Quantifying rod photoreceptor-mediated vision in retinal degenerations: Dark-adapted thresholds as outcome measures

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Experimental Eye Research (Impact Factor: 2.71). 03/2005; 80(2):259-72. DOI: 10.1016/j.exer.2004.09.008
Source: PubMed


Pre-clinical trials of treatment in retinal degenerations have shown progress toward preventing loss or restoring function of rod photoreceptors. In anticipation of human clinical trials, we assessed two psychophysical methods of quantifying rod photoreceptor-mediated function as potential outcome measures. Modified automated perimeters were used to deliver focal or full-field light stimuli and dark-adapted thresholds were measured. Patients with retinal degeneration were studied in two experimental protocols. Experiment 1 (n = 35 patients) studied dark-adapted focal chromatic stimuli in central retinal locations along the horizontal meridian. Experiment 2 (n = 146 patients) studied dark-adapted responses to a full-field stimulus test (FST) using white and chromatic stimuli. Patients in both experimental groups had testing on two different visits to determine inter-visit variability. In Experiment 1, two subgroups of patients were identified: a group with a majority of test loci detected by rod photoreceptors and a group with only cone-mediated detection. Inter-visit variability (95% confidence interval) was +/-3.1 dB for normals, +/-3.0 dB for patients with rod-mediated function and +/-2.8 dB for patients with only cone-mediated function. In Experiment 2, the dynamic range of the FST using white stimuli was sufficient to quantify sensitivity in all patients studied, including those with severe retinal degenerations. Chromatic stimuli in the FST were detectable by 85% of patients and rod- or cone-mediation could be determined. Regional retinal sources of FST were explored by comparing FST and dark-adapted perimetry in the same patients; there was a strong correlation between FST level and the loci with highest sensitivity by perimetry. Inter-visit variability (95% confidence interval) in the patients was +/-3.9 dB compared to +/-3.5 dB in normals. Dark-adapted focal threshold measurements with an abbreviated protocol in retinal degeneration patients with stable fixation may be useful as an outcome measure for therapies that can affect rod vision. FST measurements were feasible and reproducible in a large spectrum of retinal degenerative diseases and will be most applicable as a psychophysical outcome measure for treatment trials of very severe disorders in which fixation is lost and there is need for a large dynamic range of stimulus intensity.

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Available from: Artur Cideciyan, Oct 13, 2015
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    • "Tests such as chromatic FST which was used in the most recent clinical characterization (Jacobson et al., 2013) and in the clinical trial for RPE65-LCA2 (Jacobson et al., 2012) could be used to measure localized improvements in rod function. The limits of variability for this assay have already been defined in patients with various retinal degenerations, including LCA (Roman et al., 2005; Roman et al., 2007; Jacobson et al., 2009a). OCT should be performed to monitor the safety of injections performed under the fovea or para/peri- fovea, with emphasis placed on the former given the slow return of cone outer segment structure observed in LCA2 patients treated subfoveally (Jacobson et al., 2012). "
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    ABSTRACT: Vertebrate species possess two retinal guanylate cyclases (retGC1 and retGC2) and at least two guanylate cyclase activating proteins (GCAPs), GCAP1 and GCAP2. GCAPs function as Ca(2+) sensors that regulate the activity of guanylate cyclases. Together, these proteins regulate cGMP and Ca(2+) levels within the outer segments of rod and cone photoreceptors. Mutations in GUCY2D, the gene that encodes retGC1, are a leading cause of the most severe form of early onset retinal dystrophy, Leber congenital amaurosis (LCA1). These mutations, which reduce or abolish the ability of retGC1 to replenish cGMP in photoreceptors, are thought to lead to the biochemical equivalent of chronic light exposure in these cells. In spite of this, the majority of LCA1 patients retain normal photoreceptor laminar architecture aside from foveal cone outer segment abnormalities, suggesting they may be good candidates for gene replacement therapy. Work began in the 1980s to characterize multiple animal models of retGC1 deficiency. 34 years later, all models have been used in proof of concept gene replacement studies toward the goal of developing a therapy to treat GUCY2D-LCA1. Here we use the results of these studies as well as those of recent clinical studies to address specific questions relating to clinical application of a gene therapy for treatment of LCA1.
    Frontiers in Molecular Neuroscience 05/2014; 7:43. DOI:10.3389/fnmol.2014.00043 · 4.08 Impact Factor
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    • "Kinetic visual fields and dark-and light-adapted chromatic static threshold perimetry (200-msec duration, 650-and 500-nm stimuli, dark-adapted, and 600 nm, light-adapted; 1.7° diameter target) were performed with a modified HFA-750i analyzer (Zeiss-Humphrey, Dublin , CA). Our methods for data collection and analyses have been published ( Jacobson et al., 1986, 2010; Roman et al., 2005). Reflectance imaging and reduced-illuminance autofluorescence imaging (RAFI) were performed with nearinfrared (NIR) and short-wavelength (SW) lights with a confocal scanning laser ophthalmoscope (SLO) (HRA2; Heidelberg Engineering, Heidelberg, Germany) as described (Cideciyan et al., 2007, 2011; Jacobson et al., 2011). "
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    ABSTRACT: Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.
    Human gene therapy 12/2011; 23(4):367-76. DOI:10.1089/hum.2011.169 · 3.76 Impact Factor
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    • "We determined whether the residual foveal ONL in the LCA5 patients was expected to be associated with light perception vision. In vivo histopathology of the LCA5 patients was compared to a group of patients with retinal degeneration and similar foveal ONL thickness, and who had been found, by dark-adapted chromatic perimetry, to be at a stage of disease that had reduced vision to a central island with only abnormal cone function [41] (Figure 2B-D). "
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    ABSTRACT: To determine the retinal disease expression in the rare form of Leber congenital amaurosis (LCA) caused by Lebercilin (LCA5) mutation. Two young unrelated LCA patients, ages six years (P1) and 25 years (P2) at last visit, both with the same homozygous mutation in the LCA5 gene, were evaluated clinically and with noninvasive studies. En face imaging was performed with near-infrared (NIR) reflectance and autofluorescence (AF); cross-sectional retinal images were obtained with optical coherence tomography (OCT). Dark-adapted thresholds were measured in the older patient; and the transient pupillary light reflex was recorded and quantified in both patients. Both LCA5 patients had light perception vision only, hyperopia, and nystagmus. P1 showed a prominent central island of retinal pigment epithelium (RPE) surrounded by alternating elliptical-appearing areas of decreased and increased pigmentation. Retinal laminar architecture at and near the fovea was abnormal in both patients. Foveal outer nuclear layer (ONL) was present in P1 and P2 but to different degrees. With increasing eccentricity, there was retinal laminar disorganization. Regions of pericentral and midperipheral retina in P1, but not P2, could retain measurable ONL and less laminopathy. P2 had a small central island of perception with >5 log units of sensitivity loss. Pupillary responsiveness was present in both LCA5 patients; the thresholds were abnormally elevated by >or=5.5 log units. LCA5 patients had evidence of retained photoreceptors mainly in the central retina. Retinal remodeling was present in pericentral regions in both patients. The NIR reflectance and NIR-AF imaging in the younger patient suggested preserved RPE in retinal regions with retained photoreceptors. Detailed phenotype studies in other LCA5 patients with longitudinal follow-up will help determine the feasibility of future intervention in this rare disease.
    Molecular vision 06/2009; 15:1098-106. · 1.99 Impact Factor
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