Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes

Area of Science:

• Gene therapy
• Viral vectors
• Pulmonary medicine

Background:

• Adeno-associated virus type 2 (AAV2) vectors are used for gene transfer in the lung.
• Gene expression from AAV2 vectors can be transient and repeated administration is often blocked by neutralizing antibodies.

Purpose of the Study:

• To investigate the potential of AAV2 vectors pseudotyped with AAV serotypes 2, 3, and 6 for readministration in the mouse lung.
• To evaluate the immunogenicity and cross-reactivity of different AAV serotypes for lung gene therapy.

Main Methods:

• Mice received primary administration of AAV2, AAV3, or AAV6 vectors.
• Subsequent administration of AAV2 or AAV6 pseudotyped vectors was performed to assess transduction rates.
• Sera from mice and humans were analyzed for neutralizing antibodies against AAV2 and AAV6.

Main Results:

• AAV6 vectors transduced lung cells effectively, similar to AAV2 vectors, while AAV3 vectors showed lower transduction rates.
• Prior administration of AAV2 or AAV3 vectors did not impede AAV6 vector transduction, indicating no cross-neutralization.
• Prior AAV2 administration blocked subsequent AAV2 vector transduction, but AAV6 administration only partially inhibited subsequent AAV6 vector transduction.
• AAV6 was found to be less immunogenic than AAV2 in both mice and humans.

Conclusions:

• AAV6 pseudotype vectors are suitable for readministration in the lung, even after prior exposure to AAV2 or AAV3 vectors.
• The reduced immunogenicity of AAV6 compared to AAV2 supports its development for sustained lung gene therapy.
• AAV6 vectors can be used alone or in combination with AAV2 vectors for improved gene therapy outcomes in the lung.