Title: Gene editing to treat X-linked lymphoproliferative disease (XLP)
Funder: Action Medical Research

Abstract: Background_x000D_ X-linked lymphoproliferative disease (XLP) is a severe genetic disorder of the immune system that affects an estimated 300 to 500 boys worldwide. Affected boys become sick in childhood or early adolescence. Symptoms vary, but the most common effect of XLP is that the immune system over-reacts to certain viral infections with serious, sometimes life-threatening, complications. In addition, about a third of patients develop lymphoma, a cancer of the immune cells. The only curative treatment is to transplant blood stem cells (immature cells found in the blood and bone marrow) from a healthy donor, but the results depend on having a well-matched donor and transplanting before any symptoms develop. These researchers have already shown that using gene therapy to insert a copy of the correct gene into a patient's own blood stem cells improves the condition. This is safer than using donor cells and means we can use less toxic drugs than in a bone marrow transplant from a donor. However, this approach results in the gene being inserted at random, and, unlike in healthy people, being permanently active, which could lead to abnormal immune cell function. _x000D_ _x000D_ The research project_x000D_ The team believes that by using newer, targeted gene editing techniques (such as CRISPR) they can correct the faulty gene at its natural location in the genome so it will function as it does in a healthy person. They have shown that they can edit the genes in white blood cells from XLP patients to restore function. Now they want to use the same technology in blood stem cells to develop an alternative treatment for XLP patients. This approach has the potential to correct all parts of the immune system therefore curing patients of the disease. The researchers aim to optimise the efficiency of a gene editing procedure in blood stem cells, and then see if patient cells that have been corrected in this way can produce a fully functional immune system when transplanted into a mouse model of XLP. If successful, these findings could pave the way to a clinical trial and lead to an exciting new treatment for boys with XLP. In addition, the techniques developed in this study could be used to accelerate gene-edited stem cell cures for other serious genetic diseases which currently have no effective treatments._x000D_ _x000D_

Lay abstract: Background_x000D_ X-linked lymphoproliferative disease (XLP) is a severe genetic disorder of the immune system that affects an estimated 300 to 500 boys worldwide. Affected boys become sick in childhood or early adolescence. Symptoms vary, but the most common effect of XLP is that the immune system over-reacts to certain viral infections with serious, sometimes life-threatening, complications. In addition, about a third of patients develop lymphoma, a cancer of the immune cells. The only curative treatment is to transplant blood stem cells (immature cells found in the blood and bone marrow) from a healthy donor, but the results depend on having a well-matched donor and transplanting before any symptoms develop. These researchers have already shown that using gene therapy to insert a copy of the correct gene into a patient's own blood stem cells improves the condition. This is safer than using donor cells and means we can use less toxic drugs than in a bone marrow transplant from a donor. However, this approach results in the gene being inserted at random, and, unlike in healthy people, being permanently active, which could lead to abnormal immune cell function. _x000D_ _x000D_ The research project_x000D_ The team believes that by using newer, targeted gene editing techniques (such as CRISPR) they can correct the faulty gene at its natural location in the genome so it will function as it does in a healthy person. They have shown that they can edit the genes in white blood cells from XLP patients to restore function. Now they want to use the same technology in blood stem cells to develop an alternative treatment for XLP patients. This approach has the potential to correct all parts of the immune system therefore curing patients of the disease. The researchers aim to optimise the efficiency of a gene editing procedure in blood stem cells, and then see if patient cells that have been corrected in this way can produce a fully functional immune system when transplanted into a mouse model of XLP. If successful, these findings could pave the way to a clinical trial and lead to an exciting new treatment for boys with XLP. In addition, the techniques developed in this study could be used to accelerate gene-edited stem cell cures for other serious genetic diseases which currently have no effective treatments._x000D_ _x000D_

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