The first positive results from the first-in-human gene therapy study as long-term X-linked Chronic Granulomatous Disease (X-CGD) treatment were reported last January in Nature Medicine. Very encouraging, the results show that 6 of 9 treated patients are now free of new CGD-related infections.
Chronic granulomatous disease is a rare inherited disorder (1 in 217 000 births worldwide) caused by a mutation on the X chromosome, which affects only males. This mutation is located on the gene encoding a subunit of an enzyme called NAPDH oxidase 2 (Nicotinamide Adenine Dinucleotide Phosphate). This enzyme has an important role in the immune system, helping innate immune cells (macrophages, monocytes, neutrophils) to destroy bacteria and fungus they have ingested during phagocytosis*. In the absence of this defensive weapon, patients have a predisposition to severe or life-threatening infections from the first years of life, leading to the formation of granulomas, abscesses, pneumonia and chronic inflammation. The conventional treatment for CGD is the administration of antibiotics and antifungals throughout the patient’s life to prevent and improve symptoms. To date, the only permanent curative treatment is a bone marrow transplant from a healthy matched donor. However, all patients do not have a compatible donor and the risk of rejection linked to this operation remains high.
How does the treatment work?
The European study piloted by Genethon, in collaboration with an American multicentric study, proposes a new therapeutic approach, gene therapy, to treat this disease. This approach consists in restoring the activity of the defective NADPH oxidase in the patient’s innate immune cells (monocytes, macrophages, neutrophils), by transferring a functional version of the gene using a vector so called lentiviral vector (LV). This lentiviral vector is derived from HIV-1, which has retained its ability to integrate itself into the DNA of target cells, but which has been completely inactivated to ensure safety. Once entered into the target cells, the vector allows stable and sustainable NADPH oxidase production. To do this, the patient’s blood stem cells are removed from the patient, then genetically modified in the laboratory by addition of the vector carrying the therapeutic gene, before being reintroduced into the patient. To ensure the engraftment of modified cells and to eliminate residual cells, patients receive chemotherapy treatment. Once transplanted, the corrected cells mature into innate immune cells that can produce the NADPH in order to eliminate pathogenic microorganisms. Whether effective in larger trials, this therapy would be an attractive alternative to bone marrow transplantation.
The viral delivery system is a French production
The G1XCGD vector, the viral delivery system for the X-CGD gene therapy used in this clinical trial, was developed in Genethon laboratories, Evry by Dr. Anne Galy (Inserm/UMR951, Généthon, Evry university, Paris-Saclay university) in collaboration with Dr. Adrian Thrasher from Great Ormond Street Institute of Child Health, London, and Pr. Manuel Grez from Frankfurt. The clinical vector batches were produced in France by the company YposKesi, the industrial production platform for gene therapy products created by the AFM-Telethon and BPI France.
Encouraging results for 6 to 9 enrolled patients
The results figure out enrollment of 9 patients (4 in Great Britain and 5 in the United States) aged from 2 to 27 years old with a clinical history of severe X-CGD-related infections. After administration of gene therapy treatment, 6 of the treated patients did not acquire any infection during the 12 to 36 months following the treatment and even stopped the preventive antibiotic treatments. The study shows that for these patients, the number of neutrophils harbouring an enzymatic activity linked to NAPDH is greater than 15% after 1 month and remains stable in the 12 months after treatment (16 to 46% depending on patients), demonstrating the engraftment and allowing the cessation of antibiotic treatments.
However, the situation was different for 3 of the enrolled patients. According to the study, two of them died within 3 months of treatment, due to infections contracted before the transplant and unrelated to the drug product itself. The third patient has not contracted new infections following the therapy, but is still receiving antibiotic treatment. Indeed, for this patient, the number of neutrophils harbouring an enzymatic activity linked to the NADPH, declined during the trial, suggesting a low engraftment. According to the study, this data could result from chronic inflammation contracted before treatment or from the linezolid antibiotic treatment, known to have myelosuppressive activity.
We are very proud of these clinical results which, once again, demonstrate the unique capacity of our laboratory to develop therapeutic projects, from concept to clinical trial by integrating the drug production. This trial also results from a high collaboration with the best British and American expert clinicians.says Frédéric Revah, CEO of Genethon.
“This is the first time that long-term treatment has been obtained with gene therapy in this disease, confirming the benefits of the lentiviral technology that has been used to treat hematopoietic stem cells” says Anne Galy, Director of the “Blood and Immune System Disorders” program in Genethon and coordinator of the European Net4CGD project.
A solid European collaboration
This international work has been possible thanks to the support of the European Commission through the European Net4CGD consortium entirely dedicated to the implementation of effective gene therapy to treat this disease. Many European and French partners are involved in this consortium, notably the APHP, through Pr. Marina Cavazzana, also coordinator of the DIM Gene Therapy.
Towards a CGD treatment for patients in Europe and the United States?
The clinical data have resulted in a strategic alliance between Genethon and the British biotechnology company, Orchard Therapeutics, to enable the development of a product for patients. Indeed, Orchard Therapeutics, of which several co-authors of the study are the co-founders, wishes to continue larger clinical trials to further study this innovative treatment in Europe and in the United States with the aim to obtain a MAA (marketing authorisation application). Similar treatments could thus be developed for the other forms of CGD, since 4 other mutations affect the same immune function.
Beyond that, the success of this trial is a great hope for patients with protein deficiency of innate immune cells, who could, one day, benefit from a treatment developed on the same approach.
Aurélie Laubier, PhD, Project manager DIM Thérapie Génique
* phagocytosis: phagocytosis is a cellular mechanism that allows certain specialized cells to internalize large material such as cell debris or pathogenic bacteria. This mechanism participates in the immune response by providing the first line of defense within the body.