Long non-coding RNAs (lncRNAs) are nucleic acids now recognised as fundamental regulators of transcription and translation, acting as signal, decoy, scaffold, guide, or enhancer of these critical cellular functions. SINEUPs are derived from this family of regulatory RNAs, and they act to specifically increase translation of the target mRNAs they bind to. The power of this versatile technology platform can be harnessed across a wide range of disease and indications in medicine, as well as for biomanufacturing and research applications.
A functional SINEUP® is modular and comprises two essential domains: an mRNA binding domain, providing recognition, and an effector domain, responsible for recruiting the translation machinery. The specificity towards a target protein is engineered and tightly controlled by designing a bespoke mRNA-binding domain. The effector domain imparts the translation-enhancing function by directly and efficiently recruiting ribosomes to the mRNA initiation complex. The resulting modular SINEUP therefore accelerates the rate of translation of a chosen mRNA, boosting endogenous protein expression of the protein it encodes in a very specific manner.
SINEUP specificity enables exquisite precision in targeting the expression of a single protein whilst maintaining the ratio of isoforms. The antisense-sense pairing of the SINEUP binding domain to its target mRNA provides a key safety feature by enabling high specificity and avoiding off-target effects. Furthermore, by acting on translation and not at the genomic or transcriptional level, SINEUPs do not introduce change in the DNA or alter the nature or balance of cellular RNAs.
SINEUPs can be engineered to target any cellular protein for which some mRNA is present. Therapeutic SINEUPs have broad applicability and can restore protein level whose expression is affected by a genetic alteration, such as in haplo-insufficiencies. The capability to boost a beneficial cellular pathway to rescue function in a tissue affected by a pathology also offers potential to treat complex disease such as neurodegeneration.
SINEUPs avoid aberrant effects in ‘the wrong’ cell type because they rely on the presence of a naturally expressed mRNA encoding the protein of interest: A SINEUP effect can only be achieved in a cell where a protein would be naturally translated and expressed. Furthermore, the increase in protein expression is maintained within physiological levels providing a further safety feature.
SINEUP mRNA recognition is driven by the rules of nucleic acid hybridisation, which makes them programmable. SINEUPs can easily and rapidly be engineered for any new target. Their small size opens up multiple options for delivery that could be adapted for specific indications, including direct delivery as oligonucleotide or via viral or non-viral vectors.