Type 1 diabetes (T1D) is an incurable disease, often starting in childhood, with a risk of devastating complications, premature mortality, and high social burden. It is caused by the autoimmune destruction of insulin-producing beta cells, yet the standard of care is insulin replacement, acting only at the symptom level. Thus, T1D is a disease with a high unmet need for innovative therapy. Ideally, such therapy shall suppress selectively the immune cells driving T1D without impairing protective immunity. Regulatory T cells (Tregs) are the guardians of human immune tolerance, and genetic defects in Tregs are associated with T1D. Tregs additionally possess tissue regenerative capacity, making them ideal to treat T1D in cell therapy. However, such therapy, performed with polyclonally expanded patient Tregs, showed limited efficacy in T1D. These expanded Tregs are however poor in relevant autoreactive Tregs to save insulin-producing cells. In fact, the identification and manufacturing of autoreactive Tregs remain fundamental technical challenges to successfully apply these cells in the clinic. ARTiDe aims at a breakthrough in antigen-specific Treg therapy in T1D by establishing the production of human Tregs genetically engineered to express an autoreactive T cell antigen receptor (TCR) ready for clinical use. To achieve this ambitious goal, ARTiDe combines the complementary expertise of 8 partners providing novel technologies for the systematic identification of autoantigen-specific Tregs in humans, the selection of optimal TCR to produce protective Tregs, and innovative humanized T1D pre-clinical models to test their efficacy and safety, as well as Treg supporting strategies, in vivo. World-leading biotechs for adoptive T cell therapy will establish novel GMP-compatible manufacturing of highly purified TCR-engineered Tregs. ARTiDe will deliver a Treg production process and regulatory certificates that will allow launching a phase 1 clinical trial just after the project.

ENDONANO (Quantitative detection of bacterial endotoxin by novel nanotechnological approaches) addresses a key regulatory and safety issue, i.e., the unbiased quantitative detection of bacterial endotoxin in products for medical use and in drug development and toxicological studies. The currently adopted LAL assays are reliable only in limited conditions and prone to interference at several levels, and therefore cannot be applied to all products and substances. ENDONANO will exploit new concepts, based on the capacity of metal nanoparticles to adsorb endotoxin, and new detection methods, based on molecular beacons, for developing novel assays to quantitatively detect endotoxin in complex matrices and in a wide range of conditions. The scientific and technological goals of ENDONANO include: 1. Investigating the capacity of endotoxin to specifically inducing inflammatory reactions in human primary blood cells; 2. Developing new methods based on endotoxin capture by metal nanoparticles in complex matrices (biological fluids, emulsions, gels, etc.); 3. Designing and implementing signal generation and detection methods for the quantitative endotoxin measurement; 4. Planning assay prototypes to be developed and validated for commercial purposes. ENDONANO will train 4 PhD students in an overarching training programme that will include training-by-research, courses of technical, scientific, and transferrable skills, active participation to public scientific events, and intense intersectoral networking. The ENDONANO consortium encompasses three academic institutions with strong expertise in inflammation, advanced biosensing, and top expertise in nanotechnology and use of nanoparticles for modulating bacterial functions, two SMEs expert in development and commercialisation of diagnostic detection assays and one biotech company specialised in (magnetic) microbead technology, and two Participant Organisations (SMEs). All have proven experience in higher education and training,

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.