Effective measurement and analysis for optimisation of Sixfold’s functionally enhanced Programmable Oligonucleotide Delivery System (PODS) for delivery of Cell and Gene therapeutics

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"The project combines Sixfold's Programmable Oligonucleotide Delivery System (PODS) with NPL's deep expertise in analysis and measurement of physicochemical and biofunctional properties of nanomaterials. PODS have demonstrated a highly promising safety profile for delivery of Cell & Gene therapeutics such as short interfering RNA (siRNA) for gene silencing. The aim now is to optimise siRNA-PODS's efficacy by incorporating enhanced functionalitie(s) including endosomal escape mechanism(s). To that end, the project employs an iterative technical approach, takes advantage of the interdisciplinary expertise of the consortium and leverages NPL's unique facilities, equipment and know-how. This allows for optimisation of PODS that can be seamlessly integrated into the development of Advanced Therapy Medicinal Products (ATMPs). As such, the project enables PODS to quickly progress through preclinical development, and expediting commercialisation.Given their high specificity and selectivity for gene silencing, siRNAs have the potential to provide effective treatment options for a variety of genetically-driven diseases including cancer. The first ever regulatory approval of Alnylam's siRNA therapy in 2018 \[1\] has validated the clinical and commercial opportunity for such therapies. The major limiting factor for their further clinical and commercial success is the lack of safe and effective systems for systemic delivery of siRNAs to specific diseased cells. This is recognised by academia and industry \[2\]. Current approaches (viral-based/lipid-based) are sub-optimal given their limited specificity, toxicity, and complex/expensive manufacturing \[2\], limiting the type and number of addressable disease indications.PODS can address the drug delivery challenge given their unique, biocompatible design based on a central nanoscaffold, which can be functionalised with multiple therapeutics and highly specific targeting molecules that recognise biomarkers on cancer -but not healthy- cells.Preclinical data indicates siRNA-PODS' efficacy is limited by their entrapment in intracellular vesicles (endosomes) upon cancer cell entry. This prevents siRNAs from reaching the cytoplasm where they exert their therapeutic effect. To address this, Sixfold has designed novel endosomal escape mechanism(s).The collaboration with the NPL will enable the necessary advanced analysis and measurement of the enhanced functionality PODS (ef-PODS), allowing Sixfold to effectively optimise their therapeutic effiacy. This would accelerate the completion of preclinical development, unlocking Sixfold's ability to generate first revenue from licensing agreements and expediting clinical development not only for our primary indication but also for other diseases, contributing to the competitiveness of the UK's ATMP sector.\[1\]Alnylam\_Press Release\_30.08.18.\[2\]Karim\_ME\_et\_al.\_Pharmaceutic 2018"