Molecular Strategies for RPGR Gene Therapy.

Mutations affecting the () gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%-20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, characteristic for its early onset and rapid progression to blindness in young people. At present there is no cure for -related retinal disease. Recently, however, there have been important advances in research from bench to bedside that increased our understanding of function and led to the development of potential therapies, including the progress of adeno-associated viral (AAV)-mediated gene replacement therapy into clinical trials. This manuscript discusses the advances in molecular research, which have connected the RPGR protein with an important post-translational modification, known as glutamylation, that is essential for its optimal function as a key regulator of photoreceptor ciliary transport. In addition, we review key pre-clinical research that addressed challenges encountered during development of therapeutic vectors caused by high infidelity of the genomic sequence. Finally, we discuss the structure of three current phase I/II clinical trials based on three AAV vectors and sequences and link the rationale behind the use of the different vectors back to the bench research that led to their development.