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

Román, Alejandro J.; Schwartz, Sharon; Alemán, Tomás S.; Cideciyan, Artur V.; Chico, John D.; Windsor, Elizabeth A. M.; Gardner, Leigh M.; Ying, Gui‐Shuang; Smilko, E.E.; Maguire, Maureen G.; Jacobson, Samuel G.

doi:10.1016/j.exer.2004.09.008

Cited by 148 publications

(196 citation statements)

References 44 publications

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…4), a psychophysical test designed for patients with severe visual loss (Roman et al, 2005(Roman et al, , 2007b. In an earlier study, untreated RPE65-LCA subjects showed visual sensitivities in response to full-field light stimuli that were 3-4 log units decreased compared with normal ; the three patients in the current study showed similar pretreatment results (Fig.…”

Section: Fig 1 Fundus Images With Near-infrared Illumination Of a Nsupporting

confidence: 67%

See 1 more Smart Citation

Treatment of Leber Congenital Amaurosis Due toRPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial

et al. 2008

Self Cite

View full text Add to dashboard Cite

Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form is caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry the human RPE65 gene (rAAV2-CB SB -hRPE65), restored vision in animal models with RPE65 deficiency. A clinical trial was designed to assess the safety of rAAV2-CB SB -hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21-24 years) with RPE65-LCA received a uniocular subretinal injection of 5.96 ϫ 10 10 vector genomes in 150 l and were studied with follow-up examinations for 90 days. Ocular safety, the primary outcome, was assessed by clinical eye examination. Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing (FST); central retinal structure was monitored by optical coherence tomography (OCT). Neither vector-related serious adverse events nor systemic toxicities were detected. Visual acuity was not significantly different from baseline; one patient showed retinal thinning at the fovea by OCT. All patients self-reported increased visual sensitivity in the study eye compared with their control eye, especially noticeable under reduced ambient light conditions. The dark-adapted FST results were compared between baseline and 30-90 days after treatment. For study eyes, sensitivity increases from mean baseline were highly significant (p Ͻ 0.001); whereas, for control eyes, sensitivity changes were not significant (p ϭ 0.99). Comparisons are drawn between the present work and two other studies of ocular gene therapy for RPE65-LCA that were carried out contemporaneously and reported. 979

show abstract

Section: Fig 1 Fundus Images With Near-infrared Illumination Of a Nsupporting

confidence: 67%

“…Visual function was measured using ETDRS visual acuity (Ferris et al, 1982) and dark-adapted full-field sensitivity testing (FST; Roman et al, 2005Roman et al, , 2007b. Briefly, FST was performed with blue stimuli after subjects were dark-adapted for 1 hr.…”

Section: Visual Function and Retinal Structurementioning

confidence: 99%

Treatment of Leber Congenital Amaurosis Due toRPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Dark-adapted chromatic thresholds were measured by using a modified automated perimeter (25,52). SW-cone sensitivity measurements were made according to published methods (53).…”

Section: Methodsmentioning

confidence: 99%

Human cone photoreceptor dependence on RPE65 isomerase

Jacobson

Alemán

Cideciyan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

144

View full text Add to dashboard Cite

The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.optical coherence tomography ͉ retinal degeneration ͉ retinoid cycle ͉ Leber congenital amaurosis ͉ gene therapy V ertebrate retinas have two types of photoreceptors: rods for the perception of dim light and cones for the perception of bright light. Light absorbed by visual pigments of photoreceptors triggers a series of enzymatic reactions known as phototransduction (1). The light-capturing part of the visual pigment, the chromophore, must then be regenerated. The pathway for regeneration of rhodopsin (the rod visual pigment) is known as the visual (retinoid) cycle (2, 3) and involves both rod cells and the adjacent retinal pigment epithelium (RPE). All-trans-retinal is reisomerized to 11-cis-retinal by a reaction in the RPE that requires the retinal isomerase, retinal pigment epithelium-specific 65-kDa protein (RPE65), and lecithinretinol acyltransferase (LRAT) activities. Functional visual pigment is then reformed by combining the 11-cis-chromophore with the photoreceptor opsin apoprotein (4). Molecular knowledge of the visual cycle has increased as the genes encoding the enzymes of this pathway have been elucidated (2, 5, 6).Decades ago, cone pigment regeneration was proposed to be RPE cell-independent (7, 8). More recently, cone-dominant ground squirrel and chicken retinas have been shown to exhibit retinoid isomerase activity that is distinct from RPE65 (5, 9, 10). Murine double knockout experiments, however, provide evidence that RPE65 and the RPE are essential for cone function (11...

show abstract

“…Foveal ONL and distal substructure thicknesses were measured from three OCT scans through the fovea obtained at the same visit in the NPHP5-LCA patients, and compared with measurements in groups of patients with four other genotypes. The structural data were compared with foveal function (absolute threshold at fixation, 650-nm target (48,49); a normal data set with both measurements was used (n ¼ 16, ages 22-62). Dogs.…”

Section: Optical Coherence Tomography (Oct) Imaging and Analysesmentioning

confidence: 99%

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

Self Cite

View full text Add to dashboard Cite

Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

show abstract

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

Cited by 148 publications

References 44 publications

Treatment of Leber Congenital Amaurosis Due toRPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial

Treatment of Leber Congenital Amaurosis Due toRPE65Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial

Human cone photoreceptor dependence on RPE65 isomerase

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Contact Info

Product

Resources

About