Mechanistic Insights into the Enhancement of Adeno-Associated Virus Transduction by Proteasome Inhibitors |
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| Authors: | Angela M. Mitchell R. Jude Samulski |
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| Affiliation: | Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAa;Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAb;Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAc |
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| Abstract: | Proteasome inhibitors (e.g., bortezomib, MG132) are known to enhance adeno-associated virus (AAV) transduction; however, whether this results from pleotropic proteasome inhibition or off-target serine and/or cysteine protease inhibition remains unresolved. Here, we examined recombinant AAV (rAAV) effects of a new proteasome inhibitor, carfilzomib, which specifically inhibits chymotrypsin-like proteasome activity and no other proteases. We determined that proteasome inhibitors act on rAAV through proteasome inhibition and not serine or cysteine protease inhibition, likely through positive changes late in transduction. |
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