Repair of urea cycle defects in mice by rAAV-mediated gene transfer: Towards gene therapy for genetic liver disease

通过rAAV介导的基因转移修复小鼠尿素循环缺陷：遗传性肝病的基因治疗

• 批准号: nhmrc : 423400
• 负责人: A/Pr Kevin Carpenter
• 金额: $ 29.71万
• 依托单位: Children's Medical Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/repair-urea-cycle-liver-disease/100362
• 关键词: Repair; urea; cycle; defects; mice

Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the development of improved AAV vectors with dramatically higher gene transfer efficiencies (up to two orders of magnitude in the liver). This places successful liver-directed gene therapy within reach. Initial human studies will only be possible in the context of severe diseases where existing therapies are high risk or inadequate. Accordingly, we have chosen the most common urea cycle defect, OTC deficiency, as a disease model. In its severe form neonatal hyperammonaemia is associated with a high risk of death and significant disability in those who survive the newborn period. Using the spf(ash) mouse model of OTC deficiency we propose to develop gene therapy strategies capable of achieving life-long disease cure. Preliminary data has confirmed feasibility, and suggests that the greater number of cells in the human liver requiring genetic repair will not prove insurmountable. The proposal focuses on issues critical to success in humans. These include strategies to minimise the number of repaired liver cells required for clinical benefit, overcoming the effects of liver growth, investigating the potential impact of OTC mutations on gene therapy, and establishing the likely efficiency of gene transfer in human liver cells and large animal livers equivalent in size to the human neonate. These studies are part of a long-term commitment to progress through to human clinical trials of gene therapy for urea cycle defects. The potential health and economic benefits are immense.

基因治疗有可能治愈许多遗传性代谢性肝病。关键的挑战是开发基因转移技术--具有必要的有效性和安全性的战略。基于腺相关病毒(AAV)的载体在将基因转移到肝脏方面显示出特殊的前景，已经在小动物和大动物模型中进行了广泛的评估。目前的挑战是实现人类治疗所需的更高水平的基因转移。最近的一项量子进展是开发了具有显著更高的基因转移效率(在肝脏中高达两个数量级)的改进型AAV载体。这使得成功的肝脏导向基因治疗触手可及。只有在现有治疗方法高风险或不足的严重疾病背景下，才有可能进行初步的人体研究。因此，我们选择了最常见的尿素循环缺陷--OTC缺乏症作为疾病模型。新生儿高氨血症的严重形式与那些在新生儿期存活下来的人死亡和严重残疾的高风险有关。利用SPF(ASH)小鼠的OTC缺乏模型，我们建议开发能够实现终生疾病治愈的基因治疗策略。初步数据已经证实了可行性，并表明人类肝脏中需要基因修复的更多细胞并不是无法克服的。该提案关注的是对人类成功至关重要的问题。这些措施包括最大限度地减少临床所需的修复肝细胞数量，克服肝脏生长的影响，研究OTC突变对基因治疗的潜在影响，以及建立在人类肝细胞和大小相当于人类新生儿的大型动物肝脏中进行基因转移的可能效率。这些研究是一项长期承诺的一部分，旨在通过尿素循环缺陷的基因治疗的人类临床试验取得进展。潜在的健康和经济效益是巨大的。