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

NCT05189925 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 22000122-I-0001
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Infection; Chronic Granulomatous Disease

Keywords

Primary Immune Deficiency; systemic infection; autologous transfusion; Apheresis

Outcome Measures

Primary Outcomes (3)

• Feasibility: Recruitment, implementation, and manufacturing of gp91-Grans for infusions.

  Determine feasibility of gp91-Grans infusion.

  3 months

• 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.

  3 months

• Safety: Frequency of grade 3 or greater adverse events or serious adverse events related to the study agent

  Determine safety of gp91-Grans infusion.

  3 months

Secondary Outcomes (2)

• Determine percent of circulating dihydrorhodamine (DHR) positive granulocytes following study agent infusion.

  3 months

• Serial measurement of circulating DHR+ granulocytes from peripheral blood until day 3 following study agent infusion or disappearance of DHR+ granulocytes.

  3 days

Study Arms (3)

IV infusion of gp91-Grans at dose K: 1e6 cells/kg

EXPERIMENTAL

Adult CGD patients without systemic infection will participate in a dose-escalation trial to identify the most effective yet safe dose of study agent. Subjects enrolled will receive 1 administration of study agent at dose K, and safety of dose will be determined.

Biological: gp91 Grans

IV infusion of gp91-Grans at dose K+1:1e7 cells/kg

EXPERIMENTAL

Adult CGD patients without systemic infection will participate in a dose-escalation trial to identify the most effective yet safe dose of study agent. Subjects enrolled will receive 1 administration of study agent at dose K+1, and safety of dose will be determined.

Biological: gp91 Grans

IV infusion of gp91-Grans at dose K+2: 1-5e8 cells/kg

EXPERIMENTAL

Adult CGD patients without systemic infection will participate in a dose-escalation trial to identify the most effective yet safe dose of study agent. Subjects enrolled will receive 1 administration of study agent at dose K+2, and safety of dose will be determined.

Biological: gp91 Grans

Interventions

gp91 Grans BIOLOGICAL

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.

IV infusion of gp91-Grans at dose K+1:1e7 cells/kg; IV infusion of gp91-Grans at dose K+2: 1-5e8 cells/kg; IV infusion of gp91-Grans at dose K: 1e6 cells/kg

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals must meet all of the following criteria to be eligible for study participation:
• 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
• For men who engage in activities that can result in pregnancy, agree to use contraception when engaging in sexual activities that can result in pregnancy. Contraception must be used from screening through 3 months after the CGD-Grans infusion. Acceptable methods of contraception include the following:
• Hormonal contraception
• Male or female condom

You may not qualify if:

• Individuals meeting any of the following criteria will be excluded from study participation:
• 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 m\^2 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.
• History of arrhythmias that are symptomatic and deemed clinically unsafe for participation by NIH CC Cardiology consultation.
• Current or history of invasive cancers that require chemotherapy within 5 years of screening.
• Active hepatitis B, C, or HIV infections at screening.
• Unstable hypertension requiring addition of new anti-hypertensives within 2 weeks of screening.
• Impaired renal function that is unstable, with serum creatinine \>3.0 mg/dL and rising.
• Serum transaminases and bilirubin that are \>3 x the upper limit of normal.
• Electrocardiogram abnormalities indicative of acute myocardial injury, or arrhythmias that presents anesthetic risks, at screening.
• Anemia with hemoglobin \<8 g/dL (transfusions to correct anemia permitted).
• Thrombocytopenia (platelets \<50 x10\^9 cells/L) (platelet transfusions to correct thrombocytopenia permitted).
• Profound thrombocytopenia (platelet counts \<10,000/microliter) that is not reversible with platelet transfusions.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (3)

• Marciano BE, Allen ES, Conry-Cantilena C, Kristosturyan E, Klein HG, Fleisher TA, Holland SM, Malech HL, Rosenzweig SD. Granulocyte transfusions in patients with chronic granulomatous disease and refractory infections: The NIH experience. J Allergy Clin Immunol. 2017 Aug;140(2):622-625. doi: 10.1016/j.jaci.2017.02.026. Epub 2017 Mar 22.

  PMID: 28342916 BACKGROUND

• Stroncek DF, Leonard K, Eiber G, Malech HL, Gallin JI, Leitman SF. Alloimmunization after granulocyte transfusions. Transfusion. 1996 Nov-Dec;36(11-12):1009-15. doi: 10.1046/j.1537-2995.1996.36111297091747.x.

  PMID: 8937413 BACKGROUND

• Heim KF, Fleisher TA, Stroncek DF, Holland SM, Gallin JI, Malech HL, Leitman SF. The relationship between alloimmunization and posttransfusion granulocyte survival: experience in a chronic granulomatous disease cohort. Transfusion. 2011 Jun;51(6):1154-62. doi: 10.1111/j.1537-2995.2010.02993.x. Epub 2010 Dec 22.

  PMID: 21175646 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Granulomatous Disease, Chronic; Infections; Primary Immunodeficiency Diseases; Toxemia

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Suk S De Ravin, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joanna L Peterson

CONTACT

(301) 346-9780; joanna.peterson@nih.gov

Suk S De Ravin, M.D.

CONTACT

(301) 496-6772; sderavin@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2022
• First Posted: January 13, 2022
• Study Start: July 22, 2022
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: April 24, 2026

Record last verified: 2025-10-16

Locations

US (1)