Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following...

Area of Science:

• Gene therapy
• Immunology
• Virology

Background:

• Adeno-associated viral (AAV) vectors are crucial for gene therapy but face challenges like immune responses.
• T-cell mediated clearance of transduced cells can limit the long-term efficacy of AAV gene therapy.

Purpose of the Study:

• To investigate the potential of proteasome inhibitors to mitigate anti-AAV immune responses.
• To evaluate if bortezomib can enhance gene expression and reduce capsid antigen presentation by hepatocytes.

Main Methods:

• Utilized an AAV capsid-specific T-cell reporter (TCR) line to assess antigen presentation.
• Administered bortezomib, a proteasome inhibitor, to hepatocytes in vitro and in vivo.
• Measured Factor IX (FIX) expression from AAV vectors in mice.

Main Results:

• Bortezomib inhibited AAV capsid antigen presentation on hepatocytes at pharmacologic doses.
• Capsid antigen presentation was observed at low multiplicities of infection (MOIs).
• Bortezomib enhanced Factor IX expression from AAV2 vectors in mice but not AAV8 vectors.

Conclusions:

• Proteasome inhibition with bortezomib can decrease T-cell activation against AAV vectors.
• This strategy shows promise for improving liver-directed gene transfer by enhancing transduction and reducing immune-mediated clearance.
• Further research is needed to optimize this approach for various AAV serotypes and clinical applications.