Cell/gene transfer based therapies for IPEX Syndrome and FOXP3-gene independent diseases with immune dysregulation

Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome is a life-threatening disease due to mutations of a gene known as Forkhead box P3 (FOXP3). FOXP3 mutations cause the dysfunction of a specific arm of the immune system, the regulatory T cells (Tregs), whose role is to control dysregulated reactions towards self-antigens. The disease, which affects male children, usually manifests in neonates with multiple autoimmune symptoms, including severe diarrhea, eczema with elevated serum IgE and insulin-dependent diabetes. Affected children are usually treated with immunosuppressive drugs, but often the disease is lethal since drugs are only partially efficacious. Currently the only curative treatment is bone marrow transplantation, but its application is limited by the availability of suitable donors and by the danger of treating already compromised patients. The present project is focused on the search of alternative therapeutic strategies for the cure of children with IPEX syndrome. We have previously observed that the generation of functional Tregs by transfer of the correct FOXP3 gene into patients- cells is feasible. In the present project we propose to develop preclinical studies to assess safety and efficacy of a gene therapy approach for the cure of IPEX patients. We also propose to explore a gene-correction strategy based on the replacement of the mutated gene with its correct counterpart directly in patients Tregs. In addition, in order to better understand the disease pathogenesis and to better dissect the role of FOXP3 in immunity, we will investigate factors other than Tregs, which may contribute to disease progression. Results from these studies will offer novel therapeutic options not only to IPEX patients, but also to other patients suffering with autoimmunity of different origin.