Chronic septic granulomatosis is a rare genetic disease, linked to a gene located on the X chromosome and causing a predisposition to infections caused by viruses or bacteria. Without treatment, sufferers have a reduced life expectancy. Genethon has developed and conducted the first clinical studies for a gene therapy product, now sponsored by Orchard Therapeutics.
Contribution of Genethon to the design of the gene therapy product, proof of concept in animals, clinical design and Généthon sponsor of the French trial.
R&D collaboration with AP-HP and license agreement with Orchard.
What is chronic septic granulomatosis?
X-linked chronic septic granulomatosis (XCGD) is a rare genetic disease, affecting mainly boys. The disease is caused by mutation of the CYBB gene, reducing the enzyme activity of the NADPH oxidase of the immune system’s cells. The reduction of this activity prevents destruction of micro-organisms entering the body. Because of this deficiency, patients suffering from chronic septic granulomatosis are predisposed to infections caused by fungi and bacteria.
From the first year of life, XCGD patients suffer from repeated infections, sometimes deep abscesses, atypical pneumonia as well as chronic inflammation, including in the gums and digestive tract.
The disease is severe and debilitating, requiring constant treatments to limit infections, sometimes accompanied by lengthy hospitalizations. Life expectancy without treatment is 30 to 40 years.
The prevention of bacterial and fungal infections is crucial with this disease. This is why patients generally receive long-term anti-bacterial treatment and anti-fungal treatment.
Grafting of hematopoietic stem cells is currently the only curative treatment for this disease. Granulocyte transfusion may also be indicated in the event of severe infections.
Chronic septic granulomatosis: Genethon’s role
Gene therapy, based on gene correction in the autologous hematopoietic stem cells, represents a hope for recovery for patients who are not candidates for bone marrow grafts. The gene therapy approach involves expressing the CYBB gene in the patient’s phagocyte cells using a lentiviral vector. This lentiviral vector has been developed by Genethon.
Genethon obtained the label “Orphan drug” from the European Medicines Agency (EMA) for this product. It is the sponsor of two clinical trials for patients carrying mutation in this gene coding for gp91phox (involving around 75% of XCGD patients).
The first trial took place in France, at Necker-Enfants Malades hospital, and the second in Great Britain at Great Ormond Street Hospital and at University College Hospital in London. Eight patients were treated in total (note that some patients received the treatment in the form of compassionate treatment). Recruitment for these two trials is now closed, and Genethon continues to monitor the patients treated to confirm tolerance over the long term.
This international effort has been supported by the European Commission through funding by the 7th health framework program as part of the European Net4CGD project, for which Genethon was the coordinator.
Genethon also provided the vector for a clinical trial in the United States.
Genethon signed a partnership agreement with Orchard Therapeutics, who continues to develop this product.