CGD RT funded researchers at the University’s Children’s Hospital in Zurich, Switzerland have shown in cooperation with the Max Planck Institute for Infection Biology in Berlin, Germany, that they can restore the formation of important cell structures that help clear fungal infections by gene therapy for X-CGD.
These structures are formed by neutrophils, a specialised white blood cell that is affected in CGD and are called Neutrophil Extracellular Traps, NETs for short. NETs are an important part of the body’s defence mechanism against bacteria and fungi. Like their name, these are net-like structures produced by dying neutrophils to trap and bind micro-organisms outside neutrophils and provide a high local concentration of anti-microbials to efficiently kill germs.
The work published in the journal ‘Blood’ describes the successful treatment of a life-threatening Aspergillus nidulans infection in a young boy with X-linked CGD by gene therapy and the link between the restoration of a functional oxidase enzyme system, formation of NETs and the clearing of serious infection that was unresponsive to conventional drugs.
Dr Janine Reichenbach, pictured left, the principal investigator on the project explains: ‘Aspergillus infections are a major health problem in CGD and we believe that NETs play an essential role in eliminating fungi because their hyphae, the long branching filamentous cell of a fungus, are too large to be ‘eaten’ by neutrophils. We know that the ability to form NETs is dependent on reactive oxygen species being produced by the enzyme affected in CGD, the NADPH oxidase. People with CGD are unable to make NET structures because this enzyme does not work properly and we think the inability to form NETs in CGD might explain the vulnerability to Aspergillus infections we see in people with CGD'.
Professor Reinhard Seger takes up the story - ‘The patient we treated was suffering from an otherwise incurable fungal infection and lacked a matched donor for stem cell transplant. Gene therapy was offered as a salvage procedure using the currently available gene delivery tools after carefully weighing up the safety risks highlighted in previous gene therapy trials with the parents. The treatment was very encouraging. We found that gene therapy was rapidly beneficial to our patient and we were able to restore enough functional NADPH oxidase in neutrophils to clear infection 6 weeks after administration of gene corrected cells. What we found was the patient’s neutrophils were now able to make NETs after the therapy and the percentage of cells releasing NETs correlated with the numbers of cells expressing a functional oxidase system and that the gene corrected cells were able to kill Aspergillus fungi’.
Three months after gene therapy the child remains free of aspergillosis.
Dr Reichenbach comments ‘This study has provided a clear link between NET formation and having a working NADPH oxidase enzyme and the ability to clear Aspergillus infections. We have shown that by providing a healthy working copy of the gene affected in X-CGD we can restore the formation of NETs in patient’s cells so leaving the patient better able to clear invasive Aspergillus infections. In collaboration with A. Zychlinsky, Max Planck Institute for Infection Biology, Berlin, work is ongoing through CGDRT funding to study further how much oxidase function is to be restored by gene therapy to give protection against Aspergillus infections, the role of NETs and how they are formed. This work is on-going hand-in-hand with collaborations with other groups developing safer and more effective gene therapy treatments.’
Publication
Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009 Jul 9. [Epub ahead of print]. Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, Reichenbach J.
IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
© 2001-2007 The Chronic Granulomatous Disorder (CGD) Research Trust
Registered Charity No. 1003425 email:cgd@cgdrt.co.uk
The CGD Research Trust is a member of the Association of Medical Research Charities (AMRC), the Genetic Interest Group (GiG) and an associate member of the International Patient Organisation of Primary Immunodeficiencies (IPOPI)
Site Map | Terms and Conditions | Privacy
