RNA therapy: miRNA target protectors
Novel method to disrupt specific miRNA-mRNA pairs in vivo
It is estimated that approximately half of the 3,000 disease-related genes cannot be manipulated by small molecule drugs. Similarly, therapeutic proteins and mAbs are limited to extracellular targets. RNA therapy can potentially be used to inhibit the activity of any protein, allowing access to over 1,000 targets that cannot be “drugged” by other means and the associated commercial rewards.
MicroRNAs (miRNAs) are a class of small RNAs (17 to 27 nucleotides in length) that control gene expression by regulating mRNA translation. miRNAs participate in keeping the balance of genes regulating networks that determine the cells’ fate. Deregulation of miRNAs, which is a frequent outcome in human cancer, seriously weakens this balance, thereby contributing to oncogenesis and cancer progression. Studies have reported that miRNAs affect the expression of genes and pathways involved in cancer pathogenesis from initiation to metastasis disease. As more and more targets of miRNAs are validated, technology that controls specific miRNA:mRNA targeted genes will be very useful as targeted cancer therapy.
Innovations and Advantages
A miRNA:mRNA pair is usually perfectly complementary between nucleotides 2 and 8 from the 5’ end of the miRNA (seed region). Target protectors (TPs) are small oligonucleotides with perfect complementarity to the seed region and to 5’ and 3’ flanking sequences in the 3’ UTR of specific miRNA target genes. Thus, TPs prevent miRNA access to those sites.
The Schier group utilized a target protector as a novel method to disrupt a specific miRNA-mRNA pair in vivo. Morpholino oligomer is an antisense technology that is utilized to block access of other molecules to specific sequences within nucleic acid. Although originally devised to block translation into a protein or as a modifier of pre-mRNA splicing, the Schier group devised a way to utilize this technology to specifically inhibit miRNA-mRNA binding in order to regulate mesoderm induction in zebrafish embryos.
More importantly, this led to their discovery of a method by which one could test the role of specific miRNA-mRNA pairs in vivo. In addition, one could utilize target protectors in the regulation of the translation and stabilization of particular mRNAs that could result in the suppression of hypomorphic mutations or the upregulation of beneficial genes (particularly tumor suppressor genes in the case of cancer).
Target protectors are advantageous in cases in which the mRNA targets of miRNAs are known. High-throughput analyses have reported altered miRNA expression in all tumors investigated to date. In the years to come, as more and more targets of miRNAs are validated, this technology will become very useful as targeted cancer therapy.
Intellectual Property Status: Patent pending.
Choi WY, Giraldez AJ, Schier AF. 2007. Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science. 318(5848):271-4.
Schier, Alexander F
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Reference Harvard Case #3025