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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy (pCCLCHIM-p47) for individuals with Chronic Granulomatous Disease (CGD), a genetic condition that weakens the immune system and complicates infection control. Researchers aim to determine if this treatment can safely replace the missing gene in patients' white blood cells, potentially providing a safer alternative to current methods. Participants will have their blood cells collected, modified to include the missing gene, and then returned to their body. Suitable candidates for this trial include those with CGD, a history of infections, and no suitable stem cell donor. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this gene therapy is likely to be safe for humans?

Research shows that the new gene therapy treatment, pCCLCHIM-p47, has promising safety results from early studies. These studies tested the treatment in mice, where it successfully corrected the gene issue causing chronic granulomatous disease (CGD). Importantly, the mice did not experience any serious side effects, indicating potential safety for humans.

In these tests, the mice improved in fighting infections after receiving the treatment, and no major negative effects were reported. This suggests the treatment is well-tolerated in animals, marking a hopeful step towards human testing. As this trial is in the early stages of human testing, the main goal is to confirm safety and observe how people respond to the therapy. Current data offers hope that the treatment could be safe for humans as well. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for Chronic Granulomatous Disease, which often involves antibiotics and antifungal agents to manage infections, pCCLCHIM-p47 is a gene therapy aimed directly at the root cause of the condition. This treatment is unique because it introduces a corrected version of the defective NADPH oxidase gene into patients' cells, potentially restoring normal immune function. Researchers are excited about this approach because it offers the possibility of a long-lasting solution by repairing the underlying genetic defect, rather than just managing symptoms.

What evidence suggests that this gene therapy might be an effective treatment for chronic granulomatous disease?

Research has shown that the pCCLCHIM-p47 gene therapy, which participants in this trial will receive, could help treat chronic granulomatous disease (CGD). In earlier studies, this therapy reduced bacterial levels in mice with CGD, indicating its potential to fight infections. The therapy uses a lentiviral vector as a delivery system to insert the missing gene back into the patient’s cells. This process helps restore the function of white blood cells, which are essential for fighting infections. Initial results in animal studies have been positive, suggesting that this therapy might be an effective option for people with CGD. ^{3 6 7 8 9}

Who Is on the Research Team?

Elizabeth M Kang, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7500983/

Lentiviral gene therapy rescues p47phox chronic ... Lentiviral gene therapy improves the outcome of Salmonella Typhimurium infection in p47phox-deficient CGD mice. We completed the efficacy ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06253507

Study Details | NCT06253507 | pCCLCHIM-p47 (Lentiviral ... Primary Objectives: To evaluate the efficacy of pCCLCHIM-p47 transduced autologous CD34+ cells treatment in p47 AR-CGD patients as measured by engraftment of ...

3. jacionline.org jacionline.org/article/S0091-6749(16)32124-8/fulltext

Development of a pCCLChim Lentiviral Vector for Gene ... CGD patients are susceptible to severe and recurrent infections. We propose to use a lentiviral gene therapy strategy to restore the expression of the p47-phox ...

4. cgtlive.com cgtlive.com/view/great-ormond-street-hospital-tackling-chronic-granulomatous-disease-gene-therapy-phase-trial

Great Ormond Street Hospital Tackling Chronic ... In addition, the gene therapy was able to reduce bacterial load in p47 phox-null mice with Salmonella serovar Typhimurium compared with mice ...

5. discovery.ucl.ac.uk discovery.ucl.ac.uk/id/eprint/10165959/2/PhDThesis_UCL_ASB_17110299_Final03.pdf

Lentiviral gene therapy for p47-deficient Chronic ... All together, these results prove the efficacy of the pCCLChim-p47 lentiviral gene therapy to correct truly haematopoietic stem cells. Of note, myeloid ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8575060/

Preclinical Optimization and Safety Studies of a New ... Preclinical optimization and safety studies of a new lentiviral gene therapy for p47 phox-deficient chronic granulomatous disease.

7. nature.com nature.com/articles/s41434-020-0164-6

Lentiviral gene therapy rescues p47 phox chronic ... Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice. Andrea Schejtman, ...

8. researchgate.net researchgate.net/publication/350198652_Preclinical_Optimization_and_Safety_Studies_of_a_New_Lentiviral_Gene_Therapy_for_p47_phox_-Deficient_Chronic_Granulomatous_Disease

(PDF) Preclinical Optimization and Safety Studies of a New ... PDF | Chronic granulomatous disease (CGD) is an inherited blood disorder that renders patients susceptible to infections and inflammation.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33740872/

Preclinical Optimization and Safety Studies of a New Lentiviral ... Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation.