A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Safety of Reduced Conditioning Regimen
研究概览
简要总结
This is phase I/II protocol to evaluate the safety and efficacy of WAS gene transfer into hematopoietic stem/progenitor cells for the treatment of Wiskott Aldrich Syndrome.
详细描述
Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene which encodes the WAS protein (WASP), a cytoskeletal regulator which is expressed exclusively in hematopoietic cells.
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of WAS defined by genetic mutation and at least one of the following criteria:
- •Severe WAS mutation
- •Absence of WASP expression
- •Severe clinical score (Zhu clinical score ≥ 3
- •No HLA-identical sibling donor
- •Negative search for a matched unrelated donor (10/10) or an adequate unrelated cord blood donor (5-6/6) within 4-6 months
- •Patients of > 5 years of age who are not candidate to unrelated allogeneic transplant based on clinical conditions.
- •Parental/guardian/patient signed informed consent.
排除标准
- •Patients positive for HIV-infection.
- •Patients affected by neoplasia.
- •Patients with cytogenetic alterations typical of MDS/AML.
- •Patients with end-organ functions or any other severe disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study.
- •Patients who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months.
- •Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.
结局指标
主要结局
Safety of Reduced Conditioning Regimen
时间窗: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
The absence of prolonged aplasia (defined as ANC \<0.5×10\^9/L \[\<500/μL\] at Day +60, with no evidence of BM recovery and requiring backup administration) was assumed as demonstrating the safety of the RIC regimen.
Presence of Detectable Vector-derived WASP
时间窗: Median duration: 11.1 years (range: 8.01 -13.3 years)
The percentage of subjects who present the proportion of PB cells expressing WASP was assessed by flow cytometry analysis.
Overall Survival
时间窗: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
Participant survival was monitored throughout the study.
Safety of Lentivirus Gene Transfer Into HSC
时间窗: after 48 hours after Telethon003 infusion
Safety and tolerability of lentiviral-transduced cell infusion. This will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion.
Improved Platelet Count and MPV Normalization
时间窗: up to 3 years after Telethon003 infusion
Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile
Sustained Engraftment of Genetically Corrected Haematopoietic Stem Cells in Peripheral Blood and/or in Bone Marrow
时间窗: at 1 year after Telethon003 infusion
Engraftment is characterized by the presence of gene modified cells in the BM or PB compartments. The main indicator of gene correction is detection of the WAS LVV sequences in the HSPCs and their progeny. The VCN, which is the mean number of integrated copies of the vector sequences per cell genome, was measured using PCR-based methods in DNA samples extracted from BM and PB cell populations at various timepoints post-treatment. Adequate engraftment was defined as either ≥0.04 VCN/cell in BM CD34+ cells or ≥0.01 VCN/cell in PB CD3+ cells.
Improved T-cell Functions
时间窗: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
Improvement in in vitro T-cell proliferation was assessed upon stimulation with 3 doses of anti-immobilized CD3 (CD3i) monoclonal antibodies ≥1 year after Telethon003 infusion (as compared with pre-GT values) in PBMC and/or T-cell lines. The degree of correction was evaluated with respect to healthy controls.
Antigen-specific Responses to Vaccination
时间窗: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
The ability to mount a protective humoral response to at least 4 out of 5 nominal antigens including antibodies to T-cell dependent antigens and conjugated or unconjugated polysaccharide antigens was measured after vaccination (planned \>1 year after Telethon003 infusion). If results were available on n \<5 antigens, the rule of at least n-1 applied to define success.
次要结局
- Lack of Immune Response to Transgene(up to 3 years after Telethon003 infusion)
- Improved Quality of Life(3 year)
- Overall Safety of the Treatment(8 years)
- Reduced Frequency of Severe Infections(up to 3 years after Telethon003 infusion)
- Reduced Bruising and Bleeding Episodes(3 years)
- Reduced Autoimmunity Phenomena and Eczema(3 years)
- Multilineage Engraftment of Genetically Corrected Cells(3 years)