Base Editing Hematopoietic Stem Cell Gene Therapy for CD40L-HyperIgM Syndrome: Single Patient Study
- Conditions
- CD40L-HyperIgM Syndrome
- Interventions
- Biological: Base-edited hematopoietic stem and progenitor cells
- Registration Number
- NCT06959771
- Brief Summary
Background:
X-linked Hyper IgM (HIGM) syndrome is caused by a mutation in the 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. Stem cell transplant can cure this disease. However, transplanting stem cells donated by other people can have serious complications. Another approach is gene therapy; this treatment repairs the mutation in a person's own stem cells by base editing. Researchers want to know if these base-edited stem cells can help people with CD40L-HIGM syndrome.
Objective:
To test base-edited stem cell transplant in 1 person with CD40L-HIGM syndrome.
Eligibility:
A male with CD40L-HIGM syndrome.
Design:
Participant will be screened. Tests will include medically indicated imaging scans, blood tests, and a sample of tissue and fluid (biopsy) may be taken from the bone marrow.
Participant may undergo apheresis to collect stem cells. The collected stem cells will undergo base editing to repair the mutation.
For treatment, participant will be admitted to the hospital for 5 weeks or more. For 2 weeks he will receive drugs to prepare his body for receiving the stem cells. After receiving the edited stem cells, he will remain in the hospital until his cell counts recover.
Participant will have follow-up visits every few months in the first 2 years after treatment. The bone marrow biopsy will be repeated after 2 years. 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). The study hypothesis is that base edited HSPCs will be repaired efficiently and safely to restore CD40L expression and improve immune function.
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.
Objectives:
* Primary Objective: To determine the safety and efficacy of BE HSPC CD40L
* 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
- ENROLLING_BY_INVITATION
- 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 Busulfan The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan and serotherapy. Single Arm Study Palifermin The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan and serotherapy. Single Arm Study Sirolimus The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan and serotherapy. Single Arm Study Alemtuzumab The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan and serotherapy. 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 myeloid conditioning using busulfan and serotherapy.
- Primary Outcome Measures
Name Time Method Efficacy determined by percentages of corrected alleles Through end of study To determine the safety and efficacy of BE HSPC CD40L
Safety determined by toxicities related to infusion of Study Cell Product Through end of study To determine the safety and efficacy of BE HSPC CD40L
- Secondary Outcome Measures
Name Time Method 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
Response to immunization 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