Advancing AAV5-mediated gene therapy for brain and liver indications: preclinical assessment of biodistribution, efficacy and safety in animal models

Abstract

Monogenic diseases, which arise from mutations in a single gene, are ideal candidates for gene therapy, offering the potential for long-term therapeutic intervention. Gene therapy approaches, including gene silencing, gene replacement, and gene editing, have gained significant attention for treating genetic disorders. One of the most promising delivery systems for gene therapy is adeno-associated virus (AAV), which can target different organs, depending on the AAV serotype. AAVs have the ability to transduce dividing and non-dividing cells, show long-term stable gene expression and have a favorable safety profile and low immunogenicity. These characteristics can all be used to the advantage of gene therapy and make AAV unique to other delivery systems.

This thesis explores the potential of AAV5 gene therapy for three genetic disorders—hemophilia B, Fabry disease, and Huntington’s disease—aiming to advance it to clinical applications. The efficacy, biodistribution, and safety of AAV5 are assessed through various animal models, including mice, rats, and non-human primates (NHP), to evaluate therapeutic outcomes and identify potential risks. By focusing on these key aspects, the work aims to enhance the understanding and development of AAV-based therapies for these conditions. The potential for reducing the number of animals used in preclinical studies for future programs is further discussed in context of gene therapy.

In summary, this thesis investigates the potential of AAV5-based gene therapy across three different genetic diseases, examining preclinical models and demonstrating the efficacy, safety, and therapeutic potential of AAV5.