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

Launched by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) · Jan 12, 2022

Keywords

ClinConnect Summary

This clinical trial is studying a new treatment for Chronic Granulomatous Disease (CGD), a condition where the immune system struggles to fight off infections due to a gene mutation. The researchers are testing whether adding messenger RNA (mRNA) to a person's white blood cells can help correct this gene mutation temporarily, allowing the cells to better kill germs and potentially reduce infections. This trial is specifically looking for males aged 18 to 75 who have been diagnosed with CGD and have a specific gene mutation.

Participants will spend at least a week at the NIH Clinical Center where they will undergo a procedure to collect their white blood cells. These cells will then receive the mRNA treatment before being infused back into the participant. After the treatment, participants will keep a diary of any symptoms and will have regular follow-up calls for a month, along with a visit three months later to monitor their health. It’s important to note that participants must have a doctor for ongoing care and follow specific guidelines regarding infections and other health conditions.

Gender

MALE

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 gp91phox-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 gp91-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:
• * Evidence of moderate to severe systemic infections as defined by any of the following:
• • Fevers \>=39 (Infinite)C within 3 days of treatment.
• • Absolute neutrophil count (ANC) \>12,000/microliter at screening (some CGD patients may chronically have ANC higher than the upper limit of normal value and not have a systemic infection).
• • Standard clinical diagnosis (by any imaging technology) of pneumonia, liver abscess, or other deep tissue abscess (other than chronic anal fissures or fistula or superficial skin or subcutaneous infections, which are allowable for this trial) at screening.
• • Positive blood culture within 2 weeks of treatment.
• • Receipt of a high-dose steroid, equivalent to \>1 mg/kg/day of prednisone, within 30 days of screening. There is a high percentage of CGD patients with inflammatory bowel disease on \>0.5 mg/kg/day maintenance prednisone.
• • 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.
• • Evidence of urinary tract infection at screening.
• • Evidence of streptococcal pharyngitis at 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.