Immune responses to AAV in clinical trials

Area of Science:

• Immunology
• Gene Therapy
• Hepatology

Background:

• Adeno-associated virus (AAV) vectors are used for gene therapy.
• Pre-existing CD8(+) T cell responses to AAV capsid were observed in humans.
• Clinical trials revealed immune-mediated rejection of AAV-transduced hepatocytes.

Purpose of the Study:

• Investigate the cause of transient liver enzyme elevation after AAV gene transfer.
• Understand the role of capsid-specific CD8(+) T cells in AAV gene therapy outcomes.
• Explore strategies to mitigate immune responses in AAV-based liver gene therapy.

Main Methods:

• Analysis of liver enzyme levels in human subjects receiving AAV gene transfer.
• Characterization of T cell populations in healthy donors and trial participants.
• Evaluation of competing hypotheses for AAV-mediated immune responses.

Main Results:

• Two subjects showed transient liver enzyme elevation post-AAV gene transfer.
• Immune rejection of transduced hepatocytes was mediated by AAV capsid-specific CD8(+) T cells.
• Emerging data do not support alternative hypotheses for AAV immune responses.

Conclusions:

• Pre-existing T cell immunity to AAV capsid is a significant factor in gene therapy efficacy.
• Strategies like short-term immunosuppression or lower-dose vectors may overcome immune barriers.
• Monitoring immune responses is crucial for advancing AAV gene therapy in humans.