Abstract
Contract No.: 305011; EU contribution: € 5,999,607; Total costs: € 8,302,977.60; Starting date: 01/12/2012; Duration: 48 months
Background and Objectives
The Net4CGD European consortium is focused on the clinical development of gene therapy for patients with the X-linked form of chronic granulomatous disease (X-CGD). CGD is a debilitating primary immunodeficiency affecting children and young adults. 1 This rare inherited disorder of the phagocytes is caused by absence of NADPH oxidase activity and characterized by the inability of monocytes and neutrophils to produce reactive oxygen species in response to stimuli. The X-linked recessive form is the most frequent (65% of cases) and is caused by mutations in the CYBB gene (encoding gp91phox). Affected patients present an elevated susceptibility to bacterial and fungal infections, as well as an excessive inflammatory response leading to granuloma formation. Invasive aspergillosis is the leading cause of death in patients with CGD. Conventional treatment of CGD consists of lifelong prophylaxis with antibiotics, antimycotics, and/or interferon gamma. To date, hematopoietic stem cell transplantation (HSCT) with a suitable donor allows permanent cure of CGD, and well-tolerated reduced intensity conditioning regimens have been established. 2 However, at least one-third of patients do not have an HLA-matched compatible donor, and HSCT in these patients is associated with high morbidity and mortality. Gene therapy based on autologous HSC correction may represent a definitive cure for CGD patients for whom allogeneic HSCT is not possible. 3
Several members of the Net4CGD consortium have already attempted hematopoietic gene correction of X-CGD using gp91 gammaretroviral gene transfer vectors. While functional correction and clinical benefit was initially achieved, problems arose, linked to insertional mutagenesis, vector silencing, and lack of long-term engraftment. 1 A new lentiviral vector (LV) was developed to express gp91phox in myeloid cells. 4 Encouraging results obtained in preclinical studies and through the compassionate treatment of a patient in London have prompted us to test the LV in a multicenter study in several European centers expert in CGD. The trial sponsor is Genethon, a nonprofit organization dedicated to the development of gene therapy in rare diseases. An orphan drug designation was obtained for autologous hematopoietic cells genetically modified with an LV containing the human gp91 (phox) gene (EU/3/12/957—EMA/OD/118/11).
The Net4CGD project is focused on the clinical development of this new orphan drug, which could rapidly become a new treatment option for patients with X-CGD. This will be achieved through the following objectives:
• Conducting a phase I/II trial in eligible X-CGD patients, with LV gene-modified autologous HSC to test the safety and efficacy of the technology • Collecting high-quality data by conducting trials in expert institutions, testing the same LV product with harmonized procedures and protocols to facilitate product registration • Assessing functional innate immune restoration obtained by hematopoietic gene therapy • Obtaining large-scale “omics” and vector genome stability analysis, including bioinformatic data mining, dynamic sequence data storage, and whole integrome sequencing, to evaluate vector safety in man
Approach and Methodology
The Net4CGD consortium includes seven partner laboratories with scientific and clinical expertise, three small and medium enterprises in the biotechnological and service sector, and one partner fully dedicated to the management of the consortium. The main tasks for the consortium over the next 4 years include (1) manufacturing clinical-grade vector to support clinical studies, (2) conducting a multicenter phase I/II trial in eligible X-CGD patients, with lentiviral gene-modified autologous hematopoietic stem cells to evaluate the safety and efficacy of the product, (3) ensuring high-quality and harmonization of products and procedure to facilitate future product registration, and (4) obtaining state-of-the-art information on biological efficacy and safety in patients by assessing immune restoration and large-scale integrome data. In addition, the consortium aims to communicate effectively the results of its efforts toward the scientific community, patients, families, and the general public.
Main Findings
A European multicenter gene therapy trial for X-CGD has been successfully initiated since the start of the project, and three centers are currently open to recruit adult or pediatric patients.
A unique Investigational Medicinal Product Dossier was submitted by the sponsor to the different competent national regulatory authorities in the United Kingdom, Switzerland, and Germany. The clinical trial is registered at the European Medicines Agency under EudraCT: 2012-000242-35. The trial has been approved in the different states over a period ranging from 2013 to 2014. At present three clinical centers are opened (London, Frankfurt, and Zürich) and will enroll up to five patients each.
To conduct the trial, the consortium has developed the clinical G1XCGD vector, which is a latest-generation rHIV-derived LV allowing strong expression of the transgene in myeloid cells from a chimeric promoter, 4 and capable of correcting the CGD defect in phagocytes. The process for the large-scale manufacture of clinical-grade G1XCGD LV has been developed and implemented at Genethon in compliance with Good Manufacturing Practice. Several lots of vector have been released for clinical use. The vector-specific quality control (QC) plan has been developed in the frame of the consortium. Ongoing developments in QC are expected to significantly reduce the costs of testing. In the first 18 months of the project, the partners of the consortium have also worked together to harmonize a protocol for the transduction of patients CD34+ cells with the G1XCGD vector. Preclinical optimization has greatly improved the quality of the transduced cell product obtained during manufacture over the course of the project to date.
An initial assessment of the risk–benefit of the clinical study, reviewed by an independent ethics expert, concluded that there is a clear benefit to conduct the clinical trial using the G1XCGD lentiviral vector to treat patients suffering from CGD and who have no treatment option. Regular ethics monitoring updates are included in the project and reported to the European Commission. An advisory board and data safety monitoring board have been assembled by the sponsor of the trial.
In parallel efforts with the trial, studies are ongoing to characterize the hematopoietic compartment in CGD, to generate models of the disease, 5 to investigate mechanisms regulating transgene expression, 6 and to improve the methodology for genomic insertion site analysis. The consortium meets regularly and a website has been implemented to ensure the dissemination of the work (www.net4CGD.eu).
Expected Outcome
Net4CGD represents a unique European initiative to implement advanced gene therapy through coordinated action. It is built on established European excellence in research and medicine to achieve a world-leading research program across multiple European centers. The end product is expected to be a long-lasting contribution to healthcare and tangible benefits for patients, both in terms of quality of life and also in terms of the socioeconomic burden of genetic disease. The impacts arising from Net4CGD will range from fundamental studies on advanced vector technology and hematopoietic stem cell biology, to rigorous preclinical validation of advanced gene therapies and application of multicenter European clinical studies. Furthermore, the knowledge gained will form a sustainable platform on which to build novel treatments based on similar technologies in a wider collection of inherited and acquired disease. The expected impacts of the project are schematized in Fig. 1.
Expected impacts of the project.
