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

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the treatment for Chronic Granulomatous Disease?

Research shows that gene therapy can restore NADPH oxidase activity in cells from patients with Chronic Granulomatous Disease (CGD). For example, studies have demonstrated that transferring functional genes into patient cells can correct the cellular defect, leading to improved enzyme activity, which is crucial for fighting infections. ^{1 2 3 4 5}

Is gp91 Grans treatment safe for humans?

Studies on similar treatments for chronic granulomatous disease (CGD) show that gene therapy approaches, like using mRNA-transfected cells, have been tested in animals and found to be safe, with no harmful genetic changes observed. These studies support the potential safety of such treatments in humans. ^{1 3 6 7 8}

How is the gp91 Grans treatment for Chronic Granulomatous Disease different from other treatments?

The gp91 Grans treatment is unique because it uses mRNA-transfected granulocyte-enriched cells to correct NADPH oxidase activity, which is a novel approach compared to traditional gene therapy methods that focus on directly modifying stem cells or using viral vectors. ^{1 3 4 9 10}

Research Team

Suk S De Ravin, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2017]

2. United States 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Gene transfer to primary chronic granulomatous disease monocytes. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Signed outside: a surface marker system for transgenic cytoplasmic proteins. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

NADPH oxidase deficiency in X-linked chronic granulomatous disease. [2018]

6. United States 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. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

NADPH oxidase correction by mRNA transfection of apheresis granulocytes in chronic granulomatous disease. [2021]

8. England 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. [2021]

9. United States 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent. [2019]