Base-Edited Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of CXCR4-WHIM

WHIMGeneticsRare diseaseChildren's healthImmune and autoimmuneDrugBiologicalPhase 1, Phase 2

What this study is

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.

What's being tested

Busulfan
Intervention · DRUG
Myeloid conditioning agent, administered once daily x 2 days, targeting a total AUC of 9000 micromol*min/L.
Palifermin
Intervention · DRUG
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).
Plerixafor
Intervention · DRUG
Filgrastim
Intervention · DRUG
Base-edited hematopoietic stem and progenitor cells
Intervention · BIOLOGICAL
The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning.

Both Plerixafor and Filgrastim

Hematopoietic stem cell mobilizing agent necessary for the collection of the hematopoietic stem and progenitor cells (HSPCs) to create the study product.

Study details

Official title: Phase 1/2 Base-Edited Hematopoietic Stem/Progenitor Cell Gene Therapy for Treatment of CXCR4-WHIM
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Conditions: WHIM · Warts · Hypogammaglobulinemia · Immunodeficiency · Myelokathexis
Enrolling: 10 people
Starts: 2026-10-21
Est. completion: 2033-12-31
Design: Open-label, single group, Phase 1, Phase 2
Record: View on ClinicalTrials.gov ↗

Who can join

Age 3 Years – 75 YearsSex ALLHealthy volunteers Not accepted

You may qualify if

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 from start of busulfan conditioning through at least one-year post-treatment. Acceptable forms of contraception are:; Hormonal contraception in continuously effective use.; Male or female condom with spermicide as indicated.; Diaphragm or cervical cap in consistent and effective pattern of use with a spermicide.; Intrauterine device in-situ

You can't join if

Acute onset infection as indicated by symptoms such as persistent fevers, or imaging (new pneumonia on CT for example), isolated pathogen and requiring medical intervention.
Severe liver dysfunction with transaminases > 6 fold upper limit will be excluded until approval by hepatology consult who will provide mitigating plans for liver protection.
Renal dysfunction-serum creatinine >3.0 x ULN.
Coagulation dysfunction- Prothrombin INR or Partial thromboplastin time >2 x ULN (patients on controlled anticoagulation agents will not be excluded for therapeutic levels).
Known hypersensitivity to busulfan or any component of the product.
Contraindications for administration of busulfan, including but not limited to: hypersensitivity, chronic lymphocytic leukemia, acute leukemia in blastic crisis, pregnancy, or lactation.
Childhood malignancy (occurring before 18 years of age) in the participant or a first degree relative, or previously diagnosed known genotype of the participant conferring a predisposition to cancer unless approved by the with appropriate consultants and approved by the study PI (no DNA or other testing for cancer predisposition genes will be performed as part of the screen for this protocol).
Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the participant, or would preclude the participant from successful study completion.

A gene therapy using base-edited stem cells for people with WHIM syndrome

What this study is

What's being tested

Study details

Who can join

Monitoring & Endpoints

Study locations (1)

Study team

National Institute of Allergy and Infectious Diseases (NIAID)

Suk S De Ravin, M.D.

Frequently asked questions