A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Conditioning regimen-related safety
研究概览
简要总结
This Phase I/II clinical trial consists of the application of lentiviral vector-based gene therapy to patients affected by Metachromatic Leukodystrophy (MLD), a rare inherited Lysosomal Storage Disorder (LSD) resulting from mutations in the gene encoding the Arylsulfatase A (ARSA) enzyme. The medicinal product consists of autologous CD34+ hematopoietic stem/progenitor cells in which a functional ARSA cDNA is introduced by means of 3rd generation VSV-G pseudotyped lentiviral vectors.
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
- — 至 7 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Pre-symptomatic MLD patients with the late infantile variant;
- •Pre- or early-symptomatic MLD patients with the early juvenile variant;
- •Patients for whom parental/guardian signed informed consent has been obtained.
排除标准
- •HIV RNA and/or HCV RNA and/or HBV DNA positive patients;
- •Patients affected by neoplastic diseases;
- •Patients with cytogenetic alterations typical of MDS/AML;
- •Patients with end-organ functions or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study;
- •Patients enrolled in other trials/other therapeutic approaches that might become available;
- •Patient who underwent allogeneic hematopoietic stem cell transplantation in the previous six months;
- •Patient who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.
结局指标
主要结局
Conditioning regimen-related safety
时间窗: at +60 days after transplantation
The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged aplasia), defined as Absolute Neutrophil Count (ANC)\<500/µl, with no evidence of Bone Marrow (BM) recovery, requiring cellular back-up administration.
Increase of residual Arylsulfatase A (ARSA) activity
时间窗: 24 months after treatment
A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total Peripheral Blood Mononuclear Cells (PBMCs)
Improvement of Gross Motor Function Measure (GMFM) score
时间窗: 24 months after treatment
An improvement of 10% of the total GMFM score in treated patients, when compared to the GMFM scores in the historical control MLD population, evaluated 24 months after treatment.
The long-term safety of lentiviral-transduced cell infusion
时间窗: 6 and 12 months after treatment, then once a year
Lentiviral vector integration site analysis will also be performed
Conditioning regimen-related toxicity
时间窗: 3 years after treatment
The absence of regimen related toxicity, as determined by a surveillance of adverse events (AEs) (NCI ≥2) and laboratory parameters (NCI ≥3) that will be applied in the short- and long-term follow-up of the treated patients in order to assess the degree of morbidity associated to the conditioning regimen
The short-term safety and tolerability of lentiviral-transduced cell infusion
时间窗: 48 hours after treatment infusion
It will be evaluated on the basis of AEs reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash). Evaluation will also consist of the absence of Serious Adverse Reactions (SARs) within 48 hours after infusion.
次要结局
- The absence of immune responses against the transgene (immunoblot analyses).(baseline, 3, 6, and 12 months after treatment, then once a year)
- Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score.(24 months after treatment)
- Transduced cell engraftment(12 months after treatment)
- IQ measurement above 55(24, 30 and 36 months after treatment)