Overview
Retinitis pigmentosa (RP) is a group of inherited blinding disorders that affects around 1 in 4000 people. Sight loss in RP happens over decades. It is due to death of the light-sensitive photoreceptor cells in the retina at the back of the eye.
There are several forms of RP, caused by faults in different genes. The most common form of a severe type of RP is due to faults in a gene called RPGR. We don’t know exactly what part the gene plays in RP but the fault also happens naturally in some animals, with the same effect.
Recent studies have showed that gene replacement therapy rescued the retina in one group of animals. But the therapy wasn’t specific enough to the gene to be used in humans.
In this study the team is modifying the gene therapy to make it suitable for humans. The ideal therapy for humans would include a section of DNA (called a promoter) that controls how much healthy protein would be produced and in which cells. But the right promoter for the RPGR gene is too big to work with the current gene therapy system. So the team is working to make it smaller by including only the sections that are most important for the job. They will then test the therapy in naturally-occurring mouse RP. The results should provide enough information to take the therapy into clinical trials.
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Scientific summary
Creation of a mini human RPGR promoter for retinitis pigmentosa gene therapy
Retinitis pigmentosa (RP) is a group of inherited diseases characterised by retinal degeneration with a prevalence of 1 in 3500. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) are the most common single cause of RP, accounting for 10-20% of all RP patients. RPGR is thought to be involved in microtubule-based transport to the connecting cilium of photoreceptors and to primary cilia in other ciliated cells, although its precise role in disease is poorly understood. Loss of RPGR results in cilia defects in mammalian cell lines and retinal degeneration in animals. There are three naturally-occurring RPGR mutant animal models, mouse (rd9) and dogs (XLPRA1 and XLPRA2), which carry mutations in RPGR exon ORF15. Those models have provided an excellent platform to investigate disease progression and evaluate the efficacy of gene-replacement therapy.
Gene therapy is considered to be a potential therapeutic option for treating RP patients with RPGR mutations. Recent gene therapy studies in the RPGR dog models showed that there was a dramatic preservation of photoreceptor structure associated with treatment (Beltran et al. PNAS, USA, 2012). Although the therapy was successful, the therapeutic gene used was regulated by a non-specific rather than gene-specific promoter. For rapid clinical translation it would be preferable that the human RPGR gene to be used in therapy is regulated by the specific human RPGR promoter. In this project, we plan to create and characterise a mini RPGR promoter for human RPGR gene therapy.