The Role of Recombinant AAV in Precise Genome Editing

• Published in: Frontiers in genome editing Vol. 3; p. 799722
• Main Authors: Bijlani, Swati, Pang, Ka Ming, Sivanandam, Venkatesh, Singh, Amanpreet, Chatterjee, Saswati
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 13.01.2022
• Subjects: AAV; gene therapy; genetic diseases; Genome Editing; homologous recombination; rare diseases; genetic diseases; rare diseases; genome editing; gene therapy; homologous recombination; AAV
• ISSN: 2673-3439; 2673-3439
• DOI: 10.3389/fgeed.2021.799722

The replication-defective, non-pathogenic, nearly ubiquitous single-stranded adeno-associated viruses (AAVs) have gained importance since their discovery about 50 years ago. Their unique life cycle and virus-cell interactions have led to the development of recombinant AAVs as ideal genetic medicine tools that have evolved into effective commercialized gene therapies. A distinctive property of AAVs is their ability to edit the genome precisely. In contrast to all current genome editing platforms, AAV exclusively utilizes the high-fidelity homologous recombination (HR) pathway and does not require exogenous nucleases for prior cleavage of genomic DNA. Together, this leads to a highly precise editing outcome that preserves genomic integrity without incorporation of indel mutations or viral sequences at the target site while also obviating the possibility of off-target genotoxicity. The stem cell-derived AAV (AAVHSCs) were found to mediate precise and efficient HR with high on-target accuracy and at high efficiencies. AAVHSC editing occurs efficiently in post-mitotic cells and tissues in vivo . Additionally, AAV also has the advantage of an intrinsic delivery mechanism. Thus, this distinctive genome editing platform holds tremendous promise for the correction of disease-associated mutations without adding to the mutational burden. This review will focus on the unique properties of direct AAV-mediated genome editing and their potential mechanisms of action.