Abstract
MERTK mutation reduces the ability of retinal pigment epithelial (RPE) cells to phagocytize the photoreceptor outer segments, which leads to accumulation of debris separating photoreceptors from RPE cells, resulting in their degeneration and loss of vision. In a rat model of Retinitis Pigmentosa due to MERTK mutation, we demonstrate that surgical removal of debris performed when about half of photoreceptors are lost (P38), allows the remaining photoreceptor cells to renew their outer segments and survive for at least 6 months – 3 times longer than in untreated eyes. In another set of experiments, patterned laser photocoagulation was performed before the debris formation (P19-25) to destroy a fraction of photoreceptors and thereby reduce the phagocytic load of shed outer segment fragments. This treatment also delayed the degeneration of the remaining photoreceptors. Both approaches were assessed functionally and morphologically, using electroretinography, optical coherence tomography, and histology. The long-term preservation of photoreceptors we observed indicates that MERTK-related form of inherited retinal degeneration, which has currently no cure, could be amenable to laser therapy or subretinal surgery, to extend the visual function, potentially for life.
Highlights
In the RCS rats, appearance of the outer segment debris begins around postnatal day (P) 19
Since retinal outer segments are shed daily, but debris accumulation does not start for a few years in patients and for a few weeks in RCS rats, while retina continues to function long after that, we hypothesized that the mutant retinal pigment epithelial (RPE) cells retain some phagocytic activity either by MERKT-independent uptake or microglia-related phagocytosis[26], and thereby can sustain a fraction of the outer-segment recycling load[27]
The outer segments start accumulating in the subretinal space and form a thick layer by P38, accompanied by thinning of the outer nuclear layer (Fig. 1)
Summary
In the RCS rats, appearance of the outer segment debris begins around postnatal day (P) 19 These debris accumulate with age[8], forming a thick insulating layer between photoreceptors and RPE cells by P35, accompanied by gradual degeneration of photoreceptors, which is complete by P180. We assumed that photoreceptors degeneration is accelerated by accumulation of a thick debris layer, which prevents oxygen and nutrients supply from the choroid Based on these hypotheses, we designed two strategies to balance the supply and demand of the outer segment recycling and thereby extend the survival of photoreceptors in RCS rats. Pattern laser photocoagulation can be applied to selectively destroy a fraction of photoreceptors prior to debris formation In both approaches, the remaining photoreceptors could be better sustained by the partially functioning RPE cells and survive much longer. We assess efficacy of these therapies for protection of photoreceptors in RCS rats as a potential therapy for patients with RP due to MERTK mutation
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