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 part of this family of regulatory lncRNAs, and they act to specifically increase translation of the target mRNAs they bind to. An intense focus on elucidating the molecular mechanisms that underlie their activity is revealing the potential for harnessing their power for medicine, biomanufacturing or research.
Maintaining normal physiological level of protein is critical for health and well-being. Conventional small chemical molecules are a proven therapeutic avenue to tune down protein activity, however fewer approaches exist to increase protein function. In some circumstances, protein replacement or gene therapy can provide a solution but their dose and their effect on non-target cells are difficult to control.
SINEUPs® are critically different in that they can tune up expression of almost any protein in an exquisitely precise and controlled manner.
Diseases of Functional Protein Insufficiency: SINEUPs® Restore Normal Protein Levels
Haploinsufficiencies are a class of diseases which arise when a cell is incapable of producing sufficient levels of a specific protein and therefore cannot maintain its normal cellular function. In the majority of cases, the cause is genetic and due to mutations.
Haploinsufficiency diseases tend to be rare diseases with often very limited treatment options. SINEUP® technology can restore a single protein level back to within a physiological range, in the right cell at the right time. It represents an entirely novel approach that has the potential to address critical and underserved clinical needs in rare disease.
Compromised Cell Health: SINEUPs® Promote Cell repair and Compensate for the Disease State
By regulating regenerative pathways, critical protein factors can promote cellular repair. However, few of these important pathway regulators are druggable using conventional pharmacology.
SINEUPs® could alter the course of complex multifactorial disease by boosting endogenous cell repair. SINEUPs® can act on any expressed protein, whether it is traditionally druggable or not; and because they rely on endogenous machinery, their action is tightly targeted and regulated. By enabling the modulation of protective signalling pathways SINEUPs® opens new therapeutic options for hard to treat disease.
Biomanufacturing Bottleneck: SINEUPs® Increase Biologics Production
The protein boosting properties of SINEUPs® are far ranging and extend beyond clinical applications. Our technology could provide innovative solutions in biomanufacturing and represent important research tools to explore biology in the genomic era.
We, and others in the academic community, are investigating a range of targets for which SINEUPs® could provide a step change therapeutic approach as well as multiple applications outside medicine.
A functional SINEUP® is modular and comprises two essential domains. Specificity towards a target protein is tightly controlled by a bespoke mRNA-binding domain (BD). The effector domain (ED) imparts the translation-enhancing function by interacting with key components of the intracellular machinery. The resulting modular SINEUP® boosts endogenous protein translation in a mRNA-specific manner.
SINEUPs® avoid aberrant effects in or on ‘the wrong’ cell type. Because they rely on the presence of pre-existing mRNA, the rescue effect of SINEUPs® can only be achieved in cells where a protein would be naturally expressed. Furthermore, the increase observed is constrained by natural intracellular translation mechanisms, resulting in SINEUPs® safely tuning-up protein expression within physiological levels, typically 2-4 fold, allowing for very subtle and precise interventions.
SINEUPs® can be engineered to target any cellular protein for which some mRNA is present. Therapeutic SINEUPs® have broad applicability and can restore the level of a protein whose expression is affected by a genetic alteration or boost a beneficial cell pathway. Furthermore, the technology versatility also opens multiple applications outside of the therapeutic field.
SINEUPs® specificity enables exquisite precision in targeting the expression of a single protein. The antisense-sense pairing of the SINEUP® binding domain to its target mRNA provides a key safety feature by enabling the design of narrow specificity and avoiding off-target effects.
The small size of SINEUPs® opens up multiple options for delivery that could be adapted for specific indications, including direct delivery as oligonucleotides or via viral or non-viral vectors.
SINEUPs® structure, combining target-recognition and translation-boosting functions in two distinct domains, enables a plug and play approach to their design. Multiple SINEUPs® can easily and rapidly be engineered for any new target.