Abstract
Retinitis pigmentosa (RP) is one of the leading causes of adult blindness and has no established therapy. We have shown that valosin-containing protein (VCP) modulators, Kyoto University Substances (KUSs), ameliorated abnormally low ATP levels by inhibiting the ATPase of VCP, thereby protected several types of cells, including retinal neurons, from cell death-inducing insults. In this study, we found that KUS121, one of the VCP modulators, effectively protects photoreceptors both morphologically and functionally, in two animal models of retinal degeneration, rd12 mice and RP rabbits with a rhodopsin (Pro347Leu) mutation. In rd12 mice, KUS121 suppressed the loss of photoreceptors, not only rods but also cones, as well as the visual function deterioration. Significant protective effects existed even when the medication was started in later stages of the disease. In RP rabbits, KUS121 suppressed thinning of the outer nuclear layer and maintained visual function. In the retinas treated with KUS121, suppression of endoplasmic reticulum stress, activation of mammalian target of rapamycin and suppression of disease-associated apoptosis were evident. The ability of KUS121 to protect photoreceptors, especially cones, even in later stages of the disease may contribute to the preservation of central vision in RP patients, which is important for quality of vision.
Highlights
Available for many patients would be highly attractive
We investigated whether KUS121 (Fig. 1a)[14,16], one of the Kyoto University Substances (KUSs), has neuroprotective effects on cone photoreceptors in rd[12] mice, both in earlier disease stages and in later disease stages when retinal degeneration has progressed
In order to investigate whether KUS121 affects the electroretinogram (ERG), 3-month-old wild-type mice were assessed by photopic and scotopic ERG before and after daily administration of KUS121
Summary
Available for many patients would be highly attractive. Several clinical trials have been performed to protect photoreceptors via neurotrophic factors and stem cells[9], yet no established therapies are available. We reported that KUSs showed neuroprotective effects on rod photoreceptors in rd[10] mice[14], a retinal degeneration model with a missense mutation in the Pde6b gene[15]. KUSs prevent the degeneration-associated decrease in ATP levels, endoplasmic reticulum stress (ER stress), and subsequent cell death of rod photoreceptors[14,16], which are responsible for detection of dim light. The deterioration of visual function and photoreceptor integrity are slowly progressive even after the age of 13 months (later disease stages)[18]. We investigated whether KUS121 (Fig. 1a)[14,16], one of the KUSs, has neuroprotective effects on cone photoreceptors in rd[12] mice, both in earlier disease stages and in later disease stages when retinal degeneration has progressed. We expanded our study to confirm the neuroprotective effects of KUS121 in RP rabbits
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