Splice-Switching Antisense Oligonucleotides as a Targeted Intrinsic Engineering Tool for Generating Armored Redirected T Cells

Splice-Switching Antisense Oligonucleotides as a Targeted Intrinsic Engineering Tool for Generating Armored Redirected T Cells
Title:
Splice-Switching Antisense Oligonucleotides as a Targeted Intrinsic Engineering Tool for Generating Armored Redirected T Cells
Other Titles:
Nucleic Acid Therapeutics
DOI:
10.1089/nat.2020.0905
Publication Date:
25 March 2021
Citation:
Ceccarello, E., Tabaglio, T., Koh, S., Oei, V., Teo, W., Jonathan, O. J., … Guccione, E. (2021). Splice-Switching Antisense Oligonucleotides as a Targeted Intrinsic Engineering Tool for Generating Armored Redirected T Cells. Nucleic Acid Therapeutics, 31(2), 145–154. doi:10.1089/nat.2020.0905
Abstract:
Modification of specificity of T cells for the use in adoptive transfer (CAR- or TCR-redirected T cells) has revolutionized the therapy of liquid tumors and some infectious diseases. However, several obstacles are still hampering the efficacy of such potent therapy, hence concurrent modification of the function is also required to obtain successful results. Here we show the use of splice-switching antisense oligonucleotides (SSOs) as a tool to transiently modify T cell function. We demonstrate the possibility to transfect SSOs and an exogenous TCR into primary human T cells in the same electroporation reaction, without affecting viability and function of the transfected T lymphocytes. Moreover, we show that SSOs targeting T cell-specific mRNAs induce the skipping of the targeted exons, and the reduction of the protein and consequent modification of T cell function. This technical work paves the way to the use of SSOs in immune cells, not only for the knockdown of the functional isoform of the targeted proteins, but also for the protein manipulation by elimination of specific domains encoded by targeted exons.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research is supported by core funding from: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research
Grant Reference no. :

This research / project is supported by the National Medical Research Council, Singapore - NMRC OFIRG
Grant Reference no. : NMRC/OFIRG/0032/2017

This research / project is supported by the National Research Foundation, Singapore - NRF CRP
Grant Reference no. : NRF-CRP17-2017-06

This research / project is supported by the MSSM Seed Funding - MSSM Seed Funding
Grant Reference no. :
Description:
ISSN:
2159-3337
2159-3345