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

Phase 1

• Conditions: X-linked Severe Combined Immunodeficiency; X-SCID; XSCID
• Interventions: Genetic: Plerixafor; Drug: Filgrastim; Drug: Palifermin; Drug: Busulfan; Biological: Base-edited hematopoietic stem and progenitor cells

• Registration Number: NCT06851767
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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.

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 12 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.

Study Timeline

• Study First Submitted: 2025-02-26
• Study First Submitted QC: 2025-02-27
• Study First Posted: 2025-02-28
• Study Start: 2025-05-09
• Status Verified: 2025-05-13
• Last Update Submitted: 2025-05-16
• Last Update Posted: 2025-05-18
• Primary Completion: 2034-12-31
• Study Completion: 2034-12-31

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: Male
• Target Recruitment: 18

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Arm Study	Plerixafor	-
Single Arm Study	Filgrastim	-
Single Arm Study	Palifermin	-
Single Arm Study	Busulfan	-
Single Arm Study	Base-edited hematopoietic stem and progenitor cells	-

Primary Outcome Measures

Name	Time	Method
Quantify frequency and severity of adverse events (AEs) related to study agent from infusion to 12 months after infusion.	12 months	Evaluate the safety of treatment with BE-HSPC IL2RG in participants with X-SCID.

Secondary Outcome Measures

Name	Time	Method
Evaluate percentage of participants with >= 5% mutation-repaired alleles in PBMCs.	24 months	Measure efficacy of treatment by assessing efficiency of base editor at repair of mutations.
Evaluate editing efficiency in peripheral blood cells (such as T, B, and natural killer [NK] cells).	24 months	Measure efficacy of treatment by assessing molecular evidence for mutation repair.
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	Measure efficacy of treatment by assessing immune reconstitution as indicated by 1) increase in immune cell numbers; 2) restoration of thymic function with production of na(SqrRoot) ve T cells and CD31+ T cells; 3) Evaluate restoration of B-cell function.
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	Measure efficacy of treatment by assessing comparison of clinical status before and after treatment as indicator of response to improved immune function.
Evaluate frequency and severity of all study agent-related AEs and serious adverse events (SAEs) from time of study product infusion.	24 months	Measure efficacy of treatment by assessing intervention-related AE rate.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States