A Phase I/II, Open Labeled, Monocentric Study of Direct Intracranial Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human ARSA cDNA to Children With Metachromatic Leukodystrophy.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA
研究概览
简要总结
The objective of this open-label, single arm, monocentric, phase I/II clinical study is to assess safety and efficacy of ARSA gene transfer in the brain of children affected with early onset forms of Metachromatic Leukodystrophy (MLD). For this purpose, an adeno-associated virus serotype rh.10 (AAVrh.10) vector will be used to transfer the ARSA cDNA coding for Arylsulfatase A (ARSA) enzyme into the brain of children. Five patients with early onset form of MLD, age ranging from 6 months to 4 years, will be included in this protocol and will be followed during 24 months.
Patients will be selected at presymptomatic or early stage of their disease, following clinical, neuropsychological and brain imaging criteria.
Twelve simultaneous injections of the investigational medicinal product will be performed in the white matter of both brain hemispheres, through 6 image-guided tracks, with 2 deposits per track.
A low dose (1x10EXP12 vg total) will be administered to the first 2 patients, while the last 3 will receive a higher dose (4x10EXP12 vg total).
Safety and efficiency will be evaluated based on clinical, neuropsychological, radiological, electrophysiological and biological parameters.
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
- 6 Months 至 5 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Boys or girls with an early onset form of MLD.
- •Age between 6 months and 5 years, inclusive
- •Diagnostic of MLD based on the measurement of ARSA activity in leukocytes and the accumulation of sulfatides in urine, along with normal activity of at least one other sulfatase
- •Informed consent signed up and willingness for monitoring 2 years after treatment.
- •Normal values for standard laboratory tests
排除标准
- •Absence of ARSA protein by immunocytochemistry and/or ELISA
- •Gestational age <32 weeks of amenorrhoea and age < 1 year
- •Brain atrophy with a subdural space > 10 mm in the frontal region
- •Performance IQ<50 at WPPSI-III or cognitive function < 3rd percentile at the Bayley's test of infant development
- •If age > 16 months at inclusion, inability to walk few steps alone OR inability to walk few steps with support on one side along with inability to stand up alone
- •Impossibility for anesthesia
- •Malignancy, cardiac malformation, liver dysfunction, or renal dysfunction
- •Neurological disorder, except benign, not related to MLD.
- •Any other clinically significant untreated co-morbid medical condition as determined by the clinical investigator, including cardiac, pulmonary or kidney disease.
- •MRI impossibility
- •Evoked potential impossibility
- •Participation to another therapeutic clinical trial for MLD.
- •Unaffiliated to any French or any other National Health Insurance.
研究组 & 干预措施
AAVrh.10cuARSA
intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.
干预措施: intracerebral administration of AAVrh.10cuARSA (Genetic)
结局指标
主要结局
Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA
时间窗: During the two years follow-up
Tolerance will be measured by : * Adverse event, * Clinical and neurological exams, * Laboratory tests, * Neuroimagery (CT scan, brain MRI).
次要结局
- Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression.(During the two years follow-up)