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The androgen receptor (AR) plays a critical role in the development of prostate cancer (PCa) through the activation of androgen-induced cellular proliferation genes. Thus, blocking AR-mediated transcriptional activation is expected to inhibit the growth and spread of PCa. Using tailor-made splice-switching locked nucleic acid (LNA) oligonucleotides (SSOs), we successfully redirected splicing of the AR precursor (pre-)mRNA and destabilized the transcripts via the introduction of premature stop codons. Furthermore, the SSOs simultaneously favored production of the AR45 mRNA in lieu of the full-length AR. AR45 is an AR isoform that can attenuate the activity of both full-length and oncogenic forms of AR by binding to their common N-terminal domain (NTD), thereby blocking their transactivation potential. A large screen was subsequently used to identify individual SSOs that could best perform this dual function. The selected SSOs powerfully silence AR expression and modulate the expression of AR-responsive cellular genes. This bi-functional strategy that uses a single therapeutic molecule can be the basis for novel PCa treatments. It might also be customized to other types of therapies that require the silencing of one gene and the simultaneous expression of a different isoform., Graphical Abstract, Blocking androgen receptor (AR)-mediated transcriptional activation can inhibit the growth and spread of PCa. Using splice-switching locked nucleic acid (LNA) oligonucleotides (SSOs), we redirected splicing of the AR pre-mRNA, and destabilized the transcripts via introduction of premature stop codons. The selected SSOs silence AR expression and modulate the expression of AR-responsive cellular genes.

Four decades have passed since oligonucleotides were first used to manipulate gene expression. There were few FDA approvals prior to 2016, mostly of drugs that eventually exhibited poor performance in the market. The aura of their younger siRNA relatives had also faded during the past 15 years. However, several FDA approvals have occurred in the past 4 years, restoring hope that a new era has dawned in oligonucleotide/siRNA clinical therapeutics. Here, we review the field of oligonucleotide therapeutics and provide an update on FDA approvals of oligonucleotides from 2017 until the second quarter of 2019. We take into consideration the ethical issues looming over the still somewhat limited efficacy of these molecules, the toxicity of treatment, and the exorbitant cost of these therapeutic agents, which limits accessibility for many.