WHIM, Warts, Hypogammaglobulinemia, Immunodeficiency, Myelokathexis
Conditions
Keywords
Gene Editing, base editing
Brief summary
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.
Detailed 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.
Interventions
DRUGBusulfan
Myeloid conditioning agent, administered once daily x 2 days, targeting a total AUC of 9000 micromol\*min/L.
DRUGPalifermin
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).
DRUGPlerixafor
Hematopoietic stem cell mobilizing agent necessary for the collection of the hematopoietic stem and progenitor cells (HSPCs) to create the study product.
DRUGFilgrastim
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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 75 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the safety of base-edited autologous CD34+ cells | Initiated from the time of the infusion of base-edited cells through 2 years post-infusion | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the efficacy of base-edited autologous CD34+ cells | Assessed 12 months post-infusion of base-edited cells | Efficacy of gene therapy as determined by percentage of participants who have \>= 5 percent gene edited circulating myeloid cells |
| Evaluate genetic correction | Assessed 12 months post-infusion of base edited cells | Genetic correction as determined by the presence of \>200/uL edited neutrophils |
| Evaluate immune reconstitution | Assessed 12 months post-infusion of base edited cells | Immune reconstitution as determined by: T, B, and NK cell number improvement from baseline; immunoglobulin production |
| Evaluate clinical efficacy | Assessed 12 months post-infusion of base edited cells | Clinical efficacy as determined by: improvement from baseline problems (i.e., recurrent infections, wart burden) |
Countries
United States
Contacts
CONTACTSuk S De Ravin, M.D.
PRINCIPAL_INVESTIGATORSuk S De Ravin, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Outcome results
None listed