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

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.