NET4CGD

Gene Therapy for X-linked Chronic Granulomatous Disease (CGD)

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 Obiettivo del progetto (Objective)

'This project is focused on the clinical development of a new orphan drug that can rapidly become a new treatment option for patients with the X-linked form of chronic granulomatous disease (X-CGD). This rare primary immune deficiency of phagocytes is caused by mutations in the gp91phox gene. Affected patients are highly-susceptible to infections and develop inflammatory granulomas. 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. Net4CGD proposes future trials to achieve (i) effective transduction of hematopoietic cells, (ii) physiological expression of the transgene and (iii) long-term engraftment of gene modified cells. A new lentiviral vector (LV) was developed to express gp91phox in myeloid cells. Encouraging results obtained in preclinical studies and through the compassionate treatment of a patient, prompt us to test the LV in a multi-center study in several European centers expert in CGD, under the sponsorship of a rare disease specialist. The tasks include i) Manufacturing clinical grade vector to support clinical studies, ii) Conducting a multi-center phase I/II trial in eligible X-CGD patients, with LV gene-modified autologous hematopoietic stem cells to evaluate the safety and efficacy of the procedure iii) Ensuring high-quality and harmonization of products and procedures to facilitate future product registration iv) Obtaining state-of-the art information on biological efficacy and safety in patients by assessing immune restoration and large-scale integrome data. If positive, this study will be used to register the orphan drug. The treatment is expected to improve patients’ quality of life and will reduce the economical burden of CGD. Results should benefit other RD.'

Introduzione (Teaser)

Gene therapy can offer a solution where standard treatments fail. The genetic correction of the rare genetic disorder X-linked chronic granulomatous disease (X-CGD) is the subject of the NET4CGD study

Descrizione progetto (Article)

X-CGD is an immunodeficiency disorder associated with the inability of phagocytes to kill invading pathogens due to mutations in the enzyme NADPH oxidase. X-CGD neutrophils are unable to produce reactive oxygen species, leading to intractable infections and granulomas.

Conventional treatment of X-CGD consists of lifelong prophylactic administration of antibacterial and antifungal agents and granulocyte infusions. The only established cure to date is haematopoietic stem cell transplantation (HSCT) with a suitable donor. However, in over 60 % of patients no HLA-matched compatible donor is available, and transplantation of a not fully matched graft renders HSCT a high-risk approach.

As an alternative definitive cure, scientists have pursued gene therapy, an approach that entails the ex vivo genetic correction of patient HSCs and their re-infusion back into the patient. Attempts so far, however, have produced unsatisfactory results.

Seeking to improve the outcome of gene therapy for X-CGD, the EU-funded 'Gene therapy for X-linked chronic granulomatous disease (CGD)' (http://www.net4cgd.eu/ (NET4CGD)) network will develop a novel gene therapy strategy. Using state-of-the-art technology and expertise across Europe, the NET4CGD project has constructed an advanced lentiviral vector that carries the wild-type NADPH oxidase gene. Pre-clinical results are encouraging and show a phagocyte-specific expression of the transgene. The ultimate goal is to achieve effective transduction of haematopoietic cells and long-term engraftment of gene-modified cells.

During NET4CGD, the lentiviral vector has been produced at clinical grade and is currently being tested in a multi-centre phase I/II trial in eligible X-CGD patients. Through integrated efforts, project partners have harmonised procedures and optimised the manufacture of the vector and the final gene-modified cell product.

The clinical trial has been registered at the European Medicines Agency (EMA) and will involve approximately 15 patients. The consortium is in the process of obtaining information on biological efficacy and safety in patients, and is analysing the integration profile of the vector. Preliminary data indicate that transduced patient cells display restored biochemical activity and neutrophil oxidative function at therapeutic levels.

Partners are confident that the advanced NET4CGD gene therapy approach will correct the myeloid defect in X-CGD patients and lead to clinical benefit. A positive outcome of the clinical trial will permit the registration of a new medicinal product for the treatment of X-CGD patients, thereby improving their quality of life and reducing the overall healthcare costs.