An Open-label Dose Escalation Study of an Adeno-associated Virus Vector (scAAV2-P1ND4v2) for Gene Therapy of Leber's Hereditary Optic Neuropathy (LHON) Caused by the G11778A Mutation in Mitochondrial DNA
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Number of Treatment Related Adverse Events
研究概览
简要总结
The study is a dose-escalation study, phase 1. The objective of this proposed clinical trial is to evaluate the safety of mitochondrially targeted ND4 gene therapy with the adeno-associated viral vector in appropriate LHON patients.
详细描述
The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene replacement therapy in subjects confirmed with the G11778A mutation in mtDNA responsible for Leber's Hereditary Optic Neuropathy. Ocular and systemic toxicity will be assessed following vector administration to determine if there are adverse changes that may be associated with vector administration.
This first-in-man (FIM) clinical trial will assess the safety, tolerability, and potential efficacy of a single intravitreal injection in patient groups reflecting the acute, pre-symptomatic, and chronic stages and manifestation of the LHON disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 15 or older;
- •Patients with LHON and the G11778A mitochondrial DNA mutation. A previous CLIA-certified genetic lab result showing the LHON G11778A mutation will be accepted for inclusion;
- •Ability to perform tests of visual and retinal function;
- •Ability to comply with research procedures;
- •Able and willing to provide informed consent before undergoing any study-related procedures.
- •Good general health as based on the investigator's assessment of the history, physical examination, and laboratory testing performed at the baseline examination.
排除标准
- •Unwilling or unable to give consent,
- •Unable or unlikely to return for scheduled protocol visits
- •Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study.
- •Optic disc drusen on exam or in previous history.
- •Ocular diseases or visual dysfunction conditions other than refractive error (e.g. amblyopia, glaucoma, etc.) in the eye selected for the injection.
- •Previous eye surgery in the eye selected for injection.
- •Aspartate transaminase (AST)/alanine transaminase (ALT) >5.0 x upper limit of normal (ULN); Total bilirubin >3 x ULN; Hemoglobin < 8 g/dL; neutrophil count <1.0 x 109/L; or platelet count < 50 x 109/L
- •a) Any laboratory screening test that meets the abnormality criteria stated above can be repeated once between Baseline one to Baseline
- •Type I diabetes or the presence of diabetic retinopathy
- •History of neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
- •History of autoimmune conditions (e.g. systemic lupus erythematosus)
- •Systemic diseases having ocular manifestations likely to confound assessment of study results. History of cancer within five years other than localized basal or squamous cell carcinoma not near the orbital area. Patients with a prior history of cancer will need documentation from their cancer specialist that the cancer was cured at least 5 years before study entry.
- •Allergy to pupil dilating drops or narrow angles precluding safe dilation.
- •No Light Perception (NLP) vision in either eye.
研究组 & 干预措施
Low-dose (1.18x10e9 vg)
Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg.
Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg.
Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg
干预措施: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low), (Drug)
Medium dose (5.81x10e9 vg)
Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg.
Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg.
Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg.
干预措施: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med) (Drug)
High dose (2.40x10e10 vg)
Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg.
干预措施: injection of scAAV2-P1ND4v2 2.4 X10e10vg (High) (Drug)
Higher dose (1x10e11vg)
Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg.
Participants with Acute Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg.
Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg.
干预措施: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher) (Drug)
结局指标
主要结局
Number of Treatment Related Adverse Events
时间窗: 3 years
Number of treatment-related adverse events will be assessed as per investigator with respective to relationship to the investigative product.
次要结局
- Best-corrected Visual Acuity(up to 36 months after treatment)
研究者
Byron Lam
Greene Professor of Ophthalmology
University of Miami