NCT05189925

NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD)

NADPH Oxidase Correction in mRNA Transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD)

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) · NIH
• Sex: Male
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

Background: CGD is caused by a gene mutation. For people with CGD, their cells cannot kill germs well, so they can get frequent or life-threatening infections. Researchers want to see if a new procedure can help a person s cells kill germs for a short time. It uses messenger RNA (mRNA) to deliver correct instructions for the gene mutation to the cells. Objective: To test a procedure in which mRNA is added to a person s blood cells. Eligibility: Males aged 18-75 with CGD with a mutation in the gene that makes the protein gp91phox. Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Swab to test for strep throat Some screening tests will be repeated during the study. Participants will be admitted to the NIH Clinical Center hospital for at least 7 days. They will have apheresis. For this, a medicine is injected under their skin to prepare their white blood cells for collection. An IV line is placed into an arm vein. Blood goes through the IV line into a machine that divides whole blood into red blood cells, plasma, and white blood cells. The white blood cells are removed, and the rest of the blood is returned to the participant through an IV line in their other arm. The next day, they will get their mRNA-corrected cells via IV. They will be monitored for 3 more days. After discharge, participants will keep a symptom diary. They will be contacted weekly for one month, and then once a month. They will have a follow-up visit 3 months after the infusion.

Detailed description

Study Design: This is a phase 1, open-label, dose-escalation trial to assess the safety and feasibility of administering CGD-Grans to adult patients with X-linked CGD and to identify the maximum tolerated dose (MTD). Subjects will undergo granulocyte-enriched apheresis to provide cell product for mRNA-correction and then receive 1 administration of study agent. 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.Subjects will be hospitalized for at least 3 days after study agent administration and will return for a final study visit about 3 months after administration. Blood will be collected regularly for safety and research evaluations. The study hypothesis is that it is safe and feasible to administer mRNA-transfected autologous granulocyte-enriched apheresis product to restore protein expression and phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function in patients with CGD. Study Agent Description: The study agent is one administration of autologous CGD mRNA transfected granulocyte-enriched cells, referred to as CGD-Grans. The study agent is derived from apheresis product enriched for granulocytes, which are then transfected with CGD mRNA and administered as an intravenous (IV) infusion. CGD-Grans will be evaluated using the 3+3 modified Fibonacci model at the following 3 escalating dosages: Dose K: 1 x 10\^6 granulocyte-enriched cells/kg body mass Dose K+1: 1 x 10\^7 granulocyte-enriched cells/kg body mass Dose K+2: 1-5 x 10\^8 granulocyte-enriched cells/kg body mass Each dose will be evaluated in at least 3 subjects. Dose escalation will be managed by a predetermined algorithm depending on the occurrence of drug-related toxicity (DRT). There will be at least 1 week between study agent administration to each subject. Primary Objectives: 1. Determine the safety and feasibility of CGD-Grans infusion. 2. Determine an MTD for administration. Secondary Objectives: 1. Assess efficacy of CGD-Grans at restoring NADPH oxidase. 2. Determine the kinetics of CGD-Grans. Exploratory Objectives: 1. Assess for inflammatory responses to CGD-Grans infusion. 2. Assess for immune responses to protein expressed by the transfected mRNA. 3. Evaluate in vitro bactericidal activity of CGD-Grans. Primary Endpoints: 1. Determine safety and feasibility by: Safety: Frequency of grade 3 or greater adverse events (AEs) or serious adverse events (SAEs) related to the study agent. Feasibility: Recruitment, implementation, and manufacturing of CGD-Grans for infusions. 2. MTD determination based on the rate of AEs. MTD is defined as the highest dose level that does not cause the same grade 3 or 4 AEs in 3 or more patients. Secondary Endpoints: 1. Determine percent of circulating dihydrorhodamine (DHR) positive granulocytes following study agent infusion. 2. Serial measurement of circulating DHR+ granulocytes from peripheral blood until day 3 following study agent infusion or disappearance of DHR+ granulocytes. Exploratory Endpoint: 1. Assess for increased expression of inflammation-related genes after study agent infusion. 2. Evaluate for development of antibodies against mRNA-expressed CGDphox. 3. Perform in vitro bactericidal activity of CGD-Grans.

Conditions

• Chronic Granulomatous Disease
• Infection

Interventions

Type	Name	Description
BIOLOGICAL	gp91 Grans	Adults with gp91phox-deficient CGD without systemic infection will participate in a dose escalation trial to identify the MTD (the most effective yet safe dose) of gp91 Grans IV infusion.

Timeline

• Start date: 2022-07-22
• Primary completion: 2026-07-01
• Completion: 2026-07-01
• First posted: 2022-01-13
• Last updated: 2026-04-07

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study