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Clinical Trial Summary

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by severely reduced phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. In normal granulocytes, NADPH oxidase produces superoxide that is required for the killing of certain microorganisms. Patients with CGD have a genetic mutation for components of the NADPH oxidase. Consequently, CGD patients are at significant risk for morbidity and mortality due to serious infections and inflammatory complications. Of the types of CGD, the most common form is X-linked CGD, which occurs in about 60%-70% of CGD patients and is caused a mutation in the CYBB gene, leading to a deficiency of gp91phox protein. Despite great advances in antimicrobial options, infections remain the greatest cause of death in CGD patients. Treatment choices for intractable infections in CGD have included donor granulocyte transfusion (GT) or hematopoietic stem cell transplantation (HSCT), despite significantly increased risks of a transplant with concurrent infection. Donor GTs have been used to augment treatment of difficult infections in CGD patients for decades, including those undergoing HSCT, but can be associated with alloimmune responses that reduce the lifespan of transfused cells and increase risk of complications during subsequent HSCT. To avoid the risk of alloimmunization following donor GT, we have developed an approach to manufacture mRNA-corrected autologous granulocytes from CGD patients. In this study, we will infuse gp91phox-deficient CGD patients with autologous granulocyte-enriched cells corrected by patient-specific CGD-mRNA transfection (gp91-Grans). The eventual goal of this product is to provide short-term treatment for infections in CGD. This is a phase 1, open-label, dose-escalation study to evaluate the safety and feasibility of gp91-Grans in adults with X-linked CGD without systemic infection. Granulocyte-enriched apheresis products collected from each subject are transfected by electroporation with mRNA specific to the CGD genotype of the patient and administered by intravenous infusion. Subjects will receive one administration of study agent, followed by at least 3 days of inpatient monitoring and a final study visit about 3 months later. The first subjects enrolled will receive the study agent at the lowest dose, and when a level has been determined to be safe, the dose level will be increased to a second and then third dose level for subsequent subjects. Results of this trial will be used to determine a maximum tolerated dose (MTD) for evaluation in future trials. Efficacy of gp91-Grans will be evaluated as secondary and exploratory objectives by blood laboratory evaluations, including evaluation of circulating cells that express gp91phox.


Clinical Trial Description

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by severely reduced phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. In normal granulocytes, NADPH oxidase produces superoxide that is required for the killing of certain microorganisms. Patients with CGD have a genetic mutation for components of the NADPH oxidase. Consequently, CGD patients are at significant risk for morbidity and mortality due to serious infections and inflammatory complications. Of the types of CGD, the most common form is X-linked CGD, which occurs in about 60%-70% of CGD patients and is caused a mutation in the CYBB gene, leading to a deficiency of gp91phox protein. Despite great advances in antimicrobial options, infections remain the greatest cause of death in CGD patients. Treatment choices for intractable infections in CGD have included donor granulocyte transfusion (GT) or hematopoietic stem cell transplantation (HSCT), despite significantly increased risks of a transplant with concurrent infection. Donor GTs have been used to augment treatment of difficult infections in CGD patients for decades, including those undergoing HSCT, but can be associated with alloimmune responses that reduce the lifespan of transfused cells and increase risk of complications during subsequent HSCT. To avoid the risk of alloimmunization following donor GT, we have developed an approach to manufacture mRNA-corrected autologous granulocytes from CGD patients. In this study, we will infuse gp91phox-deficient CGD patients with autologous granulocyte-enriched cells corrected by patient-specific CGD-mRNA transfection (gp91-Grans). The eventual goal of this product is to provide short-term treatment for infections in CGD. This is a phase 1, open-label, dose-escalation study to evaluate the safety and feasibility of gp91-Grans in adults with X-linked CGD without systemic infection. Granulocyte-enriched apheresis products collected from each subject are transfected by electroporation with mRNA specific to the CGD genotype of the patient and administered by intravenous infusion. Subjects will receive one administration of study agent, followed by at least 3 days of inpatient monitoring and a final study visit about 3 months later. The first subjects enrolled will receive the study agent at the lowest dose, and when a level has been determined to be safe, the dose level will be increased to a second and then third dose level for subsequent subjects. Results of this trial will be used to determine a maximum tolerated dose (MTD) for evaluation in future trials. Efficacy of gp91-Grans will be evaluated as secondary and exploratory objectives by blood laboratory evaluations, including evaluation of circulating cells that express gp91phox. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT05189925
Study type Interventional
Source National Institutes of Health Clinical Center (CC)
Contact Joanna L Peterson
Phone (240) 292-4291
Email [email protected]
Status Recruiting
Phase Phase 1
Start date January 19, 2022
Completion date July 1, 2026

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