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Transcriptome-Wide Off-Target Effects of Steric-Blocking Oligonucleotides

Erle M. Holgersen, Shreshth Gandhi, Yongchao Zhou, Jinkuk Kim, Brandon Vaz, Jovanka Bogojeski, Magdalena Bugno, Zvi Shalev, Kahlin Cheung-Ong, João Gonçalves, Matthew O’Hara, Mark Sun, Boyko Kakaradov, Andrew Delong, Daniele Merico, Amit G. Deshwar
doi: https://doi.org/10.1101/2020.09.03.281667
Erle M. Holgersen
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Shreshth Gandhi
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Yongchao Zhou
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Jinkuk Kim
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Brandon Vaz
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Jovanka Bogojeski
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Magdalena Bugno
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
2The Hospital for Sick Children, Toronto, ON, Canada
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Zvi Shalev
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Kahlin Cheung-Ong
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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João Gonçalves
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Matthew O’Hara
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Mark Sun
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Boyko Kakaradov
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
3Skyhawk Therapeutics, Waltham, MA 02451, USA
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Andrew Delong
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Daniele Merico
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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Amit G. Deshwar
1Deep Genomics Inc., 661 University Avenue, MaRS Centre West Tower Suite 480, Toronto, ON M5G 1M1, Canada
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  • For correspondence: amit@deepgenomics.com
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Abstract

Steric-blocking oligonucleotides (SBOs) are short, single-stranded nucleic acids designed to modulate gene expression by binding to mRNA and blocking access from cellular machinery such as splicing factors. SBOs have the potential to bind to near-complementary sites in the transcriptome, causing off-target effects. In this study, we used RNA-seq to evaluate the off-target differential splicing events of 81 SBOs and differential expression events of 46 SBOs. Our results suggest that differential splicing events are predominantly hybridization-driven, while differential expression events are more common and driven by other mechanisms. We further evaluated the performance of in silico screens for off-target events, and found an edit distance cutoff of three to result in a sensitivity of 14% and false discovery rate of 99%. A machine learning model incorporating splicing predictions substantially improved the ability to prioritize low edit distance hits, increasing sensitivity from 4% to 26% at a fixed FDR. Despite these large improvements in performance, the approach does not detect the majority of events at a false discovery rate below 99%. Our results suggest that in silico methods are currently of limited use for predicting the off-target effects of SBOs.

Competing Interest Statement

All authors are current or former employees and shareholders in Deep Genomics Inc. Deep Genomics is developing steric-blocking oligonucleotide therapies.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 03, 2020.
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Transcriptome-Wide Off-Target Effects of Steric-Blocking Oligonucleotides
Erle M. Holgersen, Shreshth Gandhi, Yongchao Zhou, Jinkuk Kim, Brandon Vaz, Jovanka Bogojeski, Magdalena Bugno, Zvi Shalev, Kahlin Cheung-Ong, João Gonçalves, Matthew O’Hara, Mark Sun, Boyko Kakaradov, Andrew Delong, Daniele Merico, Amit G. Deshwar
bioRxiv 2020.09.03.281667; doi: https://doi.org/10.1101/2020.09.03.281667
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Transcriptome-Wide Off-Target Effects of Steric-Blocking Oligonucleotides
Erle M. Holgersen, Shreshth Gandhi, Yongchao Zhou, Jinkuk Kim, Brandon Vaz, Jovanka Bogojeski, Magdalena Bugno, Zvi Shalev, Kahlin Cheung-Ong, João Gonçalves, Matthew O’Hara, Mark Sun, Boyko Kakaradov, Andrew Delong, Daniele Merico, Amit G. Deshwar
bioRxiv 2020.09.03.281667; doi: https://doi.org/10.1101/2020.09.03.281667

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