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

Lead Research Organisation: University College London
Department Name: Institute of Ophthalmology


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.

Technical Summary

Leber congenital amaurosis (LCA) is a severe inherited retinal dystrophy with a population frequency around 1/50000, characterised by loss of vision in the first decade of life. Approximately 5% of LCA cases are caused by mutations in the RPE65 gene, which encodes a retinal pigment epithelium (RPE) specific protein essential for recycling of retinoids to the photoreceptor cells. Patients lack rod-mediated (night) vision from birth, but it is the loss of rods and consequently cones in the second decade, that causes profound visual impairment. Three independent clinical trials of AAV2 mediated gene therapy, including one performed by our group, have shown improvements in retinal sensitivity and vision. However, there is no evidence for preservation of photoreceptor cells and the level of improvement is lower in patients than expected from pre-clinical experiments in rodents and dogs, in which gene therapy restores the electroretinogram (ERG) and slows photoreceptor loss. This is most likely due to insufficient production of RPE65 protein from the AAV2/2 vector. In a previous DPFS-funded study (MR/J005215/1) we developed a new AAV2/5-based gene therapy vector that delivers to the RPE an RPE65 expression cassette that is markedly more potent through specific patentable modifications. The overall objective of this study is to produce clinical grade AAV2/5 vector and conduct a combined phase I/II clinical trial of gene therapy for the treatment of LCA, caused by RPE65 mutations. The objectives of the clinical trial will be to establish safety of the optimised RPE65 vector and show functional improvement that is likely to lead to photoreceptor preservation. The primary outcome for efficacy is an improvement in the rod ERG as the best surrogate marker for normal retinal physiology. Secondary outcomes will include improvements in rod and cone retinal function as determined by an array of psychophysical and other electrophysiological assessments.

Planned Impact

Leber congenital amaurosis (LCA) is the leading cause of vision loss in children, typically causing visual impairment within the first decade of life. Although LCA type 2, caused by mutations in the RPE65 gene is one of the milder forms of the disease, generally leading to blindness in the second decade. Thus far, no established successful treatments exist for this disease, but clinical trials - including one conducted by our group - for LCA caused by mutations in the RPE65 gene have resulted in encouraging, but modest improvements in retinal sensitivity and scotopic vision. However, more encouraging improvements in vision were observed in animal studies and we have data to suggest that the level of expression of RPE65 in the human retina is higher than in animals. This suggests that after further optimisation of the therapeutic vector, a more substantial rescue of vision should be feasible. Such an improvement would have considerable impact on the quality of life of the patients, with benefits ranging from improved night-vision to improved visual acuity and preservation of vision over time, depending on the condition of the retina at the time of treatment. As the best outcome is expected after treatment early in life, most commonly the end users would be pre-teen LCA2 patients, although ongoing clinical trials have shown that patients up to twenty years of age can benefit from treatment. The young age of the subjects means that an optimally successful treatment outcome could result in years of increased visual acuity and/or a wider visual field, with concomitant improvements in self-sufficiency and potentially other economic benefits. LCA is a relatively rare condition with a population frequency of approximately 1/50000. In the UK around 5% of all forms of LCA are caused by RPE65 mutations and thus potential end-users for AAV-RPE65 gene therapy. Only patients under the age of 20 are likely to benefit from treatment; however, in this group a near-complete take-up of an established therapy is expected. We do not anticipate a need for repeated administration of vector in the treated eye, although treatment of the fellow eye may be advantageous when the therapy becomes established. Retinal dystrophy is a highly diverse group of disorders that can be caused by mutations in as many as 200 different genes. The core technology used in this application - subretinal injection of AAV vectors carrying a transgene - will be suitable for the development of gene therapy protocols for the majority of retinal dystrophies. At the moment, proof-of-concept exists for the use of AAV vector mediated gene replacement therapy for twenty other forms of retinal degeneration and we have completed proof-of-concept studies for five gene therapy applications that would be suitable to progress to clinical trials in the near future. The results obtained in this project will facilitate the progression of these therapies to clinical application.


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Description BRC Theme
Amount £794,946 (GBP)
Funding ID BRC3_002 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2022
Title Optimised gene therapy vector for RPE65 deficiency 
Description Optimised AAV vector for treatment of LCA2 
IP Reference WO2016128722 
Protection Patent application published
Year Protection Granted 2015
Licensed Yes
Impact Paper published in Gene Therapy (Georgiadis et al 2016)
Company Name Athena Vision Ltd 
Description Ocular gene therapy company 
Year Established 2015 
Impact Has raised substantial funding and will develop a programme of clinical trials with 2 new multi-centre US/UK trials of ocular gene therapy over the next 3 years. Has secured GMP facility for manufacturing for viral vectors.
Description Retina Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact 300 patients and their carers attended a1 day meeting in which we told them about our work on gene and cell therapy. There were talks and posters. Forty people from the lab attended to present and answer questions.
Year(s) Of Engagement Activity 2015