Gene Therapy for Chronic Granulomatous Disease

No longer recruiting at 2 trial locations

Overseen By Augustine Fernandes, PhD

Age: Any Age

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: University of California, Los Angeles

Must not be taking: Gamma-interferon

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

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy for individuals with Chronic Granulomatous Disease (CGD), a condition that weakens the immune system and complicates infection control. The study aims to determine if G1XCGD Gene Therapy can safely and effectively enhance immune function by correcting genetic issues in blood cells. It targets those who have experienced severe infections requiring hospitalization and lack a suitable bone marrow donor match. The treatment uses a special virus to modify a person's stem cells outside the body, which are then reintroduced to improve immune function. This trial could offer hope for better health and fewer infections in CGD patients. As a Phase 1, Phase 2 trial, it focuses on understanding the treatment's mechanism in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have taken gamma-interferon within 30 days before the infusion of the gene-modified cells.

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

Research has shown that earlier gene therapy studies for X-linked chronic granulomatous disease (X-CGD) were promising and did not harm the genetic material in cells. The new G1XCGD lentiviral vector is being tested to determine if it can safely deliver the corrected gene to patients' cells.

Previously, different delivery methods sometimes caused issues like abnormal blood cell growth and conditions similar to leukemia. However, the current gene therapy employs a new method designed to reduce these risks.

This trial is in an early stage (Phase 1/2), meaning the treatment's safety is still under careful observation. At this stage, researchers focus primarily on assessing the treatment's safety for humans and identifying any side effects. The trial's progression to this phase suggests some initial safety data is promising, but further research is needed to confirm long-term safety. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for chronic granulomatous disease?

Unlike the standard treatments for Chronic Granulomatous Disease (CGD), which often involve lifelong antibiotics or risky bone marrow transplants, G1XCGD gene therapy offers a groundbreaking approach by directly modifying the patient's own stem cells. This gene therapy uses a lentiviral vector to correct genetic defects in the patient's CD34+ stem cells, potentially providing a long-lasting solution without the need for a donor match. Researchers are particularly excited about the two different approaches within this therapy: Part A involves traditional myeloreductive conditioning, while Part B uses a modified version with increased monitoring and rescue treatment, aiming to enhance safety and effectiveness. This innovative method could transform CGD management, offering hope for a more permanent and less invasive treatment.

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

Research shows that a new gene therapy method using lentiviral vectors holds promise for patients with X-linked Chronic Granulomatous Disease (X-CGD). In this trial, participants will receive one of two versions of the Lentiviral G1XCGD Gene Therapy. Studies have found that this approach can help produce white blood cells that better fight infections. Previous trials showed that gene-modified stem cells helped clear existing infections in patients. Importantly, this new method seems to have a lower risk of causing serious side effects like leukemia. Early results suggest that this gene therapy could strengthen the immune system in people with X-CGD, potentially lowering their risk of infections. ^{1 2 3 4 5}

Who Is on the Research Team?

Donald B. Kohn, MD

Principal Investigator

University of California, Los Angeles

Caroline Y. Kuo, MD

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

This trial is for male patients over 23 months old with X-linked Chronic Granulomatous Disease (CGD), confirmed by DNA tests and lab evidence. They must have had severe infections despite treatment, no perfect bone marrow donor match, and be free of certain viruses like HIV or hepatitis. Patients need to consent to the study's procedures.

Inclusion Criteria

I am a male over 23 months old with confirmed X-CGD and very low NADPH-oxidase activity.

Parental/guardian and, where appropriate, child's signed consent/assent

I do not have HIV, hepatitis B or C, adenovirus, parvovirus B19, toxoplasmosis, or an active CMV infection.

Exclusion Criteria

I haven't received gamma-interferon within the last 30 days.

I cannot undergo leukapheresis or bone marrow harvest due to anemia, heart issues, or severe bleeding disorders.

Contraindication for administration of conditioning medication (Known sensitivity to Busulfan)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo myeloreductive conditioning to prepare for stem cell transplantation

2 weeks

Treatment

Transplantation with autologous CD34+ stem cells corrected with G1XCGD lentiviral vector

12 months

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• G1XCGD Gene Therapy

Trial Overview The trial is testing a new gene therapy using a lentiviral vector called G1XCGD in CGD patients. It involves taking the patient's own bone marrow cells, modifying them with this vector to correct the genetic defect, then returning them back into the patient after chemotherapy conditioning.

How Is the Trial Designed?

Group I: Lentiviral G1XCGD Gene Therapy, Part B Experimental Treatment 1 Intervention

Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after modified myeloreductive conditioning including increased monitoring and rescue treatment

Group II: Lentiviral G1XCGD Gene Therapy, Part A Experimental Treatment 1 Intervention

Transplantation with autologous CD34+ stem cells corrected with X1XCGD lentiviral vector after myeloreductive conditioning

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Boston Children's Hospital

Collaborator

Trials

801

Recruited

5,584,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Genethon

Collaborator

Trials

16

Recruited

600+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Published Research Related to This Trial

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]

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]

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/PMC7115833/

Lentiviral gene therapy for X-linked chronic granulomatous ... These results demonstrate promising effective autologous gene therapy in severely affected patients with X-CGD without evidence of genotoxicity. Further studies ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02234934

NCT02234934 | Study of Gene Therapy Using a Lentiviral ... This study is a two-part, prospective non-controlled, non-randomized Phase I/II clinical trial to assess the safety, feasibility and efficacy of cellular gene ...

3. childrenshospital.org childrenshospital.org/clinical-trials/nct02234934

Study of Gene Therapy Using a Lentiviral Vector to Treat X ... The first gene therapy approaches in X-CGD have shown that effective gene therapy requires bone-marrow (BM) conditioning with chemotherapy to make space for the ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT07113743

Part B- G1X-CGD (Lentiviral Vector Transduced CD34+ ... Background: X-Linked Chronic Granulomatous Disease (X-CGD) is caused by a gene mutation that makes the immune system to not work properly.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29664709/

Non-Clinical Efficacy and Safety Studies on G1XCGD, a ... A new strategy was developed based on the use of the lentiviral vector G1XCGD expressing high levels of the gp91 phox transgene in myeloid cells.