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

Official title

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

Overview

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.

Interventions

• 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.

Primary outcome measures

• Feasibility: Recruitment, implementation, and manufacturing of gp91-Grans for infusions. [Time frame: 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 [Time frame: 3 months]
• Safety: Frequency of grade 3 or greater adverse events or serious adverse events related to the study agent [Time frame: 3 months]

Secondary outcome measures (2)

• Determine percent of circulating dihydrorhodamine (DHR) positive granulocytes following study agent infusion. [Time frame: 3 months]
• Serial measurement of circulating DHR+ granulocytes from peripheral blood until day 3 following study agent infusion or disappearance of DHR+ granulocytes. [Time frame: 3 days]

Eligibility criteria

• INCLUSION CRITERIA:

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

Exclusion criteria

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.

NOTE: For prospective subjects who, per PI assessment at screening, have abnormal liver function tests, and/or a significant history of liver disease, and/or liver-related complications of CGD, and who otherwise meet eligibility criteria \[i.e. those who do NOT meet any of the exclusion set forth herein\], a hepatology consult will be required at screening, and participation must be approved in writing by hepatology to the PI.

• 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.
• Abnormal prothrombin time/partial thromboplastin time (PT/PTT) values outside the ranges accepted at the NIH CC that are not corrected or that cannot be attributed to presence of Lupus anticoagulant (commonly found in CGD patients).
• Inherited bleeding disorder that precludes line placement.
• Severe oxygen-dependent pulmonary disease that increases risks of procedures that may require sedation.
• History of or current evidence of alcohol or illicit drug abuse or dependence.
• Participation in a clinical protocol that includes an intervention that, in the opinion of the investigator, may affect the results of the current study.

Subjects will be selected in an equitable manner from the available pool of potentially eligible individuals, without regard to factors such as gender, race, ethnicity, socioeconomic status, etc, except for age and sex.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• National Institutes of Health Clinical Center — Bethesda

Publications

• 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
• 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
• 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

Identifiers

NCT: NCT05189925 · 220001 · 22-I-0001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗