TY - JOUR
T1 - In vivo editing of the pan-endothelium by immunity evading simian adenoviral vector
AU - Lorincz, Reka
AU - Alvarez, Aluet Borrego
AU - Walkey, Christopher J.
AU - Mendonça, Samir A.
AU - Lu, Zhi Hong
AU - Martinez, Alexa E.
AU - Ljungberg, Cecilia
AU - Heaney, Jason D.
AU - Lagor, William R.
AU - Curiel, David T.
N1 - Funding Information:
We acknowledge the financial support from the National Institute for Health (1UG3TR002851–0). This work was initiated and completed as part of our involvement in the NIH Somatic Cell Genome Editing (SCGE) Consortium.
Funding Information:
This work was funded by NIH grants UG3 TR002851 awarded to D.T.C. This work was initiated and completed as part of our involvement in the NIH Somatic Cell Genome Editing (SCGE) Consortium.
Publisher Copyright:
© 2022
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - Gene editing of vascular endothelium
KW - Selective gene delivery
KW - Targeted nonhuman adenoviral vector
UR - http://www.scopus.com/inward/record.url?scp=85145287929&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2022.114189
DO - 10.1016/j.biopha.2022.114189
M3 - Article
C2 - 36587560
AN - SCOPUS:85145287929
SN - 0753-3322
VL - 158
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 114189
ER -