Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside

Abstract

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects.

Keywords: Grb2; antisense oligonucleotide delivery system; antisense oligonucleotides; cancer therapy; non-coding RNA.

Figure 1

Structure of antisense oligonucleotides (ASOs). R = OH for DNA, R = H for RNA. Created with BioRender.com(accessed on 16 August 2024).

Figure 2

Examples of chemical modifications of ASOs: sugar modification (substitution of R group with morpholine group (MO), base modification (G-clamp, C5′-methylation of cytosine); inter-nucleotide modification: phosphorothioate group (PS), methyl group, nitrogen; and sugar and inter-nucleotide modification (phosphorodiamidate morpholino oligomer (PMO), thiomorpholine oligomer (TMO)). Created with BioRender.com(accessed on 16 August 2024).

Figure 3

Mechanisms of ASOs. 1—inhibition of 5′ cap formation, 2—steric blocking of translation, 3—alteration of splicing, 4—activation of RNase H, and 5—inhibition of miRNA. Created with BioRender.com(accessed on 16 August 2024).

Figure 4

Molecular mechanism of action of BP1001. Created with BioRender.com (accessed on 16 August 2024).

Figure 5

Molecular mechanisms of action of FDA-approved ASOs: (A) fomivirsen, (B) eteplirsen, and (C) tofersen. Created with BioRender.com(accessed on 16 August 2024).

Figure 6

Scheme illustrating the structure of tofersen. Created with BioRender.com(accessed on 16 August 2024).