Investigating new treatments

Professor Janine Reichenbach, co-head of the immunology department at the University Children’s Hospital Zurich, leads the work to develop a gene correction therapy for people affected by p47phox deficiency. Awarded in November 2016 

Project leaders: Professor Janine Reichenbach and Dr Ulrich Siler
Location: University Children’s Hospital Zurich
PhD student employed on project: Dominik Wrona
Duration: 1 year, starting December 2016
Total project cost: £50,000
Official title: Targeted genome editing for p47phox-deficient CGD

What this research means for people with CGD

The work will establish a method to more easily identify people with p47phox deficiency so that diagnosis can be rapidly performed in any laboratory in the future. It will also create gene therapy tools for use in future clinical studies to treat patients with p47phox-deficient CGD.

Background to the work

Between 25 and 30 per cent of all CGD patients carry defects of the p47phox protein. To date, diagnosis is only possible in a few specialised laboratories. Compared with the other types of CGD, p47phox-deficient CGD is unique because 97 per cent of all patients show the same genetic defect. This characteristic makes it possible to develop a new diagnostic method to more quickly identify patients with this type of CGD. 

Until recently, patients with CGD could only be cured by transplantation of stem cells from healthy, compatible bone marrow donors. Over the last 15 years gene therapy has been developed as an alternative therapy to stem cell therapy. Currently gene therapy consists of adding a healthy copy of the faulty gene into the patient’s stem cells, using a specially designed gene transfer vehicle, known as a vector. This procedure may cure CGD patients but in some cases it has been associated with severe side effects linked to the insertion of the vector in close proximity to genes known to be involved in the development of leukaemia. To avoid these side effects, safer gene therapy vectors have since been developed and are being used in clinical trials.

New methods of gene correction are under investigation that can give specific targeted correction of genetic defects. These gene-editing techniques use special enzymes, called designer nucleases, and are able to fix specific mutations. As this gene-editing method relies on genetic correction without gene addition, it is thought to substantially increase the safety of gene therapy. Designer nucleases are especially attractive for p47phox-deficient CGD patients because most patients share the same genetic defect.

In this work led by Reichenbach and Siler, a single designer nuclease will be developed that will be able to potentially cure 97 per cent of p47phox-deficient CGD patients. The researchers will test this designer nuclease in a p47phox-deficient cell line, which they will create in the laboratory, and then in animal models of p47phox deficiency. This essential preliminary work will create gene therapy tools for use in future clinical studies to treat patients with p47phox-deficient CGD.

Further information and links

The work is being undertaken at the leading European paediatric centre of expertise at University Children’s Hospital Zurich. See
http://www.swisshealth.ch/en/patienten/spitaeler/Kispi.php