Title: Developing gene therapy for XIAP deficiency
Funder: Action Medical Research

Abstract: Background_x000D_ XIAP is a protein that is found in many types of cells, including immune cells. It helps protect these cells from self-destructing. X-linked inhibitor of apoptosis (XIAP) deficiency (also called X- linked lymphoproliferative disease-2 or XLP-2) is a rare, inherited immunodeficiency syndrome that affects boys, usually in early childhood. Symptoms can vary, but most boys develop a life threatening, over-active immune response to viral infection. Many have inflammation of the gut leading to severe colitis. There are no accurate incidence figures and it is likely that the condition is underdiagnosed but estimates suggest one in every million boys born worldwide may be affected. At present, bone marrow transplant using cells from healthy donors is the only treatment which can potentially cure the condition. However, studies have shown that survival of boys with XIAP after transplant is worse than in other conditions, with fewer than half surviving in the long term. Graft versus host disease, where the patient's body fights the donor cells, damaging organs is a particular problem and XIAP patients appear more susceptible to chemotherapy toxicity. These researchers believe that gene therapy, where a normal copy of the faulty gene is inserted into the patients' own cells, may offer boys with XIAP a safer and better treatment by removing the risk of graft versus host disease and rejection of the donor cells. _x000D_ _x000D_ The research project_x000D_ The team has already corrected a mouse model of the disease and also shown that adding a correct copy of the gene to human XIAP cells improves their function. They now want to investigate the best way to correct the faulty gene in a patient's blood stem cells, immature cells found in blood and bone marrow, which can develop into all types of blood cells. Once corrected in the laboratory, the stem cells can be transplanted back into the patient where they form the basis of long-term production of healthy blood cells. Using a patient's own cells in the transplant should remove the risk of graft versus host disease, reduce toxicity from chemotherapy and increase the chance of success. The researchers will study this process in their mouse model to determine if it is a safe and effective way of using gene therapy to correct the immune abnormalities and symptoms associated with this condition. If successful, this could pave the way for a clinical trial and ultimately improve the outlook for boys with XIAP. In addition, the techniques developed could be applied to many other diseases, including related immunodeficiency syndromes._x000D_ _x000D_

Lay abstract: Background_x000D_ XIAP is a protein that is found in many types of cells, including immune cells. It helps protect these cells from self-destructing. X-linked inhibitor of apoptosis (XIAP) deficiency (also called X- linked lymphoproliferative disease-2 or XLP-2) is a rare, inherited immunodeficiency syndrome that affects boys, usually in early childhood. Symptoms can vary, but most boys develop a life threatening, over-active immune response to viral infection. Many have inflammation of the gut leading to severe colitis. There are no accurate incidence figures and it is likely that the condition is underdiagnosed but estimates suggest one in every million boys born worldwide may be affected. At present, bone marrow transplant using cells from healthy donors is the only treatment which can potentially cure the condition. However, studies have shown that survival of boys with XIAP after transplant is worse than in other conditions, with fewer than half surviving in the long term. Graft versus host disease, where the patient's body fights the donor cells, damaging organs is a particular problem and XIAP patients appear more susceptible to chemotherapy toxicity. These researchers believe that gene therapy, where a normal copy of the faulty gene is inserted into the patients' own cells, may offer boys with XIAP a safer and better treatment by removing the risk of graft versus host disease and rejection of the donor cells. _x000D_ _x000D_ The research project_x000D_ The team has already corrected a mouse model of the disease and also shown that adding a correct copy of the gene to human XIAP cells improves their function. They now want to investigate the best way to correct the faulty gene in a patient's blood stem cells, immature cells found in blood and bone marrow, which can develop into all types of blood cells. Once corrected in the laboratory, the stem cells can be transplanted back into the patient where they form the basis of long-term production of healthy blood cells. Using a patient's own cells in the transplant should remove the risk of graft versus host disease, reduce toxicity from chemotherapy and increase the chance of success. The researchers will study this process in their mouse model to determine if it is a safe and effective way of using gene therapy to correct the immune abnormalities and symptoms associated with this condition. If successful, this could pave the way for a clinical trial and ultimately improve the outlook for boys with XIAP. In addition, the techniques developed could be applied to many other diseases, including related immunodeficiency syndromes._x000D_ _x000D_

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM