Liver Biopsy In Haemophilia Gene Therapy
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 10
- 试验地点
- 2
- 主要终点
- Analysis of AAV integration in hepatocytes using Target Enrichment Sequencing
研究概览
简要总结
To perform a liver biopsy in haemophilia A and B patients with endogenous FVIII:C/FIX:C expression at >1% any time after gene transfer following AAV mediated gene transfer. This is to obtain tissue for analysis, to understand if FIX/FVIII transgenic protein expression is mediated by AAV proviral DNA that is integrated into the host cell DNA or if stable expression in humans is mediated by episomal maintained AAV genome.
详细描述
To better understand the consequences of AAV gene transfer patients will be recruited to undergo a liver biopsy. Patients will have endogenous FVIII:C/FIX:C expression at >1% any time after gene transfer following AAV mediated gene transfer. Analysis of biopsy samples will:
- Provide a clearer insight into the AAV life cycle in human liver
- Define the number of human hepatocytes that are transduced
- Improve understanding at the human hepatocyte level of long-term consequences of AAV mediated transgene expression from the liver that will include (i) changes in the pattern of gene expression in human hepatocytes following AAV mediated gene transfer, (ii) information on the epigenetic signature in the liver following AAV mediated gene transfer and how this changes with time and (iii) the consequences of transgene expression in hepatocytes.
This study will provide new data addressing several unknowns with AAV mediated gene transfer in humans that will better inform on safety and efficacy following AAV gene transfer for patients who have already participated in gene therapy studies as well as those considering this treatment option.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Patients with a platelet count measured at <140 x109/L
- •Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study and/or would influence or interfere with evaluation and interpretation of subject safety or efficacy result.
- •Patients with abnormal kidney function (estimated GFR <50ml/min)
- •Patients with a known allergy to iodine-based intravenous contrast agents
- •Patients with a known allergy to local or general anaesthetic
- •Patients with a known reaction to FVIII/FIX concentrate infusions
- •Presence of FVIII or FIX inhibitor (done within 14 weeks of biopsy)
- •Evidence of any bleeding disorder not related to haemophilia A or B
- •Patients unable and unwilling to provide and sign an informed consent.
结局指标
主要结局
Analysis of AAV integration in hepatocytes using Target Enrichment Sequencing
时间窗: Biopsy samples will be taken from participants who are between one month and up to 15 years post gene therapy
The determination of AAV integration sites will be performed for each participant using Target Enrichment Sequencing (TES) analysis of their liver biopsy sample. This will identify DNA sequences flanking the vector genome. The sequencing data will be analyzed to determine 1. Vector-Vector Concatemers and Vector-Genome Junctions Analysis 2. Integration Site,read count, genomic position and nearest gene
次要结局
- Histology analysis using hematoxylin and eosin staining and immunohistochemical staining to determine histopathological changes in hepatocytes(Biopsy samples will be taken from participants who are between one month and up to 15 years post gene therapy)