Engineered Genetic Control Systems for Advanced Therapeutics

This application addresses engineering biology for biomedicine specifically in the area of gene therapy (GT). Cell and gene therapies (CGTs) have the potential to revolutionise healthcare and are arguably the most exciting areas of biotechnology both due to recent progress and future possibilities. Gene therapy is a technique that modifies a person's genes to treat or cure disease. Gene therapies can work by several mechanisms: Replacing a disease-causing gene with a healthy copy of the gene, inactivating a disease-causing gene that is not functioning correctly or introducing a new or modified gene to help treat a disease. The main delivery mechanisms for GTs are viral vectors including AAV and lentivirus where the virus has been modified to remove their ability to cause infectious disease and free up space in their genome for insertion of genetic "cargo" enabling therapeutic genes to be carried into human cells.
The emergence of CGTs has played a major role in reshaping the biopharmaceutical industry and has transformed the treatment paradigm of a range of life-threatening and rare diseases. The global gene therapy market value was USD 6.36 billion in 2022 driven by the increasing identification and prevalence of genetic disorders across the globe. The market size is anticipated to grow at a CAGR of 22.8% during 2023-2031 to achieve a value of USD 40.39 billion by 2031. For gene therapies to be effective and safe they need to express the transgene in the right tissue, at the right level, for the right amount of time and to be delivered efficiently to the correct tissues. Engineering Biology is the perfect technology to address these challenges and our mission is to use Engineering Biology to develop a series of engineered genetic control systems for use in Gene Therapies both in the control of expression of the therapeutic transgene but also in the development of enhanced delivery systems. This Hub will bring together a multidisciplinary team from the Universities of Edinburgh, Oxford, Imperial College London and the Beatson Cancer Research Institute to develop a new suite of engineering biology tools for control of transgene expression, delivery into cells and test them in three application spaces - oncology, cardiovascular disease and rare diseases.

To date most gene therapies have been developed in an artisanal way usually by experts in the disease that they aim to treat without any consideration of an engineering approach. This doesn't lend itself to additional learning and reuse in a different context. There has not been a focus on an underlying engineering approach to develop frameworks, architectures and controllable components that could be applied to multiple different therapeutics. The parallel development of a range of control systems and delivery vectors will enable us to try mixing of control systems with delivery of therapeutics to determine the optimal combination for patient outcome in a range of disease states. In this Engineering Biology work programme we will develop 1.cell type specific gene regulation using AI, synthetic promoters and alternative splicing devices; 2.Small molecule based control switches using aptamers, protein dimerization, and drug induced control of alternative splicing 3.we will develop control circuits that buffer expression levels of transgenes using miRNA feedback and Zn finger protein systems to influence bystander cells 4. We aim to build a range of novel GT delivery systems based on AAV, adenovirus and lentivirus derived nanoparticles. All these will be applied to the application areas of oncology, cardiovascular disease and rare diseases. All the research will be underpinned by a strong RRI framework.