Developing gene therapy to treat blindness caused by Stargardt Disease

开发基因疗法治疗斯塔加特病引起的失明

基本信息

批准号：
MR/K007629/1
负责人：
Robert MacLaren
金额：
$ 65.62万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK007629%2F1
关键词：
Developing gene therapy treat blindness

项目摘要

Stargardt disease leads to blindness in young people due to loss of the light sensing cells known as photoreceptors that line the retina at the back of the eye. Stargardt disease is caused by the deficiency of a protein known as ABCA4 which stands for "ATP Binding Cassette subtype A4". This protein is very important for recycling the visual pigments necessary for the light-sensitive photoreceptors. When there is a deficiency of ABCA4, the light-sensitive pigments accumulate in the retina which leads to toxic damage and eventual cell death. Stargardt disease usually presents in childhood and there then follows a period of several years of progressive loss of sight and blindness in many cases. There is therefore a window of opportunity of several years after diagnosis in which to intervene with some form of treatment to prevent sight loss.Gene therapy is a new technique which has been shown to be highly effective at reintroducing defective genes into the retina. Gene therapy was first used in this manner in 2007 in three clinical trials to treat inheriuted blindess caused by defiency of anothe gene known as RPE65. More recently we have started a new gene therapy treatment in Oxford to treat a photoreceptor disease known as choroideraemia and several patients have been treated so far without adverse effects. In these gene therapy trials we are using a small viral particle known as adeno associated virus, or AAV. This viral particle is one of the smallest lifeforms known and it is not associated with any disease in humans. The virus survives by remaining dormant and undetected by the immune system. We have taken advantage of AAV by removing the viral genes and replacing them with the gene that is missing for the particular retinal disease. The ability of the virus to evade the immune system is very helpful because the lack of inflammation means that the virus does not damage the retina when injected into the eye. The AAV particle is however too small to carry many genes that are missing in certain types of retinal degeneration. Unfortunately the ABCA4 gene, which would need to be replaced to cure Stargardt disease, is just too large to fit into AAV.The purpose of this project is to solve this problem by exploring a new property which has recently been identified in relation to AAV. It has recently been discovered that a large gene can be broken into two segments each of which is carried by an AAV particle and these particles are able to recombine the gene back into full length after infecting nerve cells. In this project we aim to perform a series of experiments whereby we optimise the process of recombining two fragments of the ABCA4 gene in order to deliver its successfully into photoreceptors. We will validate the function of the gene in a genetically engineered mouse, which is also deficient of the same gene and has features similar to Stargardt disease on retinal examination. If we can correct or even improve the deficiency of ABCA4 using our new vector then we would have the ideal background information to support a new clinical trial.

斯塔加特病会导致年轻人失明，原因是眼睛后部视网膜上的感光细胞（称为感光细胞）的丧失。 Stargardt 病是由一种称为 ABCA4 的蛋白质缺乏引起的，ABCA4 代表“ATP 结合盒亚型 A4”。这种蛋白质对于回收光敏感光器所需的视觉色素非常重要。当 ABCA4 缺乏时，光敏色素会在视网膜中积聚，导致毒性损伤并最终导致细胞死亡。斯塔加特病通常出现在儿童期，随后几年，许多病例会逐渐丧失视力甚至失明。因此，诊断后几年有机会进行某种形式的治疗以防止视力丧失。基因治疗是一种新技术，已被证明可以非常有效地将有缺陷的基因重新引入视网膜。 2007 年，基因疗法首次以这种方式用于三项临床试验，以治疗因另一种名为 RPE65 的基因缺陷而导致的遗传性失明。最近，我们在牛津开始了一种新的基因疗法，用于治疗一种被称为无脉络膜血症的光感受器疾病，到目前为止，已有几名患者接受了治疗，没有出现不良反应。在这些基因治疗试验中，我们使用一种称为腺相关病毒（AAV）的小病毒颗粒。这种病毒颗粒是已知最小的生命形式之一，与人类的任何疾病无关。该病毒通过保持休眠状态而不被免疫系统检测到而存活。我们通过去除病毒基因并用特定视网膜疾病缺失的基因替换它们来利用 AAV。病毒逃避免疫系统的能力非常有帮助，因为缺乏炎症意味着病毒在注射到眼睛中时不会损害视网膜。然而，AAV 颗粒太小，无法携带某些类型的视网膜变性中缺失的许多基因。不幸的是，需要替换才能治愈 Stargardt 病的 ABCA4 基因太大，无法融入 AAV。该项目的目的是通过探索最近发现的与 AAV 相关的新特性来解决这个问题。最近发现，一个大基因可以被分成两个片段，每个片段都由 AAV 颗粒携带，这些颗粒在感染神经细胞后能够将基因重组回完整长度。在这个项目中，我们的目标是进行一系列实验，优化 ABCA4 基因两个片段的重组过程，以便将其成功传递到光感受器中。我们将在基因工程小鼠中验证该基因的功能，该小鼠也缺乏相同的基因，并且在视网膜检查中具有与斯塔加特病相似的特征。如果我们能够使用我们的新载体纠正甚至改善 ABCA4 的缺陷，那么我们将拥有支持新临床试验的理想背景信息。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina.

DOI：
10.1038/gt.2017.85
发表时间：
2017-12
期刊：
Gene therapy
影响因子：
5.1
作者：
Hickey DG;Edwards TL;Barnard AR;Singh MS;de Silva SR;McClements ME;Flannery JG;Hankins MW;MacLaren RE
通讯作者：
MacLaren RE

A fragmented adeno-associated viral dual vector strategy for treatment of diseases caused by mutations in large genes leads to expression of hybrid transcripts.

用于治疗由大基因突变引起的疾病的片段化腺相关病毒双载体策略导致杂合转录本的表达。