Effective analysis and manipulation of the protein corona - increasing the efficacy of Sixfold’s delivery system for Cell and Gene therapeutics

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The project combines Sixfold's Programmable Oligonucleotide Delivery System (PODS) with the unique and deep expertise of LGC in quantitative bio-measurement of proteins, and NPL in analysis and measurement of physicochemical and biofunctional properties of nanomaterials, including advanced imaging. 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 a protein corona (PC) manipulation module. To that end, the project employs an iterative technical approach, takes advantage of the interdisciplinary expertise of the consortium and leverages LGC's/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), enabling PODS to quickly progress through preclinical development, and expediting commercialisation.Given their high specificity/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 (primarily viral- and 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 a highly competitive safety profile of siRNA-PODS cancer therapy. However, the gene-silencing efficacy remains to be optimised. siRNA-PODS' efficacy is limited by recruitment of PC onto PODS upon intravenous administration. The PC can dramatically influence the physical properties, pharmacokinetics and pharmacodynamics of nanoparticles \[3\].By utilising LGC's/NPL's expertise, the project enables the necessary advanced (i) proteomic, (ii) morphological and (iii) functional profiling of PC-bound-PODS, allowing for incorporation of optimised PC manipulation module(s) for enhanced therapeutic efficacy. 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.\[3\]Nguyen\_VH\_&\_Lee\_BJ\_Int\_J\_Nanomedicine\_2017\.