Engineering Cardiotropic Vectors: Directed Evolution of AAVs for Targeted Gene Therapy

The emergence of adeno-associated viral (AAV) vectors has revolutionized the field of gene therapy for treatment of genetic disorders. These viral vectors are favored due to their non-pathogenic nature in humans and comparably low immunogenicity. Furthermore, AAVs offer several key strengths such as the transduction of both dividing and non-dividing cells, persistence as episomal DNA without spontaneous integration into the host genome, and a versatile tissue tropism enabled by a wide array of serotypes. These attributes have paved the way to the approval of seven AAV-based gene therapies to treat human diseases over the past decade. Cardiovascular diseases remain the leading cause of mortality worldwide emphasizing the necessity for innovative treatment strategies. While cardiomyopathies and heart failure often have heterogenous, nonhereditary origins, they can be linked to related pathogenic gene mutations, making them prime candidates as targets for AAV-based gene therapy. However, transduction of cardiomyocytes in larger organisms is challenging using existing AAV vectors indicating the need for improved vectors. Therefore, the bioengineering of AAV capsids and genomes has been introduced as attractive approach for generating AAVs with novel properties.
This dissertation makes pivotal contributions to the fields of AAV engineering and AAV-based gene therapy. The AAV vectors developed here represent a valuable expansion of the cardiac AAV toolkit, poised to facilitate cardiac research, particularly in cell culture and murine models. Further experimental validation in mammalian models is warranted to fully assess the efficacy, safety, and broader applicability of these novel vectors. Ultimately, these AAV variants hold the potential for advancing into preclinical or clinical studies, addressing the critical need for cardiotropic gene delivery systems to treat a wide range of cardiac disorders

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Zitierform:
Hüttermann, L., 2024. Engineering Cardiotropic Vectors: Directed Evolution of AAVs for Targeted Gene Therapy.
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