Phase 1/2 Base-Edited Hematopoietic Stem/Progenitor Cell X-Linked Severe Combined Immunodeficiency Gene Therapy
概览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Quantify frequency and severity of adverse events (AEs) related to study agent from infusion to 12 months after infusion.
概览
简要总结
Background:
X-linked severe combined immunodeficiency (XSCID) is a rare inherited disorder that affects the immune system. It is caused by a change in the IL2RG gene. Researchers are investigating a new type of gene therapy for people with XSCID. This technique, called base-edited stem cell transplants, involves collecting a person s own stem cells, editing the genes to repair IL2RG gene, and returning the edited cells to the person.
Objective:
To test base-edited stem cell transplants in people with XSCID.
Eligibility:
People aged 3 years and older with XSCID.
Design:
Participants will be screened. They will have a physical exam. They may give blood, urine, and stool samples. They may have tests of their heart and lung function. They may have fluid and cells drawn from their bone marrow.
Participants will undergo apheresis. Blood will be taken from the body through a needle inserted into 1 arm. 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.
Participants will be admitted to the hospital 1 week before treatment. They will receive a central line: A flexible tube will be inserted into a large vein. This tube will be used to administer drugs and draw blood during their stay. They will receive drugs to prepare their bodies for the treatment.
The base-edited stem cells will be infused through the central line. Participants will remain in the hospital for at least 3 weeks while they recover.
Follow-up visits will continue for 15 years.
详细描述
Study Description:
This is a phase 1/2, non-randomized study of a single infusion of autologous hematopoietic stem/progenitor cells base-edited to repair interleukin 2 receptor gamma (IL2RG) mutations (BE-HSPC IL2RG) in 18 participants with X-linked severe combined immunodeficiency (X-SCID).
Primary Objective:
Evaluate the safety of treatment with BE-HSPC IL2RG in participants with X-SCID.
Secondary Objectives:
Evaluate efficacy of treatment with BE-HSPC IL2RG in participants with X-SCID.
Exploratory Objectives:
- Evaluate off-target (OT) editing activity.
- Compare outcomes of immune reconstitution with lentivector (LV) gene therapy.
Primary Endpoint:
Safety of treatment with BE-HSPC IL2RG, by quantifying frequency and severity of adverse events (AEs) related to study agent from infusion to 12 months after infusion.
Secondary Endpoints (24 months post-study agent infusion):
-
Percentage of participants with >=5% mutation-repaired myeloid cells.
-
Editing efficiency in peripheral blood cells (such as T, B, and natural killer [NK] cells).
-
Immune reconstitution:
-
T, B, and NK cell number improvement from baseline.
-
Emergence of naive T cells and CD31+ recent thymic emigrants.
-
B-cell function: immunoglobulin (Ig) production.
-
Specific responses to vaccines.
-
Clinical efficacy: improvement from baseline problems such as recurrent infection, chronic norovirus, protein-losing enteropathy, gastrointestinal complaints, growth failure, malnutrition, or immune dysregulation.
-
Frequency and severity of all study agent-related AEs and serious adverse events (SAEs) from time of study product infusion.
Exploratory Endpoints:
- Evaluate for frequency of off-targets (OTs) by high-throughput sequencing (HTS) of the target mutation at 2 years post-infusion.
- Compare rates of immune reconstitution with LV-X-SCID gene therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 99 Years（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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 weigh \>=10 kg
- •Patients with X-SCID
- •If previously transplanted, must be \>=18 months post-HSCT
- •Expected survival of at least 120 days.
- •Ability to undergo apheresis for stem cell collection.
- •Patients with proven mutation in the common gamma chain gene as defined by direct sequencing of patient DNA. At this time, only patients with a IL2RG p.Q144X, IL2RG p.R289X, IL2RG p.Q235X and IL2RG p.R226H mutations can be treated.
- •Participants of reproductive potential must agree to consistently use highly effective contraception throughout study participation and for at least 2 years post-treatment.
- •Acceptable forms of contraception are:
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Available HLA-matched sibling donors.
- •Known hypersensitivity to busulfan or any component of the product.
- •Contraindications for administration of busulfan.
- •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 Hematology consult team (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 patient from successful study completion.
研究组 & 干预措施
Single Arm Study
干预措施: Plerixafor (Genetic)
Single Arm Study
干预措施: Filgrastim (Drug)
Single Arm Study
干预措施: Palifermin (Drug)
Single Arm Study
干预措施: Busulfan (Drug)
Single Arm Study
干预措施: Base-edited hematopoietic stem and progenitor cells (Biological)
结局指标
主要结局
Quantify frequency and severity of adverse events (AEs) related to study agent from infusion to 12 months after infusion.
时间窗: 12 months
Evaluate the safety of treatment with BE-HSPC IL2RG in participants with X-SCID.
次要结局
- Evaluate percentage of participants with >= 5% mutation-repaired alleles in PBMCs.(24 months)
- Evaluate editing efficiency in peripheral blood cells (such as T, B, and natural killer [NK] cells).(24 months)
- Evaluate Immune reconstitution: a. T, B, and NK cell number improvement from baseline. b. Emergence of naive T cells and CD31+ recent thymic emigrants.c. B-cell function: immunoglobulin (Ig) production. d. Specific responses to vacci...(24 months)
- Evaluate clinical efficacy by improvement from baseline problems such as recurrent infection, chronic norovirus, protein-losing enteropathy, gastrointestinal complaints, growth failure, malnutrition, or immune dysregulation.(24 months)
- Evaluate frequency and severity of all study agent-related AEs and serious adverse events (SAEs) from time of study product infusion.(24 months)