Gene Therapy for Alpha 1- Antitrypsin Deficiency
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Safety of AAV8hAAT(AVL), as measured by number of subjects with at least 1 serious adverse event.
研究概览
简要总结
This is a study of gene therapy to treat alpha 1-antitrypsin (AAT) deficiency. This study aims to treat AAT deficiency with a single administration of AAV8hAAT(AVL), a gene therapy that codes for an oxidation resistant form of the AAT protein, which if safe and if efficacious, will protect the lung on a persistent basis. We hope to learn the safety/toxicity and initial evidence of efficacy of intravenous delivery of this gene therapy to alpha 1-antitrypsin deficient individuals.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •AAT genotype ZZ, or Z null heterozygotes, and if on augmentation therapy, pre-therapy AAT serum levels <11 μM
- •Emphysema as assessed by chest high resolution computational tomography (HRCT)
- •Lung function parameters consistent with mild to moderate loss of lung function and the presence of emphysema.
- •Troponin T within normal limits
- •Normal liver ultrasound and serum alpha fetoprotein
- •Normal kidney function
- •No contraindications to receiving corticosteroid immunosuppression
排除标准
- •Individuals receiving systemic corticosteroids or other immunosuppressive medications for pre-existing conditions.
- •Inability to tolerate immunosuppression with corticosteroids (e.g., uncontrolled diabetes)
- •Individuals with an immunodeficiency disease, or evidence of active infection of any type, including human immunodeficiency virus
- •Evidence of major central nervous system, major psychiatric, musculoskeletal or immune disorder
- •Prior history of myocardial infarction or cancer within the past 5 years (other than basal cell carcinoma of the skin)
- •Decompensated heart failure (NY4A class III-IV at time of baseline clinical assessment)
- •Abnormal ECG at screening with findings consistent with cardiac disease
- •Females who are currently pregnant or lactating
- •Any history of allergies to drugs used for bronchoscopy, including xylocaine, lidocaine, versed, valium, atropine, pilocarpine, isoproterenol, terbutaline, aminophylline, or any local anesthetic
- •Individuals receiving experimental medications or participating in another experimental protocol for at least 3 months prior to entry to the study
- •Use of oxygen supplementation
- •Risk for thromboembolic disease
- •History of significant cardiovascular disease, hypertension, prior myocardial infarction and/or cerebrovascular event
- •Individuals who are currently on beta-blockers, or other cardiac therapy related drugs
- •Prior history of hypersensitivity or anaphylaxis associated with the administration of any AAT product
研究组 & 干预措施
AAV8hAAT(AVL) - 5x10¹¹ gc/kg
Lowest dose of vector genome copies per kilogram
干预措施: AAV8hAAT(AVL) (Biological)
AAV8hAAT(AVL) - 2x10¹² gc/kg
干预措施: AAV8hAAT(AVL) (Biological)
AAV8hAAT(AVL) - 5x10¹² gc/kg
干预措施: AAV8hAAT(AVL) (Biological)
AAV8hAAT(AVL) - 2x10¹³ gc/kg
Highest dose of vector genome copies per kilogram
干预措施: AAV8hAAT(AVL) (Biological)
结局指标
主要结局
Safety of AAV8hAAT(AVL), as measured by number of subjects with at least 1 serious adverse event.
时间窗: Approximately 1 year
Serious adverse events will only be included if assessed as related to the gene therapy.
Toxicity of AAV8AAT(AVL), as measure by number of subjects with any dose limiting toxicity
时间窗: Approximately 2 years
If none of the first 4 dosed participants experiences a DLT by the end of Day 28 after treatment (Day 1), the dose of AAV8hAAT(AVL) will be escalated, and the next cohort of participants will start treatment at the next-higher dose level.
Establishing a maximum tolerable dose of AAV8hAAT(AVL)
时间窗: Approximately 2 years
If none of the first 4 participants treated at the highest dose level experiences a DLT by the end of Day 28 after treatment, this dose will be determined to be the maximum administered dose (MAD)
次要结局
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(5 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid(5 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(4 weeks)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(6 months)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(3 months)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(12 months)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(2 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(3 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum(4 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid(12 months)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid(2 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid(3 years)
- Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid(4 years)