Muscular dystrophies are severe genetic disorders characterised by muscle wasting, impaired mobility and premature death, which to date remain incurable. Although preclinical and clinical evidence position genetic therapies amongst the key emerging treatments for several genetic conditions, no gene therapy or genome editing strategy has been approved for any muscular dystrophies yet. The lack of robust, human(ised) models enabling precise development of such advanced therapies is a major barrier towards their clinical translation for muscle diseases. To overcome this limitation, we have assembled the multidisciplinary MAGIC consortium to build novel, high-fidelity, models of human skeletal muscle pathophysiology which will be used to develop new vectorsforsafe and efficacious neuromuscular gene therapy and genome editing. Specific rare (paediatric) diseases targeted by our consortium are Duchenne muscular dystrophy (DMD), X-linked centronuclear myopathy (XLCNM), LMNA- and COL6-related congenital muscular dystrophies (CMDs). Microfabrication, microfluidics and human stem cell differentiation technologies will be used to generate disease-specific muscle-on-chip devices qualified for commercialisation, capable of screening toxicity and cell-specificity of new adeno-associated viral vector (AAV) capsid variants, and unique muscle-specific lentiviruses. Selected vectors will be equipped with novel lineage-specific regulatory elements to further restrict transgene expression to myofibres, muscle stem cells or interstitial fibroblasts, reducing also potential immunogenicity. The same vectors will be loaded with therapeutic genes or with new mutationindependent (for DMD and XLCNM) or mutation-specific (for LMNA and COL6-CMD) gene editing tools, which will then be validated in dystrophic rodents. Finally, GMP-compatible batches of the top performing vectors will undergo advanced preclinical testing in large animals, preparing them for future clinical translation.

This project will focus on the translation of world-leading UK research into robust manufacturing processes ready for a future clinical trial to treat a life-threatening disease in infants. Babies born without a thymus gland (called complete DiGeorge Syndrome) have a fatally deficient immune system, and without treatment will die within 2-3 years. The project uses ground-breaking technology to create a new thymus using biological tissue scaffolds and thymus cells. Laboratory research has shown that this bioengineered thymus can provide the immune system functions that are lacking in infants born without a functioning thymus. During the project research work will generate data to support the manufacture, quality, safety and efficacy of a bioengineered thymus, which will be reviewed by the UK regulatory body, MHRA (Medicines and Healthcare products Regulatory Agency). The MHRA is responsible for ensuring all new and existing medicines and therapies are safe. Outcomes from reviews with the MHRA will be used by the project team to ensure the correct data is generated to support future application for a clinical trial to treat infants born without a thymus.

Many patients with blood disorders, such as cancers, can usually be treated by receiving a bone marrow transplant from another person. Usually this donor has to be a blood relation or have a compatible tissue type to ensure the transplant is not rejected. However, finding such a match is not always possible. For some years now, parents have been donating the blood found in the umbilical cord of their new-born babies. Just as with bone marrow, this 'cord blood' contains stem cells which are capable of reconstituting the entire blood and immune system of a transplant recipient. Furthermore, complete matching is not required, so cord blood cells can be used to treat patients that can't find exact matches, lowering the risk of tissue rejection. Unfortunately, the number of cells in each cord blood unit is limited and too small to treat most adults, therefore methods to expand the number of these cells in the laboratory are highly desirable. Plasticell has developed and patented formulations which, in preliminary _in vitro_ studies, allow the stem cells in the cord blood units to be multiplied by around 500-fold without affecting their properties. The company has further developed manufacturing methods in which these cells can be expanded ready for clinical use. The resulting cells have been tested _in vitro_ in the laboratory and in preliminary _in vivo_ transplantation using immune-deficient mouse models. Nevertheless, to ensure the cells are useful to patients we must carry out more extensive _in vivo_ analyses. In this project, we will test the cells ability to reconstitute the entire blood system when injected into immune-deficient mice and also aim to develop innovative solutions to ensure the stem cell product we are developing can be made and delivered to the patients that need it in a format that is safe, effective, user-friendly and affordable.