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

Trial Summary

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.

What data supports the idea that Base Editing for Chronic Granulomatous Disease is an effective treatment?

The available research shows that base editing can effectively correct genetic mutations in blood cells. For example, in one study, base editing was used to correct a mutation in cells from patients with sickle cell disease, leading to improvements in blood cell function. Although this study focused on a different condition, it demonstrates the potential of base editing to fix genetic issues in blood cells, which is relevant for treating Chronic Granulomatous Disease. Additionally, other gene editing methods, like CRISPR, have shown success in restoring immune function in cells from CGD patients, suggesting that base editing could also be effective. ^{1 2 3 4 5}

What safety data exists for base editing treatment in chronic granulomatous disease?

The research does not provide specific safety data for base editing in chronic granulomatous disease (CGD). However, it highlights the potential of base editing in hematopoietic stem and progenitor cells (HSPCs) for treating blood disorders, including the use of base editing to protect from CD33-directed therapy and restore function in Fanconi anemia. These studies suggest that base editing can be effective and may have reduced off-target effects compared to other gene editing methods, but specific safety data for CGD is not detailed. ^{4 5 6 7 8}

Is the treatment Base-edited hematopoietic stem and progenitor cells a promising treatment for Chronic Granulomatous Disease?

Yes, base-edited hematopoietic stem and progenitor cells are a promising treatment for Chronic Granulomatous Disease. This approach can correct genetic mutations in the patient's own cells, restoring the immune system's ability to fight infections. It offers a targeted and potentially safer alternative to traditional bone marrow transplants, aiming to fix the root cause of the disease. ^{2 3 5 7 9}

What is the purpose of this trial?

Background: Chronic granulomatous disease (CGD) is a rare immune disorder caused by a mutation in the CYBB gene. People with CGD have white blood cells that do not work properly. This places them at risk of developing infections that may be life-threatening. Stem cell transplant can cure CGD but transplanting stem cells donated by other people can have serious complications. In addition, not everyone has a matched donor. Another approach is a type of gene therapy that involves base-editing to correct the mutation in a person s own stem cells. Researchers want to know if the base-edited stem cells can improve the white cells' functioning and result in fewer CGD-related infections. Objective: To learn if base-edited stem cells will improve white blood cells' ability to fight against infections in people with CGD. Eligibility: Males aged 18 years and older with X-linked CGD. Design: This is a non-randomized study. Participants with the specific mutation under study will be screened during the initial phase. During the development phase, participants will undergo apheresis to collect stem cells for base-editing correction of the mutation. During the treatment phase, participants will receive the base-edited cells after chemotherapy with busulfan. Participants will remain in the hospital until their immunity recovers. Follow-up visits will continue for 15 years.

Research Team

Suk S De Ravin, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Single Arm Study Experimental Treatment 5 Interventions

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 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]

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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment. [2021]

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

Gene Editing in Chronic Granulomatous Disease. [2022]

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

Multidimensional Response Surface Methodology for the development of a gene editing protocol for p67phox-deficient Chronic Granulomatous Disease. [2023]

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

Therapeutic base editing of human hematopoietic stem cells. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. [2023]

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

Multiplex Base Editing to Protect from CD33-Directed Therapy: Implications for Immune and Gene Therapy. [2023]

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

Base Editing of Human Hematopoietic Stem Cells. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells. [2022]

9. England 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. [2023]