Transgene-induced cardiotoxicity in high-dose AAV gene transfer

Area of Science:

• Cardiology
• Molecular Biology
• Gene Therapy

Background:

• Adeno-associated virus (AAV) vectors show promise for treating monogenic diseases.
• High doses of AAV vectors have been linked to cytotoxicity and patient death.
• Cardiac symptoms have been observed in patients post-gene transfer.

Purpose of the Study:

• To investigate the cardiac effects of high-dose systemic AAV vector administration.
• To determine the relationship between transgene expression and observed cardiotoxicity.
• To evaluate strategies for preventing AAV-induced cardiotoxicity.

Main Methods:

• Systemic administration of high-dose AAV vectors expressing transgenes for Duchenne muscular dystrophy, γ-sarcoglycanopathy, and FKRP deficiency.
• Monitoring for cardiac symptoms and toxicity.
• Implementing and testing strategies to reduce or prevent cardiac transgene expression.
• Assessing safety in Non-Human Primates.

Main Results:

• High-dose AAV vector injections led to cardiotoxicity, linked to transgene expression.
• Strategies reducing cardiac transgene expression prevented cardiotoxicity.
• These preventative strategies were found to be safe in Non-Human Primates.
• Mechanisms involved stress cascade activation and cardiomyocyte death due to protein overload or dysfunction.

Conclusions:

• The heart is particularly sensitive to transgene expression during gene therapy.
• Controlling transgene expression in the heart is crucial for preventing AAV-induced cardiotoxicity.
• Developing methods for regulated gene expression is essential for safe and effective AAV-based gene therapies.