We are combining our world class medical research with synthetic and systems biology to accelerate biomedical research for improving health and wellbeing Image 1. Addressing Rett syndrome using gene therapy Lead: Professor Adrian Bird Aim: Rett syndrome is caused by a mutation in the MECP2 gene, which is found on the X chromosome. Gene therapy for Rett syndrome is therefore, at least in principle, feasible. We are exploring a variety of routes for inactivating these defective cells using synthetic biology approaches. 2. The extracellular matrix (ECM) and stem cell differentiation Lead: Professor Charles ffrench-Constant We are using synthetic biology to define and exploit interactions between extracellular matrix (ECM) interactions and CNS stem cells. These important interactions – the ECM defining the stem cell niche – have application for a wide variety of CNS diseases. Aims: Define the functional domains of a combination of extracellular matrix proteins that induce neural stem cell differentiation identified within the lab. Create a synthetic ECM protein that ‘mixes and matches’ the active domains of multiple ECM proteins, optimise design to improve affinity and specificity, and test for improved functionality. Outputs: We have designed and developed a high-throughput phenotypic screening platform for examining ECM-neural stem cell interactions. Using this we have identified a network of three proteins that promote neural stem cell differentiation and the mechanism is currently under investigation. 3. Programming and reprogramming mammalian cell lineage conversions Lead: Professor Steven Pollard Aims: We will create cocktails of master regulators to direct cell lineage conversion in a predictable, efficient and rapid manner. Read more here: Pollard et al. (2019) Reprogramming of fibroblasts to oligodendrocyte progenitor cells using CRISPR/Cas9-based synthetic transcription factors. 4. Engineering human dopaminergic neurons resistant to Parkinson’s disease Lead: Dr Tilo Kunath Aims: Parkinson’s disease is characterised by a catastrophic but selective loss of dopaminergic neurons in the substantia nigra. Early clinical trials of cell replacement therapy, involving transplantation of fetal cells, restored lost motor function but Lewy bodies were found in long-term grafted neurons. Our aim is to create pathology-resistant neurons by creating αSyn-null hESCs and iPSCs. Outputs: We successfully created pathology-resistant neurons by creating αSyn-null hESCs and iPSCs. This work has now been published. Read more here: Chen, Y et al. (2019) Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene. European J Neuroscience, in press 10.1111/ejn.14286 Kunath T, et al. (2018) Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies? European J Neuroscience. doi: 10.1111/ejn.14314. This article was published on 2024-06-17
