Base Editing for Mutation Repair in Hematopoietic Stem & Progenitor Cells for X-Linked Chronic Granulomatous Disease
- Conditions
- Chronic Granulomatous Disease (CGD)X-Linked Chronic Granulomatous Disease
- Interventions
- Biological: Base-edited hematopoietic stem and progenitor cells
- Registration Number
- NCT06325709
- Brief Summary
Background:
Chronic granulomatous disease (CGD) is a rare immune disorder caused by a mutation in the CYBB gene. People with CGD have white blood cells that do not work properly. This places them at risk of developing infections that may be life-threatening. Stem cell transplant can cure CGD but transplanting stem cells donated by other people can have serious complications. In addition, not everyone has a matched donor. Another approach is a type of gene therapy that involves base-editing to correct the mutation in a person s own stem cells. Researchers want to know if the base-edited stem cells can improve the white cells' functioning and result in fewer CGD-related infections.
Objective:
To learn if base-edited stem cells will improve white blood cells' ability to fight against infections in people with CGD.
Eligibility:
Males aged 18 years and older with X-linked CGD.
Design:
This is a non-randomized study. Participants with the specific mutation under study will be screened during the initial phase.
During the development phase, participants will undergo apheresis to collect stem cells for base-editing correction of the mutation.
During the treatment phase, participants will receive the base-edited cells after chemotherapy with busulfan. Participants will remain in the hospital until their immunity recovers.
Follow-up visits will continue for 15 years....
- Detailed Description
Study Description:
Open-label, phase 1/2 trial to determine the safety, and efficacy of a single infusion of base-edited (BE) autologous hematopoietic stem and progenitor cells (HSPCs) for treatment of X-linked chronic granulomatous disease (X-CGD). Base editing is performed to repair CYBB missense gene mutations (eg, CYBB c.676C\>T). The study hypotheses are that 1) base editing can efficiently repair gene mutations in HSPCs; and 2) BE HSPCs can engraft and differentiate into functional phagocytes with restored nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.
During the initial development phase each study participant will undergo apheresis for CD34+ HSPC collection for the development and validation of a mutation-specific BE system.
During the treatment phase, participants will receive a one-time infusion of the BE autologous HSPC Investigational Medicinal Product (IMP) after busulfan (total 12 mg/kg) conditioning.
Participants will have follow-up evaluations at months 3, 6, 12, 18, and 24, and yearly thereafter until 5 years after treatment. Key study assessments include adverse event (AE) assessment, blood laboratory evaluations of functional protein made from the target gene (CYBB, encodes for gp91\^phox), and deoxyribonucleic acid (DNA) sequencing to identify rates of gene repair and off-target mutation.
The final study follow-up under this protocol will be at 5 years, but long-term follow-up under a separate NIH protocol will continue annually to 15 years after treatment.
Objectives:
Primary Objectives:
* To evaluate the safety of BE autologous CD34+ cells.
* To evaluate the efficacy of BE autologous CD34+ cells.
Secondary Objectives:
-To evaluate:
* Efficiency of base editing (percentages of target nucleotide conversion).
* Engraftment capability of BE HSPCs.
* Efficiency in restoring gp91\^phox expression
* Efficiency in restoring NADPH oxidase function.
* Clinical efficacy.
* Stability of gene correction.
Exploratory Objectives:
-To evaluate:
* Specificity of base editing by assessing rates of off-target edits at top predicted sites.
* Random off-target edits by whole genome sequencing (WGS).
Endpoints:
Primary Endpoints:
* Safety of gene therapy using BE autologous HSPCs as measured by study agent-related AEs and serious AEs (SAEs) through 2 years after treatment.
* Efficacy of gene therapy determined as percentages of subjects who have \>= 10% oxidase-positive granulocytes at 12 months after infusion.
Secondary Endpoints:
* Determine frequency of converted target nucleotide alleles.
* Assess the frequency of gene-modified alleles compared to infusion product in peripheral blood at 12 months.
* Evaluate efficacy of restoring gp91\^phox expression.
* Evaluate efficacy of NADPH oxidase functional restoration as measured by the dihydrorhodamine (DHR) flow cytometry oxidase assay at 12 months after treatment (\>=10% oxidase-positive neutrophils), or by quantitative measurement of reactive oxygen species (ROS) using the ferricytochrome C assay on peripheral blood granulocytes.
* Evaluate clinical benefit by improvement of baseline clinical problems such as recurrent infections, growth failure, malnutrition, inflammatory bowel disease, or antibiotic usage.
* Assess stability of gene correction by serial measurement of percent of nucleotide-converted alleles.
Exploratory Endpoints:
* Evaluate specificity by assessing for off-target edits at predicted sites with high-throughput sequencing of the 5 most common candidate off-target sites identified by a comprehensive in vitro screen, Circularization for High-throughput Analysis of Nuclease Genome-wide Effects by sequencing (CHANGE-seq), in peripheral blood cells.
* Determine rate of random off-target edits WGS.
Recruitment & Eligibility
- Status
- SUSPENDED
- Sex
- Male
- Target Recruitment
- 1
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single Arm Study Base-edited hematopoietic stem and progenitor cells - Single Arm Study Plerixafor - Single Arm Study Busulfan - Single Arm Study Filgrastim - Single Arm Study Palifermin -
- Primary Outcome Measures
Name Time Method To 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 percentages ofparticipants who have \>= 10 percent oxidase-positive granulocytes
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 Outcome Measures
Name Time Method Evaluate efficacy in restoring NADPH oxidase function. Assessed 12-24 months post-infusion of base-edited cells Measure the frequency of DHR+ cells
Evaluate the efficiency of base-editing. Assessed 12-24 months post-infusion of base-edited cells Measure the percentages of gp91-expressing cells
Evaluate clinical efficacy Assessed through study completion Assess the frequency of infections and progression of co-morbidities of CGD
Evaluate the engraftment capability of base-edited hematopoietic stem progenitor cells. Assessed 12-24 months post-infusion of base-edited cells Measure the percentages of edited myeloid cells
Evaluate the efficiency in restoring gp91phox expression. Assessed 12-24 months post-infusion of base-edited cells Measure the frequency of gp91phox+ cells and the amount of gp91phox protein
Evaluate the stability of gene correction Assessed through study completion Compare frequencies of corrected alleles before infusion and at study completion
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States