Abstract
Gene therapy for adRP due to RHO mutations was recently shown to prevent photoreceptor death in a canine model of Class B disease. Among translational steps to be taken, one is to determine a method to detect efficacy in a human clinical trial. The relatively slow progression of adRP becomes a difficulty for clinical trials requiring an answer to whether there is slowed progression of degeneration in response to therapy. We performed a single-center, retrospective observational study of cross-sectional and longitudinal data. The study was prompted by our identification of a pericentral disease distribution in Class B RHO-adRP. Ultrawide optical coherence tomography (OCT) scans were used. Inferior retinal pericentral defects was an early disease feature. Degeneration further inferior in the retina merged with the pericentral defect, which extended into superior retina. In about 70% of patients, there was an asymmetric island of structure with significantly greater superior than inferior ellipsoid zone (EZ) extent. Serial measures of photoreceptor structure by OCT indicated constriction in superior retinal extent within a two-year interval. We conclude that these results should allow early-phase trials of therapy in RHO-adRP to move forward by inclusion of patients with an asymmetric extent of photoreceptor structure and by monitoring therapeutic effects over two years in the superior retina, a reasonable target for subretinal injection.
Highlights
Understanding the group of retinal diseases named retinitis pigmentosa (RP) has increased remarkably since it was first recognized by symptoms and ophthalmoscopy more than one and a half centuries ago
Altitudinal visual losses have long been associated with adRP [28], and when RHO mutations were identified as a molecular cause of the disease, there were many reports of this regional retinal distribution in RHO-adRP [25,29,30,31,32]
Among the molecular causes associated with Pericentral retinal degeneration (PRD) are RHO mutations [33,34,35]
Summary
Understanding the group of retinal diseases named retinitis pigmentosa (RP) has increased remarkably since it was first recognized by symptoms and ophthalmoscopy more than one and a half centuries ago. Histopathology of human post-mortem donor retinal tissue from RP patients [2,3] moved the field from macroscopic to microscopic levels and revealed the complex outer and inner retinal cell abnormalities underlying the diseases. Molecular identification of the many monogenic causes of RP [4,5,6] led to more specific diagnoses and to the current era when gene-specific therapies are being considered, initiated, or even ongoing [7,8]. Major advances in understanding RP disease mechanisms have resulted from studies of animals with inherited retinal degeneration [9,10]. From a limited number of “animal models” of RP with unknown genetic causes, there was subsequent identification of the molecular basis of many of these retinal degenerations. Studies revealing mechanisms came from noninvasive electrophysiological and psychophysical methods in RP patients [6]
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