Gene Therapy for Bubble Boy Disease

Overseen By Suk S De Ravin, M.D.

Age: Any Age

Sex: Male

Trial Phase: Phase 1 & 2

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

Must be taking: Intravenous gamma globulin

Disqualifiers: HLA-matched sibling, Hypersensitivity to busulfan, Childhood malignancy, others

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

Compensation: Varies

Number of Visits: 2

Duration: 3 weeks

18 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 or your doctor to get a clear answer.

What data supports the effectiveness of the treatment for Bubble Boy Disease?

Research on similar treatments shows that gene therapy using modified stem cells can correct genetic disorders by fixing enzyme deficiencies, as seen in studies on Mucopolysaccharidosis type I and II. These studies demonstrate that gene-modified stem cells can improve disease symptoms in animal models, suggesting potential effectiveness for Bubble Boy Disease. ^{1 2 3 4 5}

Is gene therapy for Bubble Boy Disease safe?

Research on similar gene therapies, like those for Mucopolysaccharidosis, shows promising safety data. Studies have shown no significant toxicity or increased risk of cancer, and the treatments have been effective in animal models without harmful side effects. ^{1 2 6 7 8}

How is the treatment for Bubble Boy Disease using base-edited hematopoietic stem and progenitor cells different from other treatments?

This treatment is unique because it uses advanced genome editing tools, like CRISPR, to precisely modify the patient's own blood-forming stem cells, potentially offering a long-term or curative solution by correcting the genetic defect directly in the cells responsible for the immune system. ^{1 8 9 10 11}

What is the purpose of this trial?

Background: X-linked severe combined immunodeficiency (XSCID) is a rare inherited disorder that affects the immune system. It is caused by a change in the IL2RG gene. Researchers are investigating a new type of gene therapy for people with XSCID. This technique, called base-edited stem cell transplants, involves collecting a person s own stem cells, editing the genes to repair IL2RG gene, and returning the edited cells to the person. Objective: To test base-edited stem cell transplants in people with XSCID. Eligibility: People aged 3 years and older with XSCID. Design: Participants will be screened. They will have a physical exam. They may give blood, urine, and stool samples. They may have tests of their heart and lung function. They may have fluid and cells drawn from their bone marrow. Participants will undergo apheresis. Blood will be taken from the body through a needle inserted into 1 arm. The blood will pass through a machine that separates out the stem cells. The remaining blood will be returned to the body through a different needle. The collected stem cells will undergo gene editing. Participants will be admitted to the hospital 1 week before treatment. They will receive a central line: A flexible tube will be inserted into a large vein. This tube will be used to administer drugs and draw blood during their stay. They will receive drugs to prepare their bodies for the treatment. The base-edited stem cells will be infused through the central line. Participants will remain in the hospital for at least 3 weeks while they recover. 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 people aged 3 years and older with X-linked severe combined immunodeficiency (XSCID), also known as 'Bubble Boy Disease'. Participants will undergo various screenings including physical exams, blood tests, and heart and lung function tests. They must be able to endure apheresis (a procedure to collect stem cells) and hospitalization.

Inclusion Criteria

I have a chronic lung condition confirmed by tests.

I have had long-term yeast infections in my mouth, throat, skin folds, or nails confirmed by lab tests.

Expected survival of at least 120 days

Exclusion Criteria

I cannot take busulfan due to health reasons.

Known hypersensitivity to busulfan or any component of the product

Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the participant, or would preclude the patient from successful study completion

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Apheresis and Gene Editing

Participants undergo apheresis to collect stem cells, which are then gene-edited to repair the IL2RG gene

1 week

1 visit (in-person)

Treatment

Base-edited stem cells are infused through a central line; participants remain in the hospital for recovery

3 weeks

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Regular follow-up visits

Treatment Details

Interventions

• Base-edited hematopoietic stem and progenitor cells

Trial Overview The trial is testing a new gene therapy for XSCID by editing the genes in a patient's own stem cells to repair the IL2RG gene defect. The process includes collecting stem cells through apheresis, gene editing in the lab, then infusing these edited cells back into patients after pre-treatment with drugs like Plerixafor, Filgrastim, Palifermin, Busulfan.

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

Hematopoietic stem cell gene therapy (HSCGT) using a lentiviral vector for the SGSH gene shows promise for treating Mucopolysaccharidosis type IIIA (MPSIIIA), with pre-clinical studies indicating effective gene transfer and safety in humanized mouse models.

The therapy demonstrated effective engraftment and biodistribution without vector shedding or germline transmission, and showed low genotoxicity, suggesting it is a safe and viable option for clinical trials in treating this neurological disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. Ellison, SM., Liao, A., Wood, S., et al.[2020]

Combining CRISPR-Cas9 editing of the BCL11A enhancers significantly enhances fetal hemoglobin (HbF) induction, which is crucial for treating β-hemoglobinopathies like sickle cell disease, as shown in patient-derived xenografts.

Editing hematopoietic stem and progenitor cells (HSPCs) without prior cytokine culture reduces the risk of unintended genetic damage while maintaining effective gene editing, suggesting a safer approach for potential in vivo therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. Zeng, J., Nguyen, MA., Liu, P., et al.[2023]

References

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

Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I. [2021]

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

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. [2022]

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

An induced pluripotent stem cell line (TRNDi006-A) from a MPS IIIB patient carrying homozygous mutation of p.Glu153Lys in the NAGLU gene. [2020]

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

A novel preclinical model of mucopolysaccharidosis type II for developing human hematopoietic stem cell gene therapy. [2023]

5. Ireland pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell gene therapy for Niemann-Pick disease and other lysosomal storage diseases. [2019]

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

Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. [2020]

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

A Highly Efficacious PS Gene Editing System Corrects Metabolic and Neurological Complications of Mucopolysaccharidosis Type I. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Cell and Gene Therapies for Mucopolysaccharidoses: Base Editing and Therapeutic Delivery to the CNS. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Therapy Development by Genome Editing of Hematopoietic Stem Cells. [2023]

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

In vivo hematopoietic stem cell modification by mRNA delivery. [2023]

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

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. [2023]