Immune Toxicities in AAV Gene Therapy: Overview for Clinicians

Area of Science:

• Immunology
• Molecular Biology
• Clinical Medicine

Background:

• Recombinant adeno-associated virus (rAAV) vectors are key for gene therapy of genetic disorders.
• Despite pre-clinical safety, clinical trials report severe adverse events like cytokine storms and organ toxicities.
• Immune responses against viral vectors and transgene products contribute to these toxicities.

Purpose of the Study:

• To review the mechanisms of immune toxicities associated with rAAV gene therapy.
• To discuss clinical syndromes and mitigation strategies for managing adverse events.
• To provide guidance for clinicians caring for gene therapy patients.

Main Methods:

• Literature review of pre-clinical and clinical studies on rAAV gene therapy.
• Analysis of immune responses (innate and adaptive) to rAAV vectors.
• Synthesis of reported adverse events and management strategies.

Main Results:

• AAV-associated toxicities stem from complex immune reactions to viral capsids and transgenes.
• Pre-existing anti-AAV immunity can exacerbate adverse events.
• Clinical care has evolved with immunomodulatory strategies to mitigate risks.

Conclusions:

• Understanding AAV immunotoxicities is crucial for safe gene therapy.
• Effective management requires recognizing specific syndromes and applying mitigation strategies.
• Continued research into immunomodulation will enhance the long-term success of gene therapies.