - physiology Factor VIII - physiology Female Gene therapy Genetic Therapy Genetic Vectors Genome, Viral Genomes Hemophilia Hemophilia B - genetics Hemophilia B - therapy Humans Liver - cytology Liver - drug effects Liver - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Original Protease Inhibitors - pharmacology Pyrazines - pharmacology Toxicity Transgenes - physiology Vectors (Biology) North Carolina Alabama United States > US
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Summary:	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 × 1013 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 P.E.M., C.D.L., and J.S. contributed equally to this work.
ISSN:	1525-0016 1525-0024
DOI:	10.1038/mt.2010.170