Clinical trial of gene therapy for the treatment of Leber congenital amaurosis

儿童失明最常见的原因是遗传性视网膜疾病，视网膜是眼睛中的感光神经层。数以千计的儿童受到影响。这些孩子只缺少数百个基因中的一个，这些基因是眼睛正常看东西所必需的基本指令。直到最近，还没有任何治疗方法。然而，我们和其他人已经开发出一种新的治疗方法，可以通过为受影响的儿童提供缺失的基因来改善他们的视力。这涉及通过将缺失基因的拷贝包装在一种改良的病毒（称为载体）中，并在一个简单的手术中将它们注射到眼睛中，从而将其提供给视网膜。然而，迄今为止，对儿童的益处有限;视力的改善有限，并且儿童无法长期防止视力丧失。这很可能是因为目前传递的基因不如所需的有效。为了改善治疗，我们对基因进行了一些修改（MRC DPFS授权MR/J 005215/1），并计划使用不同的载体更有效地递送它们。对于第一个里程碑（持续7个月），我们将生产新的优化基因治疗载体（AAV 2/5.hRPE65p.hRPE65），以达到适用于人类的标准。这将在UCL基因治疗联盟的生产设施进行。第二个里程碑（持续5个月）将是在实验室中确定新载体的安全性和有效性。这将根据既定方案通过内部研究实现。该里程碑的成功完成将定义为生产的载体批次符合适当的放行标准，并且有足够的体积按计划进行临床试验。第三个里程碑（持续4年）将是在受影响的成人和儿童中完成优化载体的临床试验。成功完成这一里程碑将被定义为可接受的安全性，以及与视网膜电功能（视网膜电图，ERG）可测量改善相关的视力受益证据。我们还将使用成像技术和敏感的视觉功能测试来研究长期保护视力丧失的证据。我们预测，我们在临床前开发中实现的载体优化（MRC DPFS赠款MR/J 005215/1）将在拟议的试验中为受影响的儿童带来实质性的益处，并将为未来开发更有效的基因治疗载体铺平道路，许多其他致盲遗传性视网膜疾病。

The commonest cause of blindness in children is inherited disease of the retina, the layer of light-sensitive nerves in the eye. Thousands of children are affected. These children lack just one of the hundreds of genes, which are the essential instructions, that are required for eyes to see normally. Until very recently no treatment at all has been available. However, we and others have developed a new treatment that can improve affected children's sight by providing them with the gene that is missing. This involves providing copies of the missing gene to the retina by packaging them in a modified virus (called a vector) and injecting them into the eye during a simple operation.However, the benefit to children to date has been only modest; improvements in sight have been limited and children are not protected against sight loss in the longer term. This is most likely because the genes currently delivered are less effective than required. To improve the treatment we have made a number of modifications to the genes (MRC DPFS grant MR/J005215/1) and plan to deliver them more efficiently using a different vector. For the first milestone (duration 7 month) we will produce the new optimise gene therapy vector (AAV2/5.hRPE65p.hRPE65) to the standard appropriate for administration to people. This will be performed at the production facility of the UCL gene therapy consortium. The second milestone (duration 5 months) will be to establish the safety and efficiency of the new vector in the laboratory. This will be achieved by studies performed in-house, according to established protocols. Successful completion of this milestone will be defined as the production of a vector batch that conforms to the appropriate release criteria, and at sufficient volume to perform the clinical trial as planned. Successful completion of this milestone will be defined as permission from the regulatory authorities to commence a clinical trial.The third milestone (duration 4 years) will be the completion of a clinical trial of the optimised vector in affected adults and children. Successful completion of this milestone will be defined as acceptable safety, and evidence of benefit to sight associated with measurable improvement in the electrical function of the retina (electroretinography, ERG). We will also investigate evidence of protection against sight-loss in the longer term using imaging techniques and sensitive test of visual function.We predict that the vector optimisation that we have achieved in preclinical development (MRC DPFS grant MR/J005215/1) will result in substantial benefit for affected children in the proposed trial and will pave the way for the future development of more potent gene therapy vectors for many other blinding inherited retinal diseases.