Base-Edited Hematopoietic Stem/Progenitor Cell X-Linked Severe Combined Immunodeficiency Gene Therapy

NCT06851767 | Enrolling By Invitation Phase 1 FDA Drug

• 2 other identifiers: 10002273002273-I
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

X-linked Severe Combined Immunodeficiency; XSCID

Keywords

base editing; Gene Therapy

Outcome Measures

Primary Outcomes (1)

• Quantify frequency and severity of adverse events (AEs) related to study agent from infusion to 12 months after infusion.

  Evaluate the safety of treatment with BE-HSPC IL2RG in participants with X-SCID.

  12 months

Secondary Outcomes (5)

• Evaluate percentage of participants with >= 5% mutation-repaired alleles in PBMCs.

  24 months

• Evaluate editing efficiency in peripheral blood cells (such as T, B, and natural killer [NK] cells).

  24 months

• Evaluate Immune reconstitution: a. T, B, and NK cell number improvement from baseline. b. Emergence of naive T cells and CD31+ recent thymic emigrants.c. B-cell function: immunoglobulin (Ig) production. d. Specific responses to vacci...

  24 months

• Evaluate clinical efficacy by improvement from baseline problems such as recurrent infection, chronic norovirus, protein-losing enteropathy, gastrointestinal complaints, growth failure, malnutrition, or immune dysregulation.

  24 months

• Evaluate frequency and severity of all study agent-related AEs and serious adverse events (SAEs) from time of study product infusion.

  24 months

Study Arms (1)

Single Arm Study

EXPERIMENTAL

Genetic: Plerixafor; Drug: Filgrastim; Drug: Palifermin; Drug: Busulfan; Biological: Base-edited hematopoietic stem and progenitor cells

Interventions

Plerixafor GENETIC

Stem Cell Mobilizing Agent: Subcutaneous administration for 2 consecutive days to improve stem cell collection.

Single Arm Study

Filgrastim DRUG

Stem Cell Mobilizing Agent: Subcutaneous administration for 6 consecutive days. It is necessary to mobilize stem cells for collection.

Single Arm Study

Palifermin DRUG

Mucositis prophylaxis: As is standard practice prior to busulfan conditioning, IV infusion of keratinocyte growth factor (palifermin) will be administered at 60 micrograms/kg/day for 3 days before initiation of busulfan (days -6 to -4), as well as for the 3 days following study agent administration (days 1 to 3).

Single Arm Study

Busulfan DRUG

Transplant Conditioning Agent: An alkylating chemotherapy drug to enhance engraftment of the study agent (base-edited stem cells). For this study, busulfan is administered once daily (3 mg/kg) x 2 days, targeting a daily busulfan AUC of 4500-6500 micromol\*min/L or a cumulative AUC of 9000 micromol\*min/L (for the 2 days of therapy if levels are available. Busulfan will be infused over 3 hours each day as per standard clinical practice.

Single Arm Study

Base-edited hematopoietic stem and progenitor cells BIOLOGICAL

Investigational/Study Agent: Base-edited autologous CD34 plus hematopoietic stem and progenitor cell product. A one-time dose \>5(SqrRoot) 10\^6 base-edited cells/kg body weight will be administered to each participant. The exact dosage depends on the number of viable cells that are repaired, cryopreserved, and thawed. The study agent will be administered by IV infusion in a volume of approximately 50 mL over about 15-30 minutes, in accordance with NIH CC DTM infusion policy.

Single Arm Study

Eligibility Criteria

• Age: 3 Years - 99 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Aged \>= 3 years and weigh \>=10 kg
• Patients with X-SCID
• If previously transplanted, must be \>=18 months post-HSCT
• Expected survival of at least 120 days.
• Ability to undergo apheresis for stem cell collection.
• Patients with proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA. At this time, only patients with a IL2RG p.Q144X, IL2RG p.R289X, IL2RG p.Q235X and IL2RG p.R226H mutations can be treated.
• Participants of reproductive potential must agree to consistently use highly effective contraception throughout study participation and for at least 2 years post-treatment.
• Acceptable forms of contraception are:
• For males: Condoms or other contraception with partner.
• Documented to be negative for HIV infection by PCR
• The patient must be judged by the primary evaluating physician to have a suitable family and social situation consistent with ability to comply with protocol procedures and the long-term follow-up requirements.
• Medical lab data (historical) of severe B cell dysfunction (low or absent IgG levels, failed immune response to vaccines);
• demonstrated requirement for intravenous gamma globulin (IVIG) (significant drop over 3 to 6 weeks between peak and trough IgG levels).
• Must be willing to have blood and tissue samples stored IN ADDITION, patients must satisfy the following Laboratory Criteria AND Clinical Criteria

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Available HLA-matched sibling donors.
• Known hypersensitivity to busulfan or any component of the product.
• Contraindications for administration of busulfan.
• Childhood malignancy (occurring before 18 years of age) in the participant or a first degree relative, or previously diagnosed known genotype of the participant conferring a predisposition to cancer unless approved by the Hematology consult team (no DNA or other testing for cancer predisposition genes will be performed as part of the screen for this protocol).
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

X-Linked Combined Immunodeficiency Diseases

Interventions

plerixafor; Filgrastim; Fibroblast Growth Factor 7; Busulfan

Condition Hierarchy (Ancestors)

Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Severe Combined Immunodeficiency; Primary Immunodeficiency Diseases; Infant, Newborn, Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Fibroblast Growth Factors; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Suk S De Ravin, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2025
• First Posted: February 28, 2025
• Study Start: May 9, 2025
• Primary Completion (Estimated): December 31, 2034
• Study Completion (Estimated): December 31, 2034
• Last Updated: February 17, 2026

Record last verified: 2026-02-10

Locations

US (1)