Abstract
Simple SummarySplicing 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.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.
Highlights
RNA splicing is a form of RNA processing in which a freshly made precursor messenger RNA is transformed into a mature mRNA
Antisense oligonucleotides (AOs) that induce RNase H-mediated mRNA degradation have been widely used for downregulation of oncogenes [11,17,18]; this review focuses primarily on six distinct studies that use AO-mediated splice modulation as a therapeutic strategy, with a discussion of different chemical modifications used and delivery strategies employed
The AO treatment reduced tumor growth [85]. This shows that the use of Locked nucleic acid (LNA) targeting exon 26 of human epidermal growth factor receptor 4 (HER4) could be explored as a therapeutic strategy
Summary
RNA splicing is a form of RNA processing in which a freshly made precursor messenger RNA (pre-mRNA, or primary transcript) is transformed into a mature mRNA. ((AA)) NNoorrmmaall ggeennee eexxpprreessssiioonn pprroocceessss;; ((BB)) AAOO--iinndduucceedd RRNNaassee HH--mmeeddiiaatteeddmmRRNNAAddeeggraraddaatitoionn; (;C(C) A) AOO-in-idnudcuecdedtratrnasnlastliaotnioanl arel prerepsrseisosnio; n(D; ()DA)OA-iOnd-iuncdeudcespdliscpelimceodmuoladtuiolant;io(En); (AEO) A-inOd-iuncdeudciendhiibnihtiibointioofnpooflypaodlyeandyelnatyiolanti;o(Fn); (AFO) A-iOnd-iuncdeudciendhiinbhitiibointioonf 5o′fc5apcpaipnpg.ing. AOs binding to the target mRNA can effectively alter the reading frame of the transcripts by inducing exon skipping, allowing the production of a partially functional protein [21]. This work led to the discovery of drisapersen, a 2 -OMe-PS AO drug targeting exon 51 that demonstrated significant restoration of the dystrophin protein and forbearance in systematic clinical trials [37] Another chemical modification that has been studied is the use of tricyclo-DNA (tcDNA) to induce exon skipping in the treatment of DMD [38,39] or to induce exon inclusion for the treatment of SMA [40]. The potential of various chemically modified oligonucleotide chimeras has been explored in recent years to further improve the AO designs for enhanced splice switching [55,56,57,58,59,60,61,62,63,64]
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