A humanized mouse model for adeno-associated viral gene therapy

Area of Science:

• Gene Therapy
• Preclinical Research
• Mouse Models

Background:

• Clinical translation of adeno-associated virus (AAV)-mediated gene therapy is hindered by variable transduction efficiency in preclinical models.
• Developing reliable experimental models is crucial for predicting AAV gene transfer efficacy in humans.

Purpose of the Study:

• To develop a transgene-free mouse model that overcomes limitations in AAV gene therapy preclinical development.
• To create a model that allows for accurate prediction of AAV gene transfer efficiency in a human context.

Main Methods:

• Development of a human liver chimeric transgene-free Il2rg^-/-/Rag2^-/-/Fah^-/-/Aavr^-/- (TIRFA) mouse model.
• Ablation of the AAV receptor (AAVR) in murine cells to render them impermissive to AAV transduction.
• Comparison of AAV transduction efficiency in human liver chimeric TIRFA mice versus humanized mice with wild-type AAVR.

Main Results:

• TIRFA mice demonstrated increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to controls.
• AAV transduction was successfully shown in human teratoma-derived primary cells and liver cancer tissue using the TIRFA model.
• Mechanistic studies indicated AAVR's essential role as both an entry and intracellular receptor for AAV transduction.

Conclusions:

• The human liver chimeric TIRFA mouse model overcomes translational roadblocks in AAV gene therapy.
• This model enables accurate prediction of AAV gene transfer efficiency and facilitates the study of AAV vector biology in a preclinical human setting.
• The TIRFA model's versatility extends to various human cell types and tissues, including cancer.