Background: Warts, hypogammaglobulinemia, infections and myelokathexis syndrome (WHIMs) is a rare disorder that affects the immune system. People with WHIMs can have severe infections all over their body. WHIMs is caused by a mutation in the CXCR4 gene. Treatment with drugs can help control the infections but does not cure the disorder. Researchers want to try a treatment where they collect stem cells from a person with WHIMS, use base-editing to replace the bad gene with a healthy version, and return the new cells to the person. This could cure WHIMs. Objective: To test a treatment using base-edited stem cells in people with WHIMs. Eligibility: People aged 3 years and older with WHIMs. Design: The study has 4 stages. Stage 1: Screening. Participants will be screened at 1 or more visits. They will have a physical exam with blood tests. A sample of tissue and fluid (biopsy) will be taken from the bone marrow in the hip. Stage 2: Apheresis. Blood will be taken from the body through a needle; 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. Stage 3: Treatment. Participants will stay in the hospital for about 4 weeks. They will receive 3 drugs to prepare their body for the procedure. Then the edited stem cells will be returned to their bloodstream. They will stay in the hospital until they recover. Stage 4: Follow-up. Participants will have 8 follow-up visits over 5 years. Long-term visits will continue for 15 years.
Study Description: This is a phase 1/2, non-randomized study of a single infusion of autologous hematopoietic stem/progenitor cells (HSPC) base-edited to repair CXCR4 mutations in 10 participants with (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) WHIM syndrome. Primary Objective: Evaluate safety of treatment with BE-HSPC CXCR4 in participants with WHIM syndrome. Secondary Objectives: Evaluate: * Efficacy. * Genetic correction. * Immune reconstitution. * Clinical efficacy. Exploratory Objective: Evaluate off-target (OT) editing activity. Primary Endpoint: Safety assessed by: * Incidence of adverse events (AEs) for each participant. * Evaluate overall incidence of AEs for the study. * Incidence of serious adverse events (SAEs). Secondary Endpoints (24 months post-study agent infusion): * Efficacy: \>= 5% gene edited circulating myeloid cells by 12 months after BE HSPC infusion. * Gene correction: --Frequency of corrected alleles in peripheral blood cells (such as myeloid, T, B, and natural killer \[NK\] cells). --\>200/microL edited neutrophils by 12 months post receipt of the BE HSPC infusion. * Immune reconstitution: * T, B, and NK cell number improvement from baseline. * B-cell function: immunoglobulin (Ig) production. * Clinical efficacy: Improvement from baseline problems such as recurrent infection, wart burden, gastrointestinal complaints, or immune dysregulation. Exploratory Endpoint: Evaluate for frequency of OTs by high-throughput sequencing (HTS) of the target mutation at the genomic locus 2 years post-infusion.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Myeloid conditioning agent, administered once daily x 2 days, targeting a total AUC of 9000 micromol\*min/L.
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).
Hematopoietic stem cell mobilizing agent necessary for the collection of the hematopoietic stem and progenitor cells (HSPCs) to create the study product.
Hematopoietic stem cell mobilizing agent necessary for the collection of the hematopoietic stem and progenitor cells (HSPCs) to create the study product.
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
To evaluate the safety of base-edited autologous CD34+ cells
Safety of gene therapy using base-edited autologous hematopoietic stem and progenitor cells as measured by study agent-related adverse events and serious adverse events
Time frame: Initiated from the time of the infusion of base-edited cells through 2 years post-infusion
Evaluate the efficacy of base-edited autologous CD34+ cells
Efficacy of gene therapy as determined by percentage of participants who have \>= 5 percent gene edited circulating myeloid cells
Time frame: Assessed 12 months post-infusion of base-edited cells
Evaluate genetic correction
Genetic correction as determined by the presence of \>200/uL edited neutrophils
Time frame: Assessed 12 months post-infusion of base edited cells
Evaluate immune reconstitution
Immune reconstitution as determined by: T, B, and NK cell number improvement from baseline; immunoglobulin production
Time frame: Assessed 12 months post-infusion of base edited cells
Evaluate clinical efficacy
Clinical efficacy as determined by: improvement from baseline problems (i.e., recurrent infections, wart burden)
Time frame: Assessed 12 months post-infusion of base edited cells
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.