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.
Males aged 18 to 75 years
CGD confirmed by DHR and deficiency subtype confirmed by protein analysis and/or genetic sequencing
Has a physician at home for follow-up care
Able to provide informed consent
Clinically unstable due to moderate to severe acute systemic infections as defined by persistent resting tachypnea, tachycardia, or hypoxia of >20% from baseline and hypotension.
Current or history of stage 4 chronic kidney disease or estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m² within 90 days of baseline.
Unstable diabetes mellitus with hemoglobin A1c >7.0% and fasting serum glucose >200 mg/dL at screening.
Current or history of heart failure stage D as defined by the American College of Cardiology Foundation/American Heart Association guidelines.
Sequential
gp91 Grans
Biological/VaccineAdults 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.
Feasibility: Recruitment, implementation, and manufacturing of gp91-Grans for infusions.
Determine feasibility of gp91-Grans infusion.
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
Determine an MTD for administration.
Safety: Frequency of grade 3 or greater adverse events or serious adverse events related to the study agent
Determine safety of gp91-Grans infusion.
Determine percent of circulating dihydrorhodamine (DHR) positive granulocytes following study agent infusion.
Assess efficacy of gp91-Grans at restoring NADPH oxidase
Serial measurement of circulating DHR+ granulocytes from peripheral blood until day 3 following study agent infusion or disappearance of DHR+ granulocytes.
Determine the kinetics of gp91-Grans.
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