Base Editing Hematopoietic Stem Cell and T Cell Gene Therapy for CD40L-HyperIgM Syndrome: Single Patient Study
- Conditions
- CD40L-HyperIgM Syndrome
- Interventions
- Biological: Base-edited hematopoietic stem and progenitor cellsBiological: Base-edited T lymphocyte cells
- Registration Number
- NCT06959771
- Brief 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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Male
- Target Recruitment
- 1
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single Arm Study 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 conditioning using busulfan and alemtuzumab. Single Arm Study Sirolimus The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab. Single Arm Study Alemtuzumab The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab. Single Arm Study Palifermin The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab. Single Arm Study Busulfan The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab. Single Arm Study Base-edited T lymphocyte cells The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following conditioning using busulfan and alemtuzumab.
- Primary Outcome Measures
Name Time Method Safety determined by toxicities related to the infusion of the Study Cell Products Through end of study To determine the safety and efficacy of BE HSPC CD40L and BE T Cells
Efficacy determined by percentages of corrected alleles Through end of study To determine the safety and efficacy of BE HSPC CD40L and BE T Cells
- Secondary Outcome Measures
Name Time Method Response to immunization Through end of study To determine restoration of CD40L expression and immune function
Level of CD40L expression in peripheral blood T cells Through end of study To determine restoration of CD40L expression and immune function
IgG production Through end of study To determine restoration of CD40L expression and immune function
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United StatesSuk De Ravin, MD, PhDContact301-496-6772sderavin@niaid.nih.govNIH Clinical Center Office of Patient Recruitment (OPR)Contact(800) 411-1222ccopr@nih.gov