Language
English
Publication Date
2-1-2023
Journal
Biomedicine & Pharmacotherapy
DOI
10.1016/j.biopha.2022.114189
PMID
36587560
Abstract
Biological applications deriving from the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 site-specific nuclease system continue to impact and accelerate gene therapy strategies. Safe and effective in vivo co-delivery of the CRISPR/Cas9 system to target somatic cells is essential in the clinical therapeutic context. Both non-viral and viral vector systems have been applied for this delivery matter. Despite elegant proof-of-principle studies, available vector technologies still face challenges that restrict the application of CRISPR/Cas9-facilitated gene therapy. Of note, the mandated co-delivery of the gene-editing components must be accomplished in the potential presence of pre-formed anti-vector immunity. Additionally, methods must be sought to limit the potential of off-target editing. To this end, we have exploited the molecular promiscuities of adenovirus (Ad) to address the key requirements of CRISPR/Cas9-facilitated gene therapy. In this regard, we have endeavored capsid engineering of a simian (chimpanzee) adenovirus isolate 36 (SAd36) to achieve targeted modifications of vector tropism. The SAd36 vector with the myeloid cell-binding peptide (MBP) incorporated in the capsid has allowed selective in vivo modifications of the vascular endothelium. Importantly, vascular endothelium can serve as an effective non-hepatic cellular source of deficient serum factors relevant to several inherited genetic disorders. In addition to allowing for re-directed tropism, capsid engineering of nonhuman primate Ads provide the means to circumvent pre-formed vector immunity. Herein we have generated a SAd36. MBP vector that can serve as a single intravenously administered agent allowing effective and selective in vivo editing for endothelial target cells of the mouse spleen, brain and kidney. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Keywords
Animals, Mice, CRISPR-Cas Systems, Gene Editing, Genetic Vectors, Genetic Therapy, Adenoviridae, Capsid Proteins, Endothelium, Gene editing of vascular endothelium, Selective gene delivery, Targeted nonhuman adenoviral vector.
Published Open-Access
yes
Recommended Citation
Lorincz, Reka; Alvarez, Aluet Borrego; Walkey, Christopher J; et al., "In Vivo Editing of the Pan-Endothelium by Immunity Evading Simian Adenoviral Vector" (2023). Faculty and Staff Publications. 3986.
https://digitalcommons.library.tmc.edu/baylor_docs/3986