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.

Gene therapy for rare inherited immune disorders has become a clinical reality. Especially for SCID, two major types of SCID (ADA-SCID, X-SCID) have been successfully treated by autologous stem cell based gene therapy. However, for the most common group of SCID, the SCID underlying recombination defects, this has not yet occurred due to the higher complexities of the affected genes involved. The aim of the current proposal is to fill the unmet medical need for the most common major category of SCID, recombination activating gene-1 (RAG-1) deficient SCID, by performing Stage I/II clinical trials using autologous hematopoietic stem cell based gene therapy. To this end we will develop novel safety assays, pre-GMP and GMP lentiviral batches and design and conduct multicenter, multinational clinical trials with input from regulatory authorities such as EMA and patient advocacy groups. The trial will be conducted with phenotypic, molecular (integration sites, therapeutic gene expression) and functional readouts and should lead to effective treatment for > 70% of all SCID patients in Europe. RECOMB forms the logical extension of highly successful previous EU consortia that have made the EU global leader in gene therapy for orphan immune diseases.

Osteogenesis imperfecta (OI) is, in its severe forms, a devastating inherited disorder characterised by brittle bones. A person with severe OI is affected throughout their lifetime with repeated, multiple fractures, considerable pain and handicap. There is no curative or effective treatment for OI. Our preclinical studies and initial clinical cases have demonstrated that transplantation of fetal mesenchymal stem cells (MSC) is a promising approach for treatment of OI. We receive regular requests for MSC transplantation from patients and their physicians; patient organisations support our approach. The principal objective of the BOOSTB4 project is to conduct a Phase I/II clinical trial of the safety and efficacy of pre- and/or postnatal MSC transplantation in the severest forms of OI (type III, severe type IV). Transplantation before birth at the onset of disease should lead to greater efficacy and engraftment with less rejection than transplantation after birth. Postnatal transplantation will be evaluated in cases where prenatal diagnosis was not made. The trial’s primary outcome is safety; secondary outcomes relate to efficacy (fracture frequency, growth, bone mineral density and quality of life). All patients will undergo molecular diagnosis to confirm OI before inclusion in the trial. Non-invasive prenatal diagnosis will be developed and validated. The BOOSTB4 consortium is led by experts in MSC, prenatal therapy and OI at the Karolinska Institutet (KI), which will also lead the international multicentre trial; five additional EU centres of excellence are included. Ethical and regulatory applications are underway to conduct this clinical trial. These are facilitated by the ethical and regulatory approvals for prenatal MSC transplantation in 10 cases of OI that have already been granted at KI. Successful prenatal transplantation represents a major step forward in the management of patients with severe OI, and beyond, to a range of other inherited birth defects.