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AAV Capsid Modification and Its Influence on Viral Protein Stoichiometry and Packaging Fitness: Current Understandings and Future Direction.
Mol Biotechnol
January 2025
Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7700, South Africa.
The field of gene therapy has witnessed significant advancements in the utilization of Adeno-associated virus (AAV) owing to its inherent biological advantages. Targeted AAV vectors are generated through genetic or chemical modification of the capsid for user-directed purposes. However, this process can result in imbalances in viral protein sequence homogeneity, stoichiometry, and functional transduction vector units, thereby introducing new challenges.
View Article and Find Full Text PDFAAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.
Nat Biotechnol
January 2025
Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice.
View Article and Find Full Text PDFAAV vector transduction restriction and attenuated toxicity in hESCs via a rationally designed inverted terminal repeat.
Nucleic Acids Res
January 2025
Ophthalmology, University of North Carolina, 130 Mason Farm Rd, Chapel Hill, NC 27517, USA.
Adeno-associated virus (AAV) inverted terminal repeats (ITRs) induce p53-dependent apoptosis in human embryonic stem cells (hESCs). To interrogate this phenomenon, a synthetic ITR (SynITR), harboring substitutions in putative p53 binding sites was generated and evaluated for vector production and gene delivery. Replication of SynITR flanked transgenic genome was similar compared to wild type (wt) ITR, with a modest increase in vector titers.
View Article and Find Full Text PDFExtensive length and homology dependent chimerism in pool-packaged AAV libraries.
bioRxiv
January 2025
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Adeno-associated viruses (AAVs) have emerged as the foremost gene therapy delivery vehicles due to their versatility, durability, and safety profile. Here we demonstrate extensive chimerism, manifesting as pervasive barcode swapping, among complex AAV libraries that are packaged as a pool. The observed chimerism is length- and homology-dependent but capsid-independent, in some cases affecting the majority of packaged AAV genomes.
View Article and Find Full Text PDFKnockout of Pro-Apoptotic BAX and BAK1 Genes in HEK293T Cells Enhances Adeno-Associated Virus (AAV) Production: AAV2 and AAV9.
Biotechnol J
January 2025
Department of Biological Sciences, KAIST, Daejeon, Republic of Korea.
Increasing demand for adeno-associated virus (AAV) used in gene therapy highlights the need to enhance AAV production. When intracellular AAV2 and extracellular AAV9 were produced in HEK293T cells using the triple transfection method, apoptosis occurred during the AAV production. To mitigate apoptosis induced by AAV production, the pro-apoptotic BAX/BAK1 genes were knocked out in HEK293T cells.
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