Base Editing for Chronic Granulomatous Disease

Overseen By Suk S De Ravin, M.D.

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

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

Disqualifiers: Hematologic malignancy, Chronic infections, Cardiac abnormalities, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new gene therapy for Chronic Granulomatous Disease (CGD), a rare condition where certain white blood cells malfunction, leading to frequent infections. Researchers seek to determine if base-edited hematopoietic stem and progenitor cells (a type of gene therapy) can improve the function of these white blood cells and reduce infections. The trial seeks men with a specific genetic mutation linked to X-linked CGD, who have experienced serious infections and are stable enough for necessary medical procedures. Participants will receive the edited cells after chemotherapy and will be monitored for 15 years to assess the treatment's effectiveness.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves chemotherapy with busulfan, it's possible that some medications might need to be adjusted. Please consult with the trial team for specific guidance.

Is there any evidence suggesting that base-edited stem cells are likely to be safe for humans?

Studies have shown that base editing in hematopoietic stem cells, which can develop into various blood cell types, is precise and effective. This new method might address the specific genetic issue causing chronic granulomatous disease (CGD).

Previous research on similar gene therapies has found them to be generally well-tolerated. However, since this trial is in the early stages (Phase 1 and 2), the main focus is on assessing the treatment's safety. Early trials like these often examine the body's reaction to the new treatment, including any side effects.

Some participants might experience side effects due to the chemotherapy administered before introducing the edited cells or from the body's immune response to the new cells. Researchers closely monitor participants' responses to ensure safety.

Prospective participants should discuss potential risks and benefits with healthcare providers, who can provide the latest information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CGD?

Unlike the standard treatments for Chronic Granulomatous Disease (CGD), which typically involve antibiotics, antifungals, and sometimes bone marrow transplants, the new approach using base-edited hematopoietic stem and progenitor cells offers a groundbreaking genetic fix. This treatment is unique because it directly edits the DNA of the patient's own stem cells to correct the genetic defect causing CGD, potentially providing a lasting cure rather than just managing symptoms. Researchers are excited about this treatment because it promises a more precise and potentially safer alternative to full bone marrow transplants, minimizing the risks of graft-versus-host disease and rejection.

What evidence suggests that base-edited stem cells might be an effective treatment for chronic granulomatous disease?

Research has shown that a new technique called base editing could help treat chronic granulomatous disease (CGD). This trial will investigate base-edited hematopoietic stem and progenitor cells as a potential treatment. The technique focuses on fixing the genetic error in the CYBB gene, which causes CGD. Studies have found that base editing can repair the faulty gene in white blood cells, improving their ability to fight infections. Early lab results showed success in correcting these cells, potentially reducing infection risk for patients. While more research is needed, these findings offer hope for boosting the immune system of 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 adult males with X-linked Chronic Granulomatous Disease (CGD), a rare immune disorder. Participants must have the specific CYBB gene mutation targeted by this study and be at least 18 years old.

Inclusion Criteria

I am healthy enough for apheresis and chemotherapy.

I have been hospitalized for a serious infection or inflammation despite treatment.

I am a male.

Exclusion Criteria

Anti-platelet antibody screening with >1 anti-platelet antibody positive in the presence of an ongoing brain infection; OR >1 anti-platelet antibody positive and considered unsafe for study participation after consultation with hematology specialist

I cannot take busulfan due to health reasons.

Cytogenetic abnormalities evidenced on bone marrow aspirate

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Development

Participants undergo apheresis to collect stem cells for base-editing correction of the mutation

2-4 weeks

Treatment

Participants receive the base-edited cells after chemotherapy with busulfan and remain in the hospital until immunity recovers

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment with evaluations at months 3, 6, 12, 18, and 24, and yearly thereafter until 5 years

5 years

Long-term Follow-up

Long-term follow-up under a separate NIH protocol will continue annually to 15 years after treatment

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Base-edited hematopoietic stem and progenitor cells

Trial Overview The trial tests if base-edited stem cells can improve white blood cell function in CGD patients, reducing infections. It involves collecting participants' stem cells, editing them to correct the genetic defect, then returning these cells after chemotherapy.

How Is the Trial Designed?

Group I: Single Arm Study Experimental Treatment 6 Interventions

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

Base editing using nucleotide deaminases linked to programmable DNA-binding proteins shows potential for treating blood disorders by modifying human hematopoietic stem and progenitor cells (HSPCs).

The study demonstrates the successful ex vivo base editing of CD34+ HSPCs through electroporation of base editor mRNA or protein, indicating a promising method for gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Base Editing of Human Hematopoietic Stem Cells. Zeng, J., Casirati, G., Nguyen, MA., et al.[2023]

Gene therapy using the CRISPR-Cas9 system has shown promise in correcting the genetic mutation responsible for chronic granulomatous disease (CGD) by restoring the function of the CYBB gene in patient-derived cells.

This approach successfully restored the oxidative burst function in immune cells, which is crucial for fighting off infections, demonstrating a potential new treatment strategy for CGD that avoids the complications of traditional gene therapy methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. Flynn, R., Grundmann, A., Renz, P., et al.[2023]

Targeted gene editing techniques like CRISPR/Cas9 and TALENs can successfully restore the function of phagocytic oxidase in stem cells from patients with chronic granulomatous disease (CGD), which is crucial for improving immune responses.

The chapter provides detailed protocols for editing human-induced pluripotent stem cells and hematopoietic stem cells, allowing for the differentiation into functional neutrophils, which can be assessed for their identity and ability to generate reactive oxygen species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Editing in Chronic Granulomatous Disease. Sweeney, CL., Merling, RK., De Ravin, SS., et al.[2022]

A new optimization method using Response Surface Methodology allows for the effective balancing of gene correction and cell health in CD34+ hematopoietic stem cells, which is crucial for treating genetic blood disorders.

Using this optimized approach, researchers successfully corrected a specific genetic defect in a patient with chronic granulomatous disease, restoring normal function in their immune cells, which is a significant step towards effective gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multidimensional Response Surface Methodology for the development of a gene editing protocol for p67phox-deficient Chronic Granulomatous Disease. Whittaker, TE., Moula, SE., Bahal, S., et al.[2023]

A proof of concept study demonstrated that optimized base editing can effectively target and correct prevalent FANCA mutations in hematopoietic stem and progenitor cells from Fanconi Anemia patients, restoring gene function.

The successful restoration of FANCA expression and FA pathway function suggests that base editing strategies could be a promising therapeutic approach for treating Fanconi Anemia in future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells. Siegner, SM., Ugalde, L., Clemens, A., et al.[2022]

A targeted CRISPR-Cas9 screen identified the p38 MAPK pathway as a key factor affecting the long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs) in X-linked chronic granulomatous disease (X-CGD).

Inhibition of p38 prior to transplantation significantly improved HSPC engraftment by increasing the expression of the homing factor CXCR4 and reducing cell death, leading to a 1.5-fold increase in donor cell engraftment in IL1B-challenged or X-CGD HSPCs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment. Klatt, D., Ha, TC., Schinke, M., et al.[2021]

Gene correction using CRISPR/Cas9 in hematopoietic stem/progenitor cells from patients with X-linked chronic granulomatous disease successfully restored the production of the gp91phox protein and reactive oxygen species (ROS) by phagocytes, which are crucial for immune function.

The study found that inserting CYBB exon 2-13 cDNA was effective in restoring gp91phox levels and ROS production, while the presence of intron 1 was necessary for optimal gene expression, highlighting the importance of donor design in gene therapy strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR/Cas9 with 53BP1 inhibition for enhanced homology-directed repair. Sweeney, CL., Pavel-Dinu, M., Choi, U., et al.[2023]

The study successfully used a base editing technique on human hematopoietic stem and progenitor cells (HSPCs) to induce therapeutic changes, specifically targeting the BCL11A enhancer to prevent sickling in sickle cell disease and correct globin chain imbalances in β-thalassemia.

Base editing resulted in high-frequency, precise modifications in HSCs, showing potential for effective treatment of blood disorders without the risks associated with traditional nuclease editing methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic base editing of human hematopoietic stem cells. Zeng, J., Wu, Y., Ren, C., et al.[2021]

The developed base editing approach effectively removes CD33 surface expression in hematopoietic stem and progenitor cells, which protects these cells from CD33-targeted therapies while maintaining normal blood cell production in both human and nonhuman primate models.

The study achieved over 70% efficiency in multiplexed editing of the CD33 and gamma globin genes, leading to long-term persistence of the edited cells and reactivation of fetal hemoglobin, suggesting a promising strategy for safer and more effective gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiplex Base Editing to Protect from CD33-Directed Therapy: Implications for Immune and Gene Therapy. Borot, F., Humbert, O., Newby, GA., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06325709

Study Details | NCT06325709 | Base Editing for Mutation ... Open-label, phase 1/2 trial to determine the safety, and efficacy of a single infusion of base-edited (BE) autologous hematopoietic stem and progenitor cells ( ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11753194/

High-fidelity PAMless base editing of hematopoietic stem ... High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease

3. trialx.com trialx.com/clinical-trials/listings/291020/base-editing-for-mutation-repair-in-hematopoietic-stem-progenitor-cells-for-x-linked-chronic-granulomatous-disease/

Base Editing for Mutation Repair in Hematopoietic Stem & ... Open-label, phase 1/2 trial to determine the safety, and efficacy of a single infusion of base-edited (BE) autologous hematopoietic stem and progenitor cells ( ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06325709?cond=X-linked%20lymphoproliferative%20disease&rank=9

Base Editing for Mutation Repair in Hematopoietic Stem & ... Open-label, phase 1/2 trial to determine the safety, and efficacy of a single infusion of base-edited (BE) autologous hematopoietic stem and progenitor cells ( ...

5. nature.com nature.com/articles/s41467-025-62738-2

Targeted gene editing and near-universal cDNA insertion ... Chronic granulomatous disease (CGD) is a severe inborn error of immunity caused by NADPH oxidase defects. Here, we develop CRISPR/Cas9-based ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1525001625003089

Clinical hematopoietic stem cell-based gene therapy Hematopoietic stem cell (HSC)-based gene therapies have seen extraordinary progress since their initial conception, now fundamentally ...