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

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Invitation-only; Phase 2; Phase 1

Conditions: WHIM; Immunodeficiency; Hypogammaglobulinemia; Myelokathexis; Warts

Treatments: Drug: Plerixafor; Drug: Palifermin; Biological: Base-edited hematopoietic stem and progenitor cells; Drug: Busulfan; Drug: Filgrastim

Study type: Interventional

Funder types: NIH

Identifiers

NCT07775313

10002691

002691-I

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 10 estimated patients

Sex: All

Ages: 3 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

• 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 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

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

• 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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

Single arm study

Experimental group

Description:

The study cell product is base edited autologous HSPCs which will be administered as a one-time infusion following myeloid conditioning using busulfan.

Treatment:

Drug: Filgrastim

Drug: Busulfan

Biological: Base-edited hematopoietic stem and progenitor cells

Drug: Palifermin

Drug: Plerixafor