NCT06851767

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

Phase 1/2 Base-Edited Hematopoietic Stem/Progenitor Cell X-Linked Severe Combined Immunodeficiency Gene Therapy

• Status: Enrolling By Invitation
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 18 (estimated)
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) · NIH
• Sex: Male
• Age: 3 Years – 99 Years
• Healthy volunteers: Not accepted

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.

Detailed description

Study Description: This is a phase 1/2, non-randomized study of a single infusion of autologous hematopoietic stem/progenitor cells base-edited to repair interleukin 2 receptor gamma (IL2RG) mutations (BE-HSPC IL2RG) in 18 participants with X-linked severe combined immunodeficiency (X-SCID). Primary Objective: Evaluate the safety of treatment with BE-HSPC IL2RG in participants with X-SCID. Secondary Objectives: Evaluate efficacy of treatment with BE-HSPC IL2RG in participants with X-SCID. Exploratory Objectives: 1. Evaluate off-target (OT) editing activity. 2. Compare outcomes of immune reconstitution with lentivector (LV) gene therapy. Primary Endpoint: Safety of treatment with BE-HSPC IL2RG, by quantifying frequency and severity of adverse events (AEs) related to study agent from infusion to 12 months after infusion. Secondary Endpoints (24 months post-study agent infusion): 1. Percentage of participants with \>=5% mutation-repaired myeloid cells. 2. Editing efficiency in peripheral blood cells (such as T, B, and natural killer \[NK\] cells). 3. Immune reconstitution: 1. T, B, and NK cell number improvement from baseline. 2. Emergence of naive T cells and CD31+ recent thymic emigrants. 3. B-cell function: immunoglobulin (Ig) production. 4. Specific responses to vaccines. 4. Clinical efficacy: improvement from baseline problems such as recurrent infection, chronic norovirus, protein-losing enteropathy, gastrointestinal complaints, growth failure, malnutrition, or immune dysregulation. 5. Frequency and severity of all study agent-related AEs and serious adverse events (SAEs) from time of study product infusion. Exploratory Endpoints: 1. Evaluate for frequency of off-targets (OTs) by high-throughput sequencing (HTS) of the target mutation at 2 years post-infusion. 2. Compare rates of immune reconstitution with LV-X-SCID gene therapy.

Conditions

• X-linked Severe Combined Immunodeficiency
• X-SCID
• XSCID

Interventions

Type	Name	Description
GENETIC	Plerixafor	Stem Cell Mobilizing Agent: Subcutaneous administration for 2 consecutive days to improve stem cell collection.
DRUG	Filgrastim	Stem Cell Mobilizing Agent: Subcutaneous administration for 6 consecutive days. It is necessary to mobilize stem cells for collection.
DRUG	Palifermin	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).
DRUG	Busulfan	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.
BIOLOGICAL	Base-edited hematopoietic stem and progenitor cells	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.

Timeline

• Start date: 2025-05-09
• Primary completion: 2034-12-31
• Completion: 2034-12-31
• First posted: 2025-02-28
• Last updated: 2026-02-17

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study