Spontaneous Regeneration of Human Photoreceptor Outer Segments

Abstract

Photoreceptors are damaged in many common eye diseases, such as macular degeneration, retinal detachment, and retinitis pigmentosa. The development of methods to promote the repair or replacement of affected photoreceptors is a major goal of vision research. In this context, it would be useful to know whether photoreceptors are capable of undergoing some degree of spontaneous regeneration after injury. We report a subject who lost retinal function in a wide zone around the optic disc, giving rise to massive enlargement of the physiological blind spot. Imaging with an adaptive optics scanning laser ophthalmoscope (AOSLO) showed depletion of cone outer segments in the affected retina. A year later visual function had improved, with shrinkage of the enlarged blind spot. AOSLO imaging showed repopulation of cone outer segments, although their density remained below normal. There was a one-to-one match between sites of formerly missing outer segments and new outer segments that had appeared over the course of the year’s recovery. This correspondence provided direct morphological evidence that damaged cones are capable, under some circumstances, of generating new outer segments.

Assessing Photoreceptor Structure in Retinitis Pigmentosa and Usher Syndrome

“…61 Additionally, a number of reports have documented diminished cone reflectivity on confocal AOSLO in patients with clinically reduced visual function, 18,20,25,33,39–41 and one case noted recovery of normal reflectivity with concurrent functional improvement. 33 Despite this, the ability to infer cone function from reflectivity is confounded by the fact that cones can spontaneously recover normal reflectivity without documented change in function 20,62 and that cone reflectivity can vary over time in RP and allied disorders (Supplementary Figure S4). In the future, applying AOSLO microperimetry technology to individuals with retinal disease may help resolve the functional status of cones with altered waveguide properties.…”

“…32,33 In retinal degenerations, photoreceptors undergo morphologic changes 34–37 that disrupt normal waveguiding 38 ; as a result, cones can have significantly altered reflective properties. 18,20,25,33,39–41 Moreover, cone reflectivity fluctuates over time, 42–46 and it has even been shown that cones with diminished reflectivity from a variety of retinal insults can spontaneously recover normal reflectivity. 20,33,47 As such, the reliance on normal waveguiding for cone visualization presents an inherent confound in analyzing and interpreting confocal AOSLO or AO flood illumination images of the cone mosaic: decreased cone density could be due to altered cone reflectivity or true loss of cone cells.…”

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

“…The hope is in the alternative possibility, that gene augmentation may lead to restoration of the structure of the POS and vision as is known to occur following correction of various insults to this important structure. [95][96][97][98][99] Although there may be examples of milder phenotypes, the majority of patients with RDH12-IRD in this and previous reports share a severe, early disease, which suggests we may have no choice but to move the window for potential treatments to younger ages when there is still treatable retina, raising new risk/benefit concerns. Early clinical trials that focus on safety are expected to include patients with the most severe abnormalities, and it can be anticipated that results in terms of efficacy may be modest.…”

Repeatability and Longitudinal Assessment of Foveal Cone Structure in Cngb3-Associated Achromatopsia

“… 26 In addition, in patients with cone mosaic disturbances, locations previously devoid of reflective cone structure were shown to regenerate a reflective confocal signal. 27 , 28 Here we present the first longitudinal study of foveal cone density in patients with CNGB3 -associated achromatopsia.…”