Gene Therapy for Chronic Granulomatous Disease

Overseen By Elizabeth M Kang, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

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

Must not be taking: Gamma-interferon

Disqualifiers: Pregnancy, HIV, Hepatitis, Anemia, others

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

Compensation: Varies

Number of Visits: 8

Duration: 1 day

10 Participants Needed

Trial Summary

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, it mentions that you cannot have taken gamma-interferon within 30 days before the infusion of the modified cells, so you may need to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment pCCLCHIM-p47 for chronic granulomatous disease?

Research shows that the pCCLCHIM-p47 treatment can restore the function of a key enzyme in cells from patients with chronic granulomatous disease, helping them fight infections better. In mice, this treatment reduced bacterial infections, suggesting it could be beneficial for patients. ^{1 2 3 4 5}

How is the treatment pCCLCHIM-p47 unique for chronic granulomatous disease?

The treatment pCCLCHIM-p47 is a gene therapy that aims to correct the genetic defect in chronic granulomatous disease by introducing a functional copy of the p47phox gene, which is crucial for restoring the activity of NADPH oxidase in immune cells. This approach is different from traditional treatments as it targets the root cause of the disease at the genetic level, potentially offering a long-term solution rather than just managing symptoms. ^{1 2 4 6 7}

What is the purpose of this trial?

Background: Chronic granulomatous disease (CGD) is a genetic disorder. People with CGD are missing a gene that affects their white blood cells. White cells are part of the immune system, and people with GCD are vulnerable to many infections. Researchers want to test a new treatment to replace the missing gene that may be safer than the current treatment for CGD. Objective: To test a new type of gene therapy in people with CGD. Eligibility: People aged 3 years or older with CGD. Design: Participants will undergo apheresis: Blood will be collected through a tube attached to a needle inserted in a vein; the blood will run through a machine that separates certain cells (stem cells); the remaining blood will be returned to the body through a second needle. The participant s stem cells will be modified in a laboratory to add the gene they are missing. Participants will stay in the hospital for about 40 days. For the first 10 days, they will undergo many exams, including imaging scans and tests of their heart and lung function. They will receive drugs to prepare their bodies for the gene therapy. They will receive a "central line": A hollow tube will be inserted into a vein in the chest, with a port opening above the skin. This port will be used to draw blood and administer drugs without the need for new needle sticks. For the gene therapy, each participant s own modified stem cells will be put into their body through the port. Participants will have 8 follow-up visits over 3 years.

Research Team

Elizabeth M Kang, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

This trial is for people aged 3 years or older who have Chronic Granulomatous Disease (CGD), a genetic disorder that makes them prone to infections due to a missing gene affecting white blood cells. Participants will undergo a procedure called apheresis and must stay in the hospital for about 40 days.

Inclusion Criteria

Willing to sign and date informed consent form (adult patient)

Parent/guardian willing to sign and date informed consent form for child, with child's assent where appropriate

Willing to allow storage of blood samples for future studies

Exclusion Criteria

Serious or anaphylactic allergic reactions to components of the Busulfan or to DMSO

Pregnancy or lactation

Neurologic deficits interfering with ability to comply with study interventions

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Participants undergo apheresis and receive drugs to prepare their bodies for gene therapy

10 days

In-hospital stay

Treatment

Participants receive a single infusion of autologous CD34+ cells transduced with pCCLCHIM-p47

1 day

In-hospital stay

Initial Follow-up

Participants are monitored for engraftment and safety, including hematological reconstitution and adverse events

3 months

Multiple visits

Long-term Follow-up

Participants are monitored for long-term engraftment, safety, and clinical efficacy

36 months

8 visits over 3 years

Treatment Details

Interventions

• pCCLCHIM-p47

Trial Overview The trial is testing new gene therapy using participants' own stem cells, which are modified in the lab to add the missing gene. After preparation with drugs and insertion of a central line for administering treatment, patients receive their modified stem cells back into their body.

Participant Groups

Group I: Single arm Experimental Treatment 1 Intervention

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

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease. [2021]

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

Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice. [2023]

4. Japan pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Gene therapy for chronic granulomatous disease. [2019]

6. England pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Future of Care for Patients With Chronic Granulomatous Disease: Gene Therapy and Targeted Molecular Medicine. [2020]