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Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation

SIMPLE SUMMARY: Splicing is an important mechanism by which precursor mRNA is modified into mature mRNA. This splicing plays a major role in the generation of different proteins required for cells. Cancer cells modulate this splicing in such a way that it facilitates uncontrolled growth and survival...

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Autores principales: Raguraman, Prithi, Balachandran, Akilandeswari Ashwini, Chen, Suxiang, Diermeier, Sarah D., Veedu, Rakesh N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583451/
https://www.ncbi.nlm.nih.gov/pubmed/34771719
http://dx.doi.org/10.3390/cancers13215555
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author Raguraman, Prithi
Balachandran, Akilandeswari Ashwini
Chen, Suxiang
Diermeier, Sarah D.
Veedu, Rakesh N.
author_facet Raguraman, Prithi
Balachandran, Akilandeswari Ashwini
Chen, Suxiang
Diermeier, Sarah D.
Veedu, Rakesh N.
author_sort Raguraman, Prithi
collection PubMed
description SIMPLE SUMMARY: Splicing is an important mechanism by which precursor mRNA is modified into mature mRNA. This splicing plays a major role in the generation of different proteins required for cells. Cancer cells modulate this splicing in such a way that it facilitates uncontrolled growth and survival. Cancer is one of the leading causes of death, and the therapies that are currently available also affect normal cells. Antisense oligonucleotides (AOs) are synthetic DNA/RNA that bind specifically to target mRNA and thereby have fewer off-target effects. These AOs have the potential to modulate the splicing mechanism. In this review, we will discuss the different modes of action of AOs and their potential in targeting cancer. ABSTRACT: Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer.
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spelling pubmed-85834512021-11-12 Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation Raguraman, Prithi Balachandran, Akilandeswari Ashwini Chen, Suxiang Diermeier, Sarah D. Veedu, Rakesh N. Cancers (Basel) Review SIMPLE SUMMARY: Splicing is an important mechanism by which precursor mRNA is modified into mature mRNA. This splicing plays a major role in the generation of different proteins required for cells. Cancer cells modulate this splicing in such a way that it facilitates uncontrolled growth and survival. Cancer is one of the leading causes of death, and the therapies that are currently available also affect normal cells. Antisense oligonucleotides (AOs) are synthetic DNA/RNA that bind specifically to target mRNA and thereby have fewer off-target effects. These AOs have the potential to modulate the splicing mechanism. In this review, we will discuss the different modes of action of AOs and their potential in targeting cancer. ABSTRACT: Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer. MDPI 2021-11-05 /pmc/articles/PMC8583451/ /pubmed/34771719 http://dx.doi.org/10.3390/cancers13215555 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Raguraman, Prithi
Balachandran, Akilandeswari Ashwini
Chen, Suxiang
Diermeier, Sarah D.
Veedu, Rakesh N.
Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
title Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
title_full Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
title_fullStr Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
title_full_unstemmed Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
title_short Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
title_sort antisense oligonucleotide-mediated splice switching: potential therapeutic approach for cancer mitigation
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583451/
https://www.ncbi.nlm.nih.gov/pubmed/34771719
http://dx.doi.org/10.3390/cancers13215555
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