Adeno-associated Virus (AAV) versus Immune Response.

Area of Science:

• Biomedical Engineering
• Gene Therapy
• Neuroscience

Background:

• Friedmann and Roblin identified key gene therapy barriers: tissue targeting, blood-brain barrier (BBB) crossing, and immune responses.
• These challenges persist, hindering the clinical translation of gene therapy, particularly for neurological applications.

Purpose of the Study:

• To review recent advances in overcoming gene therapy barriers, focusing on adeno-associated virus (AAV) engineering.
• To discuss strategies for improving tissue targeting, BBB penetration, and modulating immune responses to AAV vectors.

Main Methods:

• Analysis of structural data of AAV serotypes and antibody epitopes.
• Engineering of AAV capsids to alter tropism, reduce ubiquitination, and enhance BBB passage.
• Review of studies on immune responses to high-dose recombinant AAV (rAAV) in preclinical and clinical settings.

Main Results:

• AAV capsid engineering has enabled redirection of tissue tropism and improved BBB permeability.
• Enhanced understanding of host immune responses to rAAV in various models.
• Development of strategies to modulate immune responses against AAV vectors.

Conclusions:

• Significant progress has been made in engineering AAV vectors to address long-standing gene therapy challenges.
• While immune responses to rAAV remain a hurdle, a better understanding facilitates the development of experimental solutions.
• Continued research into AAV engineering and immunomodulation is crucial for advancing gene therapy.