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

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:

• Determine the safety and feasibility of CGD-Grans infusion.
• Determine an MTD for administration.

Secondary Objectives:

• Assess efficacy of CGD-Grans at restoring NADPH oxidase.
• Determine the kinetics of CGD-Grans.

Exploratory Objectives:

• Assess for inflammatory responses to CGD-Grans infusion.
• Assess for immune responses to protein expressed by the transfected mRNA.
• Evaluate in vitro bactericidal activity of CGD-Grans.

Primary Endpoints:

• 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.

• 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:

• Determine percent of circulating dihydrorhodamine (DHR) positive granulocytes following study agent infusion.
• Serial measurement of circulating DHR+ granulocytes from peripheral blood until day 3 following study agent infusion or disappearance of DHR+ granulocytes.

Exploratory Endpoint:

• Assess for increased expression of inflammation-related genes after study agent infusion.
• Evaluate for development of antibodies against mRNA-expressed CGDphox.
• Perform in vitro bactericidal activity of CGD-Grans.

• 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.