X-linked inhibitor of apoptosis deficiency: developing a gene therapy cure for this rare disorder

X-linked inhibitor of apoptosis (XIAP) deficiency is a devastating inherited condition that usually affects boys in early childhood. Symptoms can vary, but most will develop a life-threatening overactive immune response to an infection and many will also experience severe gut inflammation. A bone marrow transplant offers the only hope of a cure but sadly, fewer than half of boys with the condition who undergo this treatment will survive. Dr Claire Booth of UCL Great Ormond Street Institute of Child Health is aiming to develop a new gene therapy approach that she hopes could offer a safer and better treatment for boys with XIAP deficiency in the future.

How are children’s lives affected now?

XIAP deficiency is a very rare disorder affecting boys, in which their immune system does not work properly due to a faulty gene. They are usually diagnosed before they reach their 10th birthday – and, although symptoms can vary from person to person – most will develop a severe reaction to a viral infection that can be fatal, and many will also have severe inflammation of the gut (colitis).

“Currently, the only way to cure XIAP deficiency is with a bone marrow transplant to replace the patient’s faulty immune cells with healthy ones from a donor,” says Dr Booth.

But bone marrow transplants are complicated procedures and have risks. Sadly, survival for boys with XIAP deficiency receiving a transplant is worse than for other conditions, with fewer than half surviving in the long term.

“There is an urgent need for safer, more effective treatments for boys who are born with this devastating condition,” says Dr Booth.

How could this research help?

“Building on our previous success at developing gene therapies for several other immune system diseases, we are now aiming to use a similar approach for boys with XIAP deficiency,” says Dr Booth.

The team’s approach will involve inserting a correct copy of the faulty gene into the patient’s blood stem cells in the laboratory – and then transplanting these cells back into the body to seed the regeneration of a healthy immune system.

“By using the patient’s own cells, this should reduce the risk of graft versus host disease where the donor cells attack the patient’s organs, a particular problem for boys with XIAP deficiency – increasing the chance of success,” explains Dr Booth.

The researchers will develop their technique in the laboratory to work out if they can correct, using gene therapy, the immune system abnormalities and symptoms of XIAP deficiency.

“If our results show this approach is both safe and effective, this could pave the way for a future clinical trial in patients,” says Dr Booth