Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.
Foveal structure strongly correlates with its neurovascular organization. The findings support a developmental model in which the size of the FAZ determines the extent of centrifugal migration of inner retinal layers, which counteracts in some way the centripetal packing of cone photoreceptors.
Objectives:The wall-to-lumen ratio (WLR) of retinal arteries is a recognized surrogate of end-organ damage due to aging and/or arterial hypertension. However, parietal morphometry remains difficult to assess in vivo. Recently, it was shown that adaptive optics retinal imaging can resolve parietal structures of retinal arterioles in humans in vivo. Here, using adaptive optics retinal imaging, we investigated the variations of parietal thickness of small retinal arteries with blood pressure and focal vascular damage.Methods:Adaptive optics imaging of the superotemporal retinal artery was done in 49 treatment-naive individuals [mean age (±SD) 44.9 years (±14); mean systolic pressure 132 mmHg (±22)]. Semi-automated segmentation allowed extracting parietal thickness and lumen diameter. In a distinct cohort, adaptive optics images of arteriovenous nicking (AVN; n = 12) and focal arteriolar narrowing (FAN; n = 10) were also analyzed qualitatively and quantitatively.Results:In the cohort of treatment-naive individuals, by multiple regression taking into account age, body mass index, mean, systolic, diastolic and pulse blood pressure, the WLR was found positively correlated to mean blood pressure and age which in combination accounted for 43% of the variability of WLR. In the cohort of patients with focal vascular damage, neither FANs or AVNs showed evidence of parietal growth; instead, at sites of FANs, decreased outer diameter suggestive of vasoconstriction was consistently found, while at sites of AVNs venous narrowing could be seen in the absence of arteriovenous contact.Conclusion:High resolution imaging of retinal vessels by adaptive optics allows quantitative microvascular phenotyping, which may contribute to a better understanding and management of hypertensive retinopathy.
In the mouse retina, a tridimensional model of retinal microcirculation was established, showing that most microvessel connections on the arteriolar side direct the flow from the superficial to the deep layer, and vice versa on the venular side. However, the presence of direct arteriovenous connections in the superficial layer and the longer vessel length in the deep layer offer the possibility of actively modulating intraretinal flow. Compared with other capillary beds, both the capillary velocity and microhematocrit are high, a situation that favors nutrient delivery to the inner retina.
In patients with diabetes, neural and neurovascular dysfunctions both precede the onset of clinically detectable DR. To which extent these abnormalities are related to each other remains to be determined. (ClinicalTrials.gov number, NCT00839150.)
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