Ignite Creation Date:
2024-05-06 @ 8:16 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06325709
Status:
RECRUITING
Last Update Posted:
2024-05-13
First Post:
2024-03-21
Brief Title:
Base Editing for Mutation Repair in Hematopoietic Stem Progenitor Cells for X-Linked Chronic Granulomatous Disease
Sponsor:
National Institute of Allergy and Infectious Diseases NIAID
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase 12 Trial of Base Editing for Mutation Repair in Hematopoietic Stem Progenitor Cells for X-linked Chronic Granulomatous Disease
Status:
RECRUITING
Status Verified Date:
2024-10-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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 12 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 c676CT 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 mgkg 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 gp91phox 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 gp91phox 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 gp91phox 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
Open-label phase 12 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 c676CT 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 mgkg 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 gp91phox 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 gp91phox 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 gp91phox 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 001580-I | None | None | None |