Gene Therapy for Chronic Granulomatous Disease

Recruiting at 5 trial locations

Overseen By Medical Information

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Prime Medicine, Inc.

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team to understand any specific requirements.

What data supports the effectiveness of the treatment PM359 for chronic granulomatous disease?

Research shows that gene therapy can restore important enzyme activity in immune cells, which helps fight infections in chronic granulomatous disease. Studies have demonstrated that similar gene therapy approaches can correct defects in immune cells, suggesting potential benefits for patients. ^{1 2 3 4 5}

Is gene therapy for chronic granulomatous disease safe?

Gene therapy for chronic granulomatous disease has shown stable correction over time with no adverse events related to the procedure in clinical trials. Preclinical studies also reported no evidence of harmful effects, such as cancer, in human stem cells treated with the therapy. ^{1 5 6 7 8}

What makes the treatment PM359 unique for chronic granulomatous disease?

PM359 is unique because it uses a novel gene editing technique called prime editing to modify a patient's own stem cells outside the body, aiming to correct the genetic defect causing chronic granulomatous disease. This approach is different from traditional treatments as it directly targets and repairs the underlying genetic mutation, potentially offering a more permanent solution. ^{1 2 4 7 9}

What is the purpose of this trial?

This is an open-label, single-arm, multicenter Phase 1/2 study evaluating the safety and efficacy of gene therapy by transplantation of Prime Edited autologous CD34+ stem cells modified ex vivo (PM359) in participants with autosomal recessive Chronic Granulomatous Disease (CGD) caused by mutations in the NCF1 (Neutrophil Cytosolic Factor 1) gene.

Eligibility Criteria

This trial is for individuals with autosomal recessive Chronic Granulomatous Disease (CGD) due to NCF1 gene mutations. Specific eligibility criteria are not provided, but typically include factors like age, disease severity, and overall health status.

Inclusion Criteria

Willingness to participate in this study as well as a long-term follow-up study with the understanding that the total participation is 15 years

I have had a severe infection or an ongoing health issue due to CGD.

I have Chronic Granulomatous Disease with a specific genetic mutation.

Exclusion Criteria

I am under 16 and have a fully matched family donor for my treatment.

I am not allergic to the drugs used in stem cell transplant procedures.

I have no current or past cancers, except for certain early-stage skin, cervical, or colon cancers.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Mobilization and Apheresis

Autologous CD34+ cells are collected from the participant via mobilization and apheresis

1-2 weeks

Gene Editing and Conditioning

Collected cells are shipped to a central facility, modified using Prime Editing, and infused back into the participant following conditioning

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• PM359

Trial Overview The study tests a new gene therapy called PM359. It involves editing the genes of a patient's own stem cells and then transplanting them back into the body to treat CGD.

Participant Groups

Group I: PM359 Experimental Treatment 1 Intervention

PM359 is an autologous CD34+ hematopoietic stem cell (HSC) suspension that is Prime Edited at the NCF1 locus resulting in expression of the p47phox protein.

Who Is Running the Clinical Trial?

Prime Medicine, Inc.

Lead Sponsor

Trials

1

Recruited

10+

Findings from Research

Ex vivo gene therapy for chronic granulomatous disease (CGD) has previously shown only temporary improvements in neutrophil function, with less than 0.1% of neutrophils corrected.

The next generation of clinical trials will use advanced RD114 envelope pseudotyped vectors and non-ablative marrow conditioning, which could significantly enhance the effectiveness of gene therapy for CGD by improving the transduction of stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward effective gene therapy for chronic granulomatous disease. Malech, HL., Choi, U., Brenner, S.[2017]

Researchers successfully created induced pluripotent stem cells (iPSCs) from patients with all five genetic forms of chronic granulomatous disease (CGD), achieving targeted correction in 70-80% of clones using a safe harbor gene editing technique.

The corrected iPSCs differentiated into neutrophils and macrophages that showed restored oxidase activity and improved ability to fight off specific bacterial infections, demonstrating the potential of this approach for treating CGD and possibly other genetic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An AAVS1-targeted minigene platform for correction of iPSCs from all five types of chronic granulomatous disease. Merling, RK., Sweeney, CL., Chu, J., et al.[2021]

In a study of 26 boys with X-linked chronic granulomatous disease (X-CGD), haploid hematopoietic stem cell (haplo-HSC) transplantation combined with third-party umbilical cord blood (tpCB) transplantation showed promising results, with a 5-year event-free survival rate of 81% and an overall survival rate of 89%.

The treatment led to normal NADPH oxidase activity within one month post-transplantation, indicating effective restoration of immune function, and no primary implant failures were reported, highlighting the safety and efficacy of this combined transplantation approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease]. Tang, XF., Lu, W., Jing, YF., et al.[2020]

Gene replacement therapy targeting hematopoietic stem cells (HSCs) shows promise for treating chronic granulomatous disease (CGD), a condition caused by mutations affecting the immune system's ability to fight infections.

Initial Phase I clinical studies demonstrated that gene-corrected neutrophils can be produced in CGD patients, although the expression was transient, highlighting the need for improved gene transfer techniques and HSC engraftment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for chronic granulomatous disease. Barese, CN., Goebel, WS., Dinauer, MC.[2019]

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]

Transiently inhibiting the p53-binding protein 1 (53BP1) significantly enhances the efficiency of gene editing in CD34+ hematopoietic cells, achieving an impressive 80% correction rate for X-linked chronic granulomatous disease (X-CGD).

This approach addresses previous concerns about lentivector gene therapy by improving long-term safety and efficacy through more effective homology-directed repair, which restores normal protein expression in the affected cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem/progenitor cells. De Ravin, SS., Brault, J., Meis, RJ., et al.[2022]

In a first-in-human study involving nine patients with X-linked chronic granulomatous disease (X-CGD), autologous gene therapy showed promising safety and efficacy, with six out of seven surviving patients demonstrating stable gene expression and functional immune recovery at 12 months.

The treatment led to a significant reduction in CGD-related infections, with six patients able to stop antibiotic prophylaxis, indicating that this gene therapy could effectively enhance immunity in CGD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lentiviral gene therapy for X-linked chronic granulomatous disease. Kohn, DB., Booth, C., Kang, EM., et al.[2021]

A recent study on lentiviral gene therapy for p47phox-deficient chronic granulomatous disease (CGD) showed successful biochemical correction in a mouse model, indicating potential effectiveness for human treatment.

Preclinical safety assessments revealed no adverse events, such as mutagenesis or tumorigenesis, in human stem cells treated with the gene therapy, supporting the safety of proceeding to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47phox-Deficient Chronic Granulomatous Disease. Schejtman, A., Vetharoy, W., Choi, U., et al.[2023]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Progress toward effective gene therapy for chronic granulomatous disease. [2017]

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

An AAVS1-targeted minigene platform for correction of iPSCs from all five types of chronic granulomatous disease. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[A clinical study of haploid hematopoietic stem cells combined with third-party umbilical cord blood transplantation in the treatment of chronic granulomatous disease]. [2020]

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

Gene therapy for chronic granulomatous disease. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem/progenitor cells. [2022]

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

Lentiviral gene therapy for X-linked chronic granulomatous disease. [2021]

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

Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47phox-Deficient Chronic Granulomatous Disease. [2023]

9. England pubmed.ncbi.nlm.nih.gov

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