Phase 1/2, Open Label, Sequential Cohort Study of a Single Intracranial Dose of AVASPA Gene Therapy for Treatment of Children With Typical Canavan Disease
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Safety evaluation
研究概览
简要总结
Canavan Disease is a congenital white matter disorder caused by mutations to the gene encoding for aspartoacylase (ASPA). Expression of ASPA is restricted to oligodendrocytes, the sole white matter producing lineage in the brain. ASPA supports myelination in the capacity of its sole known function, namely, the catabolism of N-acetylaspartate (NAA). Inherited mutations that result in loss of ASPA catabolic activity result in a typically severe phenotype of Canavan Disease, characterized by chronically elevated brain NAA, gross motor abnormalities, hypomyelination, progressive spongiform degeneration of the brain, epilepsy, blindness, and a short life expectancy. Disease severity is correlated with residual levels of enzyme activity. Reconstitution of ASPA function in oligodendrocytes of the brains of Canavan patients is expected to rescue NAA metabolism in its natural cellular compartment and support myelination/remyelination by resident white matter producing cells. This protocol directly targets oligodendrocytes in the brain, which are intimately involved with disease initiation and progression. Targeting oligodendrocytes offers the safest and most direct therapy for affected individuals.
The latest generation AAV viral vector (rAAV-Olig001-ASPA) will be administered to patients using neurosurgical procedure which involves direct administration of gene therapy to affected regions of the brain. Outcome measures for the open label clinical trial include longitudinal clinical assessments and brain imaging.
Currently, there is no effective treatment for Canavan Disease. The purpose of this study is to validate a new technology targeted to the cells most affected by Canavan Disease in the safest way possible.
The study investigators are committed to supporting the Rare Disease & Canavan Disease Communities. For more information, please contact Jordana Holovach, Head of Communications and Community at PatientAdvocacy@myrtellegtx.com.
详细描述
rAAV-Olig001-ASPA is the first gene therapy designed to target the oligodendrocytes, which are critical for myelination and brain development.
This study is a Phase 1/2 First-In-Human protocol designed to obtain safety, pharmacodynamics, and efficacy data following neurosurgical administration of a single dose of rAAV-Olig001-ASPA delivered intracerebroventricularly in up to 24 children with Canavan Disease.
Patients with a diagnosis of typical Canavan Disease who meet all eligibility criteria may be enrolled in this open-label, sequential cohort study of a single dose of rAAV-Olig001-ASPA.
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 Months 至 60 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Definitive diagnosis of typical CD by a board certified neurologist.
- •Written informed consent from parent(s)/guardian(s). Consent to enroll into the study will include a written agreement to comply with all the conditions of the study, including attendance at follow-up visits.
- •For cohort 1: age more than 36 months and up to 60 months.
- •For cohort 2: age between 15 months and 36 months.
- •For cohort 3: age less than 15 months.
排除标准
- •At the discretion of the PI, any significant chronic medical condition, including, but not limited to neurological, cardiac, hepatic, renal, hematological, gastrointestinal, endocrine, pulmonary, or infectious disease, which would put the subject at increased risk during surgery or which would interfere with participation in the study, interpretation of safety monitoring, or the integrity of the study data.
- •History of severe allergic reaction or anaphylaxis.
- •Past participation in gene therapy trials or receipt of any other investigational product within 6 months prior to enrollment.
- •Prior intracranial surgery.
- •Any absolute contraindication to immunosuppression.
- •Any absolute contraindication to MRI.
- •Any vaccination less than 1 month prior to gene therapy.
- •Anticipated life expectancy of less than 12 months for any reason.
- •GMFM-88 total raw score >35%.
- •Clinically significant out-of-range lab values, at the discretion of clinical PI.
研究组 & 干预措施
3.7 x 10^13 v.g. rAAV-Olig001-ASPA
3.7 x 10^13 v.g. of rAAV-Olig001-ASPA administered as a single dose neurosurgically to the brain via 2 pre-defined intracerebroventricular sites
干预措施: rAAV-Olig001-ASPA (Drug)
3.7 x 10^13 v.g. rAAV-Olig001-ASPA
3.7 x 10^13 v.g. of rAAV-Olig001-ASPA administered as a single dose neurosurgically to the brain via 2 pre-defined intracerebroventricular sites
干预措施: Levetiracetam (Drug)
3.7 x 10^13 v.g. rAAV-Olig001-ASPA
3.7 x 10^13 v.g. of rAAV-Olig001-ASPA administered as a single dose neurosurgically to the brain via 2 pre-defined intracerebroventricular sites
干预措施: Prednisone (Drug)
结局指标
主要结局
Safety evaluation
时间窗: 12 Months Post Dose
Number, severity, and causal relationship of any adverse event (to either the gene therapy and/or surgical trial procedures required for vector administration) using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
次要结局
- Myelination(12 Months Post Dose)
- Neurological Evaluation - Spasticity(12 Months Post Dose)
- NAA concentration measured in Cerebrospinal Fluid (CSF)(6 months)
- Seizure Assessment(12 Months Post Dose)
- N-Acetyl-Aspartate (NAA) concentrations in the Brain(12 Months Post Dose)
- Neurological Evaluation - Motor Function(12 Months Post Dose)
- Neurological Evaluation - Neurocognitive Function(12 Months Post Dose)