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

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.

• 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.