10089608Building a VAST platform to rapidly engineer novel synthetic gene delivery vectorsClosedCollaborative R&DInnovate UKGene therapy covers a range of medicines which modify gene expression in cells to correct disease. This can be by stopping production of mutated genes, introducing normal, healthy ones or by providing completely new 'synthetic' genes. A limited set of approved gene therapies can already cure forms of blindness, muscular atrophy and cancer. It is generally necessary to confine gene therapy to a particular set of cells where it is necessary, as any modification to a cell may cause harm. For instance, expression of a synthetic gene designed to stimulate intracellular signalling on contact with cancer cells can help T-cells kill lymphoma (in Chimeric Antigen Receptor (CAR)-T therapy) but could be detrimental in other cell types. Hence therapies need to be targeted, and expression tightly controlled in time and space. Achieving such specific and efficient gene delivery to cells inside the body has not previously been possible, and therefore most approaches modify cells in a laboratory, before returning them to patients. This means traditional methods to get genes into cells can be used under controlled conditions, e.g. electroporation or viruses. However, this adds significant complexity and costs as it is difficult to safely maintain cells outside the body and has limited the reach of gene therapies, as current examples cost from £300,000-£1.8M and can only be dosed in a handful of specialist centres. Therefore gene therapies for rare diseases, or those for which a cure might be preferable but non-essential, may not pass cost-benefit thresholds. _In vivo_ gene therapy, where off-the-shelf delivery vectors are dosed into patients and modify cells inside them, can solve these issues. However, to realise this we desperately need safe, efficient and specific delivery vectors for gene payloads. Deliver Biosciences is focussed on engineering these technologies, and has started with a targeted lipid nanoparticle (tLNP) to deliver CARs specifically to T-cells. We have developed a novel safe gene expression system we call EDGE to use inside these tLNPs. In this project, we want to build a screening process to speed up our discovery of EDGE constructs and new tLNPs. We have designed a powerful system that we will evaluate, and validate its capability by optimising new EDGE constructs for T-cells and two other types. This will build better prototypes for Deliver's pipeline and a screening process to quickly engineer and derisk new synthetic biology constructs to fulfil industry needs and open new markets for gene therapy.