OligoY - a new class of oligonucleotide-based therapeutic means

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A number of RNA drugs have been developed to combat polygenic diseases such as cancer. The early enthusiasm for the promise of RNAi therapeutics was quickly weakened by the failure or limited efficacy in early clinical trials.1 Decades of studies on modification of nucleic acids which can affect pairing and chemical stability, conformation and interactions with a proteins and enzymes involved in uptake, transport or processing of targets have been the main focus of the oligonucleotide therapeutic field. While many RNA-based drugs are in development, there are still significant barriers to efficient RNA-based treatment strategies including delivery of the drug to a particular site or tissue, off-target effects and longevity of the treatment.RNAi, antisense and splice-switching oligonucleotides are the main class of therapeutic still under screening. RNAi drugs, although being showing promising result in clinical trial and having some representative drugs already FDA approved, are intrinsically presenting some limitations due to their modality of action. The RNAi and miRNA pathway share common proteins, like Ago2, which are involved in miRNA maturation. Hence, siRNA drugs compete with endogenous miRNAs for Ago2 binding, limiting the efficiency of all siRNA drugs. To compensate this, the concentration of the RNA drug must be carefully optimized avoiding an excess that could saturate the RISC machinery and inhibiting the normal miRNA pathway.The proposed project investigates the design of a new drug RNA drug, 'OligoY', which blocks the most essential mechanism in cell proliferation, DNA replication. DNA replication is the cell process of producing two identical copies of DNA from one DNA template. It is the most essential process in cell division but its initiation is still poorly understood. DNA replication in eukaryotes employs several extracellular signals to coordinate the specialized compartment of the multicellular organisms. OligoYs act indirectly on replication through the binding with a family of non-coding RNA, Y RNAs, specifically blocking the interaction of Y RNA with ORC (Origin Replication complex) during the replication initiation step. OligoYs are complexes formed by two strands of chemically modified RNAs, complementary to the Y RNA target, and a third element (peptide, aptamer, antibody, POD) conferring cell-selectivity. To test their application as drug, they will be initially evaluated in several cancer cell lines. OligoYs are potentially the first example of an oligonucleotide-based drug that acts on the DNA replication mechanism, bypassing all the drawbacks associated to variations of the disease during treatment and between patients.