Our group studies disease mechanisms in inherited retinal degenerations (IRDs), and evaluates efficacy and safety of potential treatments. IRDs result in vision loss due to mutations in more than 200 different genes and include diagnoses such as Retinitis Pigmentosa, Stargardt Disease, Leber Congenital Amarousis, and others. There are multitudes of different pathological mechanisms resulting from different mutations. Our group uses non-invasive tests to link changes in retinal structure and function to underlying molecular pathology. We also develop and evaluate novel outcome measures for use in clinical trials.
October 25, 2016: Paper Published in Human Molecular Genetics
Inherited retinal degenerations, including retinitis pigmentosa (RP), refer to a heterogeneous group of Mendelian disorders caused by mutations in over 200 genes. There is visual dysfunction due to loss of structure and function of rod and/or cone photoreceptors. Among the most common genetic causes of IRDs are mutations in the RPGR gene located on the X-chromosome; by far the majority of the RPGR mutations are located in the ORF15 exon of the gene. Most, but not all, patients with RPGR-ORF15 mutations are diagnosed with X-linked RP (XLRP). In addition to causing visual disability in humans, naturally-occurring mutations in ORF15 exon are also found in dogs and mice with retinal degeneration. The exact function of RPGR in the rod and cone photoreceptors remains poorly understood but it is suggested to be involved in regulating ciliary transport. We have previously been involved in successful experiments in gene augmentation therapy at different disease stages of dogs with RPGR-ORF15 mutations.
We now present results that are a prerequisite to the translation of preclinical experiments to human clinical trials. We evaluated disease features in 70 patients with RPGR-ORF15 mutations in order to determine when and where to treat and what outcomes to use. We found that patients had pronounced macular disease. Across the retina, rod and cone dysfunction showed a range of patterns and a spectrum of severity between individuals, but a high symmetry was observed between eyes of each individual. Genotype was not related to disease expression. Longitudinal results in patients revealed localized rod and cone dysfunction with progression rates of 1.3 to 2.5 log per decade in sensitivity loss. We estimate that relatively retained rod and cone photoreceptors in mid- and far-peripheral temporal-inferior and nasal-inferior visual field regions should be good targets for future localized gene therapies in patients.
Charng J, Cideciyan AV, Jacobson SG, Sumaroka A, Schwartz SB, Swider M, Roman AJ, Sheplock R, Anand M, Peden MC, Khanna H, Heon E, Wright AF, Swaroop A. Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration. Human Molecular Genetics 25:5444–5459, 2016. [PubMed]
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