gp91 Grans for Chronic Granulomatous Disease

Overseen By Suk S De Ravin, M.D.

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: High-dose steroids

Disqualifiers: Systemic infections, Kidney disease, Diabetes, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 3 days

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore a new treatment for Chronic Granulomatous Disease (CGD), a condition caused by a gene mutation that impairs cells' ability to fight infections. The treatment, called NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells, uses messenger RNA (mRNA) to instruct blood cells to temporarily enhance their germ-killing ability. Researchers seek to determine the safety and effectiveness of different doses. Men with CGD, specifically those with a mutation in the gp91phox gene and without severe infections, might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on high-dose steroids, you must not have taken them within 30 days before screening.

What prior data suggests that this procedure is safe for humans?

Earlier studies have shown promise in using mRNA to address certain gene-related problems. Researchers found it safe to use mRNA to improve cell function in patients with CGD, helping restore protein function without major issues.

The treatment aims to deliver mRNA into blood cells to enhance their ability to fight infections. Reports suggest that side effects are generally mild and manageable. However, as this is an early-stage trial, researchers are closely monitoring safety. This stage primarily focuses on ensuring the treatment's safety for humans. Participants in this trial will receive different doses to determine the safest and most effective amount. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about gp91 Grans for Chronic Granulomatous Disease (CGD) because it represents a novel approach using NADPH oxidase correction. Unlike traditional treatments that primarily focus on managing symptoms and preventing infections, gp91 Grans work by directly targeting the underlying genetic defect in CGD. This new treatment involves mRNA-transfected granulocyte-enriched cells to boost the immune system’s function. By focusing on correcting the genetic issue, gp91 Grans have the potential to offer a more effective and long-lasting solution for CGD patients, which is why there's significant interest in this innovative approach.

What evidence suggests that this trial's treatments could be effective for CGD?

Research has shown that mRNA can help restore cells' ability to fight infections in people with Chronic Granulomatous Disease (CGD). In earlier studies, mRNA provided cells with the correct instructions, successfully fixing the gene problem that causes the disease. This method worked well in tests, with many cells remaining healthy and effectively receiving the mRNA. These findings suggest that using mRNA to correct the genetic issue in CGD cells can enhance their ability to kill germs. In this trial, participants will receive an IV infusion of gp91-Grans at different doses to determine the most effective and safe dose. Although researchers are still studying this approach, early results are promising for boosting the immune system in people with CGD. ^{1 2 3 5 6}

Who Is on the Research Team?

Suk S De Ravin, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

This trial is for males aged 18-75 with Chronic Granulomatous Disease (CGD) due to a gp91phox gene mutation. Participants must be able to consent, have follow-up care arranged, and agree to use contraception if they can cause pregnancy.

Inclusion Criteria

Able to provide informed consent

I agree to use contraception methods like condoms or hormonal contraception.

My CGD and its gp91phox-deficiency subtype are confirmed by specific tests.

Exclusion Criteria

Evidence of moderate to severe systemic infections as defined by fevers >=39°C within 3 days of treatment, ANC >12,000/microliter at screening, standard clinical diagnosis of pneumonia, liver abscess, or other deep tissue abscess, positive blood culture within 2 weeks of treatment, receipt of high-dose steroid within 30 days of screening, current or history of stage 4 chronic kidney disease, unstable diabetes mellitus, current or history of heart failure stage D, history of symptomatic arrhythmias, current or history of invasive cancers requiring chemotherapy within 5 years of screening, evidence of urinary tract infection, evidence of streptococcal pharyngitis, active hepatitis B, C, or HIV infections, unstable hypertension requiring addition of new anti-hypertensives within 2 weeks of screening, impaired renal function with serum creatinine >3.0 mg/dL, serum transaminases and bilirubin >3 x the upper limit of normal, electrocardiogram abnormalities indicative of acute myocardial injury or anesthetic risks, anemia with hemoglobin <8 g/dL, thrombocytopenia, profound thrombocytopenia not reversible with platelet transfusions, abnormal PT/PTT values outside accepted ranges, inherited bleeding disorder precluding line placement, severe oxygen-dependent pulmonary disease, history of alcohol or illicit drug abuse or dependence, participation in a clinical protocol that may affect study results

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Apheresis and mRNA Transfection

Participants undergo apheresis to collect granulocyte-enriched cells, which are then transfected with mRNA

1 day

1 visit (in-person)

Treatment

Participants receive an IV infusion of mRNA-corrected cells and are monitored for safety and efficacy

3 days

Hospitalization for at least 3 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including regular blood tests and a final study visit

3 months

Weekly contact for 1 month, then monthly contact, with a final visit at 3 months

What Are the Treatments Tested in This Trial?

Interventions

• NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells

Trial Overview The study tests a procedure where mRNA is added to blood cells in CGD patients. It aims to correct the gene defect temporarily so cells can better fight infections. Patients will undergo cell collection, receive mRNA-corrected cells via IV, and be monitored.

How Is the Trial Designed?

Group I: IV infusion of gp91-Grans at dose K: 1e6 cells/kg Experimental Treatment 1 Intervention

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.

Group II: IV infusion of gp91-Grans at dose K+2: 1-5e8 cells/kg Experimental Treatment 1 Intervention

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.

Group III: IV infusion of gp91-Grans at dose K+1:1e7 cells/kg Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Researchers created a human cell model of X-linked chronic granulomatous disease (X-CGD) by disrupting the gene responsible for the gp91phox subunit, which is crucial for superoxide production in immune cells.

The study found that introducing wild-type gp91phox cDNA into these cells restored their ability to produce superoxide, indicating that even low levels of gp91phox can effectively correct the respiratory-burst activity, which is important for potential gene replacement therapies for X-CGD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene targeting of X chromosome-linked chronic granulomatous disease locus in a human myeloid leukemia cell line and rescue by expression of recombinant gp91phox. Zhen, L., King, AA., Xiao, Y., et al.[2022]

A new gene therapy using a lentiviral vector (G1XCGD) has shown promise in treating chronic granulomatous disease (CGD) by successfully expressing the gp91phox transgene in myeloid cells, which is crucial for restoring phagocyte function.

Extensive safety studies demonstrated that the G1XCGD treatment did not cause harmful mutations in cells, allowing for the approval of clinical trials in Europe and the United States for patients with X-linked CGD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Clinical Efficacy and Safety Studies on G1XCGD, a Lentiviral Vector for Ex Vivo Gene Therapy of X-Linked Chronic Granulomatous Disease. Brendel, C., Rothe, M., Santilli, G., et al.[2019]

Gene therapy using a retrovirus to deliver the p67phox gene to CD34+ hematopoietic progenitors from a patient with chronic granulomatous disease (CGD) successfully corrected the functional defect in phagocyte oxidase activity in vitro, achieving up to 32% oxidase-positive granulocytes.

The transduced progenitors demonstrated significant restoration of superoxide production, with some cultures showing correction rates of oxidase activity in myeloid cells as high as 44%, indicating a promising approach for treating p67phox deficient CGD without needing selective enrichment of transduced cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic correction of p67phox deficient chronic granulomatous disease using peripheral blood progenitor cells as a target for retrovirus mediated gene transfer. Weil, WM., Linton, GF., Whiting-Theobald, N., et al.[2021]

A novel gene therapy using a retroviral vector successfully restored superoxide-generating activity in cells from patients with X-linked chronic granulomatous disease (X-CGD), achieving up to 85% transduction of CD34+ cells from bone marrow.

The transduced cells demonstrated corrected NADPH oxidase activity at 45-52% of normal levels, indicating that this genetic modification could provide a curative approach for X-CGD patients, as even a small amount of superoxide production can protect against serious infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of respiratory burst activity in X-linked chronic granulomatous cells to therapeutically relevant levels after gene transfer into bone marrow CD34+ cells. Becker, S., Wasser, S., Hauses, M., et al.[2017]

Phagocytosis significantly enhances NADPH oxidase activity in neutrophils, increasing it fourfold under optimal conditions, which is crucial for the immune response.

Neutrophils from patients with X-linked chronic granulomatous disease (CGD) show a marked deficiency in NADPH oxidase activity, highlighting the importance of this enzyme in effective phagocytic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NADPH oxidase deficiency in X-linked chronic granulomatous disease. Hohn, DC., Lehrer, RI.[2018]

Chronic granulomatous disease (CGD) patients show altered T-cell responses, including skewed TCRV-beta distribution and reduced proliferation in CD8+ T cells, especially in older individuals, indicating potential adaptive immune system involvement.

The study found that T cells do not express the gp91phox protein, and their reactive oxygen species (ROS) generation is independent of the NADPH oxidase pathway, suggesting that the immune dysfunction in CGD is not due to T cell activity but rather linked to the underlying phagocytic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent. Chiriaco, M., Casciano, F., Di Matteo, G., et al.[2019]

A novel gene therapy vector for chronic granulomatous disease was developed, allowing for the effective measurement of p47phox expression using a surface marker, ΔLNGFR, linked to the p47phox transgene.

This system demonstrated that the p47phox product restored important immune function in various cell types, indicating potential for effective treatment in patients with this immunodeficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signed outside: a surface marker system for transgenic cytoplasmic proteins. Wohlgensinger, V., Seger, R., Ryan, MD., et al.[2017]

A recombinant adenovirus carrying a functional copy of the gp91phox gene successfully restored respiratory burst activity in monocyte-derived macrophages from patients with X-linked chronic granulomatous disease (X-CGD), with 74% of cells showing phenotypic correction.

This approach suggests that adenoviral gene transfer could be a promising therapeutic strategy for X-CGD, potentially allowing for the use of genetically corrected autologous monocytes to help patients combat life-threatening infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated gene transfer into monocyte-derived macrophages of patients with X-linked chronic granulomatous disease: ex vivo correction of deficient respiratory burst. Schneider, SD., Rusconi, S., Seger, RA., et al.[2021]

Using an adenovirus vector to deliver the p47phox gene to monocytes from patients with chronic granulomatous disease (CGD) successfully restored NADPH oxidase activity, indicating a potential therapeutic strategy.

This method not only provides a rapid way to diagnose the specific molecular defect in CGD but also shows promise for future gene therapy applications to correct the cellular defect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer to primary chronic granulomatous disease monocytes. Thrasher, AJ., Casimir, CM., Kinnon, C., et al.[2019]

A novel treatment using mRNA electroporation can restore the function of granulocytes in patients with chronic granulomatous disease (CGD), improving their ability to fight infections by enhancing NADPH oxidase activity.

In nonhuman primate studies, this approach demonstrated safety and persistence of the treated cells in the bloodstream, suggesting it could be a promising nonalloimmunizing therapy for CGD patients facing severe infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NADPH oxidase correction by mRNA transfection of apheresis granulocytes in chronic granulomatous disease. De Ravin, SS., Brault, J., Meis, RJ., et al.[2021]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324920303613

Development of a gmp manufacturing process for nadph ... Viability and GFP transfection efficiency were high in final product (∼ 4 hours post transfection)(99±0.6% and 91.9±3.6%, respectively). Patient stored RO ...

2. withpower.com withpower.com/trial/phase-1-granuloma-2022-6816b

gp91 Grans for Chronic Granulomatous Disease 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 ...

3. clinicaltrial.be clinicaltrial.be/fr/details/34502?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

NADPH Oxidase Correction in mRNA-transfected ... 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- ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05189925

Study Details | NCT05189925 | NADPH Oxidase ... The study hypothesis is that it is safe and feasible to administer mRNA-transfected autologous granulocyte-enriched apheresis product to restore protein ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7724899/

NADPH oxidase correction by mRNA transfection ... Efficient clinical-scale correction of oxidase activity in X-linked CGD patient apheresis granulocytes is achieved by mRNA transfection.

6. aging.networkofcare.org aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT05189925?keyword=%22Apheresis%22

NADPH Oxidase Correction in mRNA-transfected Granulocyte- ... The study hypothesis is that it is safe and feasible to administer mRNA-transfected autologous granulocyte-enriched apheresis product to restore protein ...