Programmable gene silencing: non-disruptive miRNA harnessing in the design of a candidate cell therapy

Hard-to-treat cancers cause approximately 165,000 UK deaths annually. While cell-and-gene therapies (CGT) provide new hope compared to traditional treatments, they still face significant challenges. CGT treatments can offer patients an average of 5.8 extra years of good-quality life. However, the tumour microenvironment (TME) --- the area surrounding, created by the tumour --- often weakens a sufferer's immune system, making it difficult to mount a defensive-response to a tumour. Current therapies, such as CAR-T can lose effectiveness over time as tumour-associated-macrophages (TAMs) help protect the tumour and allow it to survive. One promising solution is gene-silencing technology, which aims to shut down certain genes that promote tumour-growth, thereby invigorating the immune response. However, existing gene-silencing methods have limitations: siRNA (small-interfering-RNA) works only for a short period before it degrades, shRNA (short-hairpin-RNA) can be switched off by changes in the cell, and miRNA-based therapies can also be inactivated, reducing their long-term effectiveness. To address these challenges, Laverock Therapeutics proposes a 21-month project to develop, test its novel gene-silencing platform called Non-disruptive scaffold-insertion (NDSI). This new technology affords improvements over existing approaches. It's a unique platform leveraging the natural process within a cell to regulate gene silencing. It provides long-lasting gene-silencing that can be dialled-in and-out of action when a cell needs it, which is matchless. Furthermore, the technology supports fine-tuning of the silencing effect, with access to a library of thousands of miRNA-based designs, enabling an optimum one to be found per treatment. Dialling-in-out gene silencing reflecting how the cell responds over time. A major advantage is that it can target multiple genes for silencing at once in a therapeutic cell. This is critical as cancer involves several genes working together to protect the tumour as it evades current therapy. This enables a cell-therapeutic to deploy counter-measures to immune-evasive-tumours. Silencing multiple gene-targets simultaneously increases the chances of overcoming the tumour's defences. This project will focus on using NDSI to target specific genes in TAMs. There are several known, and this project will discover more. After initial lab testing, studies will be conducted to assess how well it works in reducing tumours in living systems. Addressing current therapy weaknesses, this approach will strengthen the immune system's ability to fight tumours effectively, enhancing cancer treatment. Support from the Cell & Gene Therapy Catapult focuses on showcasing the project successes with the NHS and potential partners from the pharmaceutical industry to support post-project product development.