NCT06959771

Base Editing Hematopoietic Stem Cell and T Cell Gene Therapy for CD40L-HyperIgM Syndrome: Single Patient Study

Base Editing Hematopoietic Stem Cell and BE T Cell Gene Therapy for CD40L-HyperIgM Syndrome-Single Patient Study

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 1 (estimated)
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) · NIH
• Sex: Male
• Age: 37 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

Background: X-linked hyper-IgM (HIGM) syndrome is caused by a mutation in the CD40 ligand (CD40L) gene. People with this disease have white blood cells that do not work properly. These people are at risk of severe infections and autoimmune diseases. Researchers want to know if these base-edited stem cells and T cells can help people with CD40L-HIGM syndrome. Objective: To test base-edited stem cells and base-edited T cells in 1 person with CD40L-HIGM syndrome. Eligibility: A single male with CD40L-HIGM syndrome. Design: A single participant is planned to receive a single dose of edited stem cells and supportive treatment with edited T cells. Participant stem and T cells will undergo base editing to repair the mutation. In preparation for the gene therapy, the participant will receive busulfan chemotherapy and alemtuzumab. After treatment, the participant will have follow-up visits every few months in the first 2 years after treatment. Long-term visits will continue annually for 15 years.

Detailed description

Study Description: This is a single participant gene therapy study to provide a participant with CD40L c.658C\>T; p.Q220X-Hyper IgM syndrome with autologous base-edited hematopoietic stem/progenitor cells (HSPC) and base-edited T cells (BE T). The study hypothesis is that base edited HSPCs will be repaired efficiently and safely to restore CD40L expression and improve immune function long term. BE T cells will provide functional T cells to support subject against immunodeficiency and lymphopenia. The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan administered once daily for 2 days with a daily target AUC of 4500 micromol\*min/L or a cumulative AUC of 9000 micromol\*min/L (approximately 6 mg/kg) and serotherapy (alemtuzumab (Campath)) 10 mg/m\^2 total dose divided over 3 days by subcutaneous injection on days -21, -20, and -19. Following infusion, the participant will be evaluated at months 3, 6, 9, 12, 18, 24. Long-term annual follow up will be performed on a separate protocol. Base edited autologous T cells will be administered at 2 weeks following BE HSPC infusion that function as 'donor lymphocyte infusions' to protect the patient from the diseaserelated T-cell immunodeficiency and alemtuzumab-related lymphopenia. Subsequent doses of BE T cells may be infused monthly as indicated to achieve T cell reconstitution for treatment of infections. Objectives: * Primary Objective: To determine the safety and efficacy of BE HSPC CD40L and BE T cells. * Secondary Objectives: To determine restoration of CD40L expression and immune function * Exploratory Objectives: * Assess for potential unintended edits * Kinetics of immune reconstitution Endpoints: * Primary Endpoint: * Efficacy determined by percentages of corrected alleles * Safety determined by toxicities related to infusion of Study Cell Product * Secondary Endpoints: * Level of CD40L expression in peripheral blood T cells * IgG production * Response to immunization * Exploratory Endpoints: * Repeat WES at 24 months after study cell product infusion * Evaluate for gene correction levels in peripheral blood CD34s and isolated immune cell lineages

Conditions

• CD40L-HyperIgM Syndrome

Interventions

Type	Name	Description
BIOLOGICAL	Base-edited hematopoietic stem and progenitor cells	The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning.
DRUG	Alemtuzumab	Serotherapy agent, 10 mg/m\^2 on days -21, -20 and -19
DRUG	Sirolimus	Immunophilin drug, will start on day -1, targeting a trough level between 4-12 ng/mL.
DRUG	Palifermin	Mucositis prophylaxis agent, will be administered at 60 mcg/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	Myeloid conditioning agent, administered once daily (3 mg/kg) x 2 days, targeting a daily AUC of 4500 micromol\*min/L or a cumulative AUC of 9000 micromol\*min/L for the 2 days of therapy, if levels are available
BIOLOGICAL	Base-edited T lymphocyte cells	The secondary study cell product is base edited autologous which will be administered as a one-time infusion two weeks following the infusion of the base-edited autologous HSPCs.

Timeline

• Start date: 2025-07-16
• Primary completion: 2027-10-28
• Completion: 2027-10-28
• First posted: 2025-05-07
• Last updated: 2026-03-27

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study