Severe combined immunodeficiency (SCID) is a devastating rare disorder of immune system development. Affected infants are born without functional immune systems and die within the first year of life unless effective treatment is given. Treatment options are limited to allogeneic haematopoietic stem cell transplantation and autologous stem cell gene therapy. Over the last 15 years, gene therapy for two forms of SCID (SCID-X1 and ADA SCID) has shown significant safety and efficacy in correcting the immunodeficiency and allowing children to live normal lives. Proof of concept of gene therapy for 3 other SCID forms has also been shown by members of the proposed SCIDNET consortium and is ready for translation into clinical trials. We are therefore in a position whereby, over the next 4 years, we can offer gene therapy as a curative option for over 80% of all forms of SCID in Europe. Importantly for 1 of these conditions (ADA SCID) we will undertake clinical trials that will lead to marketing authorisation of the gene therapy product as a licensed medicine. In addition, we will investigate the future technologies that will improve the safety and efficacy of gene therapy for SCID. Our proposal addresses an unmet clinical need in SCID, which is classified as a rare disease according to EU criteria (EC regulation No. 141/2000). The proposal also addresses the need to develop an innovative treatment such as gene therapy from early clinical trials though to a licensed medicinal product through involvement with regulatory agencies and is in keeping with the ambitions of the IRDiRC. The lead ADA SCID programme has Orphan Drug Designation and clinical trial design is assisted by engagement with the European medicines Agency. The ADA SCID trial will act as a paradigm for the development of the technologies and processes that will allow gene therapy for not only SCID, but also other bone marrow disorders, to become authorised genetic medicines in the future.

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in childhood, with more than 25,000 patients in Europe. It is due to mutations in the DMD gene that preclude the production of the protein dystrophin. In addition to the progressive muscle weakness, 50% of affected individuals have debilitating central nervous system (CNS) co-morbidities, including intellectual disability, neurodevelopmental problems encompassing autism, Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder. These co-morbidities are due to the deficiency of multiple dystrophin isoforms in brain whose expression is differentially affected by the site of the DMD mutation. They represent a major obstacle for patients to live a fully independent life. Current therapies do not address these co-morbidities. The postnatal restoration of one dystrophin isoform using genetic therapies in the DMD mouse model improves the neurobehavioral phenotype. This raises the exciting possibility that some of the CNS co-morbidities could improve with genetic therapies in patients. We need to address several knowledge gaps before considering clinical applications of these therapies: i. dystrophin isoforms localisation in the CNS; ii. which of the neurobehavioural features of the dystrophic mice improve after dystrophin restoration, and circuitries involved; iii. deep phenotype patients to define robust outcome measures. This project developed in partnership with advocacy groups, meets gender criteria and offers for the first time insight into how dystrophins’ affect CNS function, and on the reversibility of the DMD CNS co-morbidities, providing essential information to the field of neurodevelopmental disorders, and for other syndromes arising from dystrophin associated proteins. Our efforts to develop novel therapies that can cross the blood brain barrier could be transformative for the field of neurodegeneration and neurodevelopmental disorders.