Gene correction for immune cells in patients with Chronic Granulomatous Disease

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

This study is testing a new way to fix a gene in immune cells from people with Chronic Granulomatous Disease to see if it can help their immune system work better.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years to 75 Years
• Sex: Male
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT05189925 on ClinicalTrials.gov

What this trial studies

This phase 1 trial aims to evaluate the safety and feasibility of using messenger RNA (mRNA) to correct a genetic mutation in granulocyte-enriched cells from patients with Chronic Granulomatous Disease (CGD). Participants will undergo apheresis to collect their white blood cells, which will then be transfected with mRNA to restore the function of the NADPH oxidase protein. The study will assess the maximum tolerated dose of the mRNA treatment and monitor participants for safety and efficacy over a period of time. The trial will involve hospitalization for monitoring and follow-up visits to evaluate the treatment's impact.

Who should consider this trial

Good fit: Ideal candidates are males aged 18 to 75 with a confirmed diagnosis of CGD due to a mutation in the gp91phox gene.

Not a fit: Patients with moderate to severe systemic infections or those with other significant health issues may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve the immune response in patients with CGD, reducing their susceptibility to infections.

How similar studies have performed: While gene therapy approaches have shown promise in other conditions, this specific method using mRNA for CGD is novel and has not been extensively tested.

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.

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Suk S De Ravin, M.D. — National Institute of Allergy and Infectious Diseases (NIAID)
• Study coordinator: Joanna L Peterson

Conditions Chronic Granulomatous Disease; Infection; Primary Immune Deficiency; systemic infection; autologous transfusion; Apheresis