National Institute of Allergy and Infectious Diseases (NIAID)
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 assesse…
* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria: * Aged \>= 3 years and weighing \>=15 kg. * Confirmed CXCR c.1000C\>T, pR334X mutation. * Ability to undergo apheresis for stem cell collection. * Medical lab data (historical) of neutropenia, or B cell dysfunction (low or absent IgG levels, or on IV gamma globulin. * Expected survival of at least 120 days. * Must be willing to have blood and tissue samples stored. * Participants of reproductive potential must agree to consistently use effective contraception fro…
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.