Inflammation can hold back gene therapy for chronic granulomatous disorder

Children affected by chronic granulomatous disorder (CGD) suffer from recurrent infections because of a fault in their white blood cells. Patients also experience inflammatory complications that remain even when the infective agent has been dealt with.

Unfortunately inflammation can affect the function of many types of cells, including blood stem cells from which all red and white cells are formed. Blood stem cells, also known as haematopoietic stem cells, are unique cells that reside in the bone marrow. When the body needs to form new blood cells, these stem cells become active and also regenerate themselves.

Stem cells are used in bone marrow transplantation and in gene therapy (GT) procedures, as they are able to reconstitute the blood of an individual for life. In GT protocols, the patient’s own blood stem cells are collected and manipulated in the laboratory to correct the genetic fault. The modified cells are then re-infused back into patients, just like a blood transfusion, after which they ‘home’ in on the bone marrow and start to produce normally functioning cells that are able to fight infection properly.

In CGD, researchers think that one problem for GT could be the quality of blood stem cells, particularly if patients have had a long period of infection and inflammation. Manuel Grez, of the Georg-Speyer-Haus – Institute for Biomedical Research Frankfurt, and collaborators have found that chronic inflammation changes the properties of blood stem cells taken from the bone marrow of X-CGD mice, a really useful model of the human disease. These cells seem to be less able to regenerate themselves, meaning that they are weaker than expected in transplantation or GT. Indeed, when used in transplantation experiments, CGD blood stem cells were less able than normal stem cells to supply blood for the long term. These findings have been reported in a landmark article entitled ‘Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions’, which appeared recently in the journal of Allergy and Clinical Immunology.

‘These results are important for the development of gene therapy of CGD,’ says Dr Giorgia Santilli, Senior Researcher at the Institute of Child Health, London, ‘as they really highlight the need to treat patients before their stem cells become damaged by long periods of infection and inflammation.’

‘During the past few years, thanks to the funds from the CGD Society, we have developed an effective procedure for the GT of X-CGD,’ says Professor Adrian J Thrasher, leader of the Gene Therapy Programme at Great Ormond Street Hospital. ‘Using this new protocol and blood stem cells taken from patients who have been cleared from inflammation could hold the key to success for the GT of CGD. Young children who have not yet experienced recurrent infections and are clear from inflammatory processes should have a healthier pool of blood stem cells than older patients. Therefore, the timing of the GT procedure could make all the difference.’


Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions.
Weisser M, Demel UM, Stein S, Chen-Wichmann L, Touzot F, Santilli G, Sujer S, Brendel C, Siler U, Cavazzana M, Thrasher AJ, Reichenbach J, Essers MA, Schwäble J, Grez M.
J Allergy Clin Immunol. 2016 Feb 4. pii: S0091-6749(16)00031-2. doi: 10.1016/j.jaci.2015.11.028. [Epub ahead of print]