Lebers congenital amaurosis (LCA) is a devastating disease leading to the failure of vision because the light-sensing photoreceptor cells in the eye do not work properly even within the first few years of life. There is currently no cure or treatment for LCA. Inherited genetic mistakes in the AIPL1 gene are one of the causes of LCA. In this study, we want to create a new laboratory system that accurately models the human disease, so that we can test novel therapies to treat LCA caused by faults in the AIPL1 gene. Using state-of-the-art technologies optimised in our group, we will take cells isolated from the urine of LCA patients and reprogramme them to so called induced pluripotent stem cells (iPSC) from which we will grow three dimensional 'optic cups' in a dish in the laboratory, the 'retina in a dish'. This is important, as it is not possible to isolate and culture the light sensitive photoreceptor cells of the retina that are faulty in LCA directly from patients. Therefore, the derivation of these photoreceptor cells from LCA patients via formation of optic cups is critical to model the disease in humans and will be invaluable to validate new AIPL1-targeted therapies that may treat or cure this devastating disease. We will first test a pharmacological approach that targets a class of mutations encountered in up to 60% of all LCA patients with AIPL1 faults. These drugs, which can be safely applied as an eye drop, or as a tablet, target the cell machinery that converts a gene to a protein. We will test whether these drugs can rescue the normal AIPL1 protein from the faulty AIPL1 gene. The rescued AIPL1 protein will be able to perform its normal function in the cell. We will also develop treatments for a different kind of mutation in the AIPL1 gene that interferes with the way different parts of the AIPL1 gene are stitched or 'spliced' together to form the full-length message for the AIPL1 protein. We will test whether our custom-design therapeutic agents can 'override' these splice mutations to form a normal full-length AIPL1 message coding for a normal full-length and functional AIPL1 protein. These novel therapies will be tested on optic cups made from patients harbouring these classes of different AIPL1 mutations. The findings of this research are a critical step towards the application of these novel therapies to treat AIPL1 LCA patients in the clinical setting. The drug that will be used in this study has already been approved by NICE for the treatment of another disease caused by stop mutations, and a similar therapeutic agent targeting splice mutations in another gene causing LCA will shortly enter phase I clinical trials. Hence, the potential for our findings to rapidly enter the clinical phase and make a difference to patients' lives is very high.