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

  • End date
    Jul 1, 2026
  • participants needed
  • sponsor
    National Institute of Allergy and Infectious Diseases (NIAID)
Updated on 27 October 2022



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.


To test a procedure in which mRNA is added to a person s blood cells.


Males aged 18-75 with CGD with a mutation in the gene that makes the protein gp91phox.


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.


Study Design:

This is a phase 1, open-label, dose-escalation trial to assess the safety and feasibility of administering gp91-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 gp91mRNA transfected granulocyte-enriched cells, referred to as gp91-Grans. The study agent is derived from apheresis product enriched for granulocytes, which are then transfected with CYBB

gp91 mRNA and administered as an intravenous (IV) infusion.Gp91-Grans will be evaluated using the 3+3 modified Fibonacci model at the following 3 escalating dosages:

Dose K: 1(SqrRoot) 106 granulocyte-enriched cells/kg body mass

Dose K+1: 1(SqrRoot) 107 granulocyte-enriched cells/kg body mass

Dose K+2: 1-5(SqrRoot) 108 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 gp91-Grans infusion.
  2. Determine an MTD for administration.

Secondary Objectives:

  1. Assess efficacy of gp91-Grans at restoring NADPH oxidase.
  2. Determine the kinetics of gp91-Grans.

Exploratory Objectives:

  1. Assess for inflammatory responses to gp91-Grans infusion.
  2. Assess for immune responses to protein expressed by the transfected mRNA.
  3. Evaluate in vitro bactericidal activity of gp91-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 gp91-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 genesafter study agent infusion.
  2. Evaluate for development of antibodies against mRNA-expressed gp91phox.
  3. Perform in vitro bactericidal activity of gp91-Grans.

Condition Chronic Granulomatous Disease, Infection
Treatment gp91 Grans
Clinical Study IdentifierNCT05189925
SponsorNational Institute of Allergy and Infectious Diseases (NIAID)
Last Modified on27 October 2022


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