The relation of rhodopsin and scotopic retinal sensitivity in sector retinitis pigmentosa

We used reflection retinal densitometric, psychophysical, and electroretinographic techniques to study the scotopic retinal function of a mother and her three daughters who had clinical evidence of a sectoral type of retinitis pigmentosa. Retinal regions with, and those without, ophthalmoscopic signs of degeneration were investigated. During dark adaptation, the time courses of rhodopsin regeneration and recovery of scotopic sensitivity were similar to normal as was the relation of rhodopsin to scotopic threshold. In dark-adapted eyes, threshold increases were not proportional to rhodopsin loss. The results of psychophysical tests of background adaptation and temporal summation, and analysis of the relation of electroretinographic a- to b-wave amplitudes, led to the conclusion that abnormalities of photoreceptor cell function central to the rhodopsin-bearing outer segments accounted for the increased thresholds.     

P23H rhodopsin transgenic rat: correlation of retinal function with histopathology

PURPOSE: To correlate retinal functional changes with structural changes in P23H rhodopsin transgenic rats as a model of autosomal dominant retinitis pigmentosa. METHODS: P23H heterozygote (lines 1 and 3) and Sprague-Dawley control rats were studied at 4 to 29 weeks by retinal histology, electroretinogram (ERG), and a-wave transduction modeling. RESULTS: Both line 1 (faster degeneration) and line 3 (slower degeneration) showed progressive rod outer segment (ROS) shortening and outer nuclear layer (ONL) cell loss with age. ERG b-wave maximum amplitude (Vb(max)) decreased with age, but b-wave threshold remained constant within each line despite progressive ONL thinning and ROS shortening. The only exception was in line 1 at 29 weeks, which showed a slight threshold change relative to earlier ages. Va(max) and a-wave threshold changed more rapidly and were more sensitive than the b-wave in reflecting histologic degeneration. Va(max) was linearly proportional to the product of (ROS x ONL) across a two log unit range of data combined from both lines. The photopic b-wave was normal for both lines until the ONL thinned beyond 50%. Phototransduction sensitivity was normal for both lines, and dark-adaptation recovery after bleaching rhodopsin was normal. CONCLUSIONS: The P23H transgenic rat has a slow rod degeneration with initially normal cone function, consistent with clinical findings of P23H patients. However, the normal bleach recovery and the normal phototransduction sensitivity in this rat model are different from human P23H disease. a-Wave measures were more sensitive than the b-wave for tracking changes. b-Wave threshold was inexplicably poor for tracking degeneration. Although line 1 degenerated faster than line 3, the functional-structural correlates were the same. The tight linear relationship between saturated a-wave amplitude and the product of (ROS x ONL) indicates that the density of cGMP-gated channels per unit ROS plasma membrane area remains constant over a wide range of degenerations.     

Improving the diagnostic power of electroretinography by transient alteration of the ocular perfusion pressure.

In this report we present the results of a series of studies focusing on the effects of transient changes in the ocular perfusion pressure (OPP) on retinal function in normals as assessed by the flash electroretinogram (ERG). A transient increase or decrease in the OPP affected by body inversion and compression/suction ophthalmodynamometry (ODM), respectively, is shown to affect differentially the b-wave of scotopic and photopic ERG's. However, under dark-adapted conditions, the cone component of the red flash ERG b-wave exhibited a vulnerability to decreased OPP which approached that seen for the b-wave of the scotopic blue flash ERG b-wave. Similar test procedures used to investigate the functional response of the inner plexiform layer during altered OPP revealed component-specific changes in white flash scotopic oscillatory potentials (OP's). The results of these provocative tests of retinal function offer new insights into basic retinal physiology and encouraging prospects for practical clinical diagnostic procedures with enhanced sensitivity and specificity for subclinical retinal disorders.     

Diagnosis and classification of macular degenerations: an approach based on retinal function testing

The results from literature concerning some aspects of retinal function in macular degenerations (MDs) were reviewed in order to evaluate whether (a) specific patterns of retinal dysfunction may be linked to different clinical phenotypes, and (b) distinct functional profiles may help in orienting molecular diagnosis of diseases. Examined clinical phenotypes included: Stargardt disease/fundus flavimaculatus (St/FF), age-related maculopathy (ARM) and macular degeneration (AMD), pattern dystrophies (PD), Best vitelliform dystrophy (BVD), Sorsby's fundus dystrophy (SFD), autosomal cone-rod dystrophies (CRD). The following functional tests were evaluated: (1) electroretinogram (ERG) (scotopic and photopic according to ISCEV standards, rod and cone photoresponses, rod and cone b-wave intensity-response function, focal ERGs); (2) dark adaptometry (pre-bleach sensitivity and post-bleach recovery kinetics); (3) fundus reflectometry (pigment density and regeneration kinetics). Specific patterns of retinal dysfunction were identified for St/FF, ARM/AMD, SFD and BVD, whereas partially overlapping profiles were found for PD and CRD. Specific functional patterns were associated with different peripherin/RDS gene mutations, as well as with CRX mutations. Combined analysis of different retinal function tests may help to identify different phenotypes of MD, and to orient molecular diagnosis for selected genotypes.     

Hereditary retinal degeneration in the Abyssinian cat: Correlation of ophthalmoscopic and electroretinographic findings

Ophthalmoscopic and electroretinographic (ERG) findings were correlated in a group of Abyssinian cats affected by a slowly progressive and hereditary retinal degenerative disease. According to ophthalmoscopic findings the disease was divided into stages. At stage 1 and 2 retinal changes were minor; showing a gray discoloration most often in the peripheral and midperipheral tapetal fundus. At stage 3 discoloration was generalized and there was marked vascular attenuation. A generalized retinal atrophy was found at stage 4. ERG recordings showed an abnormally depressed stimulus response curve for the b-wave at stage 1 of disease when 30-Hz cone flicker responses were indistinguishable from normal. With progression of disease there was a successive decrease of a- and b-wave amplitudes before there was a significant reduction also of the c-wave amplitude (first seen at stage 3). The ERG was nonrecordable at stage 4. These findings suggest that the photoreceptors are affected primarily by the disease, before there is a functional involvement also of the pigment epithelium. The rod system seems to be affected early in the disease as compared with the cone system. A staging of the disease by ophthalmoscopy correlated more to the function of the rods than to that of the cones.     

Changes of retinal functions following the induction of ocular hypertension in rats using argon laser photocoagulation

BACKGROUND: Electroretinography (ERG) provides a longitudinal monitoring of pathological changes in retina. Scotopic threshold response (STR) of ERG was shown to reflect inner retinal activity and is particularly useful in the evaluation of inner retinal changes in ocular hypertension models. Recently, STR was demonstrated to be attenuated after the induction of ocular hypertension using injection of hypertonic saline into episcleral veins which indicates an impairment of retinal function. However, little is known on the changes of retinal function in an ocular hypertension model induced by laser photocoagulation at episcleral veins and limbal veins. METHODS: Ocular hypertension was induced unilaterally using laser photocoagulation at episcleral veins and limbal veins in adult Sprague-Dawley rats. Intraocular pressure was monitored and the number of retinal ganglion cell loss was counted across the 8-week experimental period. The animals were dark adapted overnight and flash ERGs were measured before the laser treatment, 5 and 8 weeks after treatment. The changes of STR, scotopic negative response, a-wave and b-wave were analysed. RESULTS: Approximately 1.6-fold elevation of intraocular pressure was induced in the experimental eyes and 3% retinal ganglion cell loss per week was found. The amplitude of STR was significantly attenuated which indicates an impairment of inner retinal activities. There was also a reduction of scotopic negative response, a-wave and b-wave after the induction of ocular hypertension. CONCLUSION: The laser-induced ocular hypertension model in the present study produced a substantial reduction of retinal functions. Understanding the characteristic of pathological changes is crucial for further study using this model.     

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

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.     

Retinal light damage: Mechanisms and protection

By its action on rhodopsin, light triggers the well-known visual transduction cascade, but can also induce cell damage and death through phototoxic mechanisms – a comprehensive understanding of which is still elusive despite more than 40 years of research. Herein, we integrate recent experimental findings to address several hypotheses of retinal light damage, premised in part on the close anatomical and metabolic relationships between the photoreceptors and the retinal pigment epithelium. We begin by reviewing the salient features of light damage, recently joined by evidence for retinal remodeling which has implications for the prognosis of recovery of function in retinal degenerations.  We then consider select factors that influence the progression of the damage process and the extent of visual cell loss. Traditional, genetically modified, and emerging animal models are discussed, with particular emphasis on cone visual cells. Exogenous and endogenous retinal protective factors are explored, with implications for light damage mechanisms and some suggested avenues for future research. Synergies are known to exist between our long term light environment and photoreceptor cell death in retinal disease. Understanding the molecular mechanisms of light damage in a variety of animal models can provide valuable insights into the effects of light in clinical disorders and may form the basis of future therapies to prevent or delay visual cell loss.     

In vivo toxicity study of rhodamine 6G in the rat retina

PURPOSE: To investigate the intraocular effect of rhodamine 6G (R6G) on retinal structures and function in an in vivo rat model and to develop an in vivo method for accurate evaluation of new dyes for intraocular surgery. METHODS: R6G in physiologic saline solution (PSS) was injected into the vitreous of adult Brown Norway rats at concentrations of 0.0002%, 0.002%, 0.02%, 0.2%, and 0.5%. Control animals received only PSS. Retinal toxicity was assessed by retinal ganglion cell (RGC) counts, light microscopy 7 days later, photopic electroretinography (ERG), and measurement of scotopic sensitivity and recovery of dark adaptation 48 hours and 7 days after intravitreous injection. RESULTS: R6G at concentrations of 0.2% and 0.5% led to a dose-dependent loss of RGC. The most significant loss occurred at 0.5%. Lower concentrations (0.0002%, 0.002%, and 0.02%) produced no statistically significant retinal ganglion cell loss. Analysis of the eyes by light microscopy showed no structural changes in the central retina, although injections of 0.5% R6G were followed by impressive degenerative changes adjacent to the injection sites. ERGs showed no effects of the highest R6G concentration on rods, kinetics of rhodopsin recovery after bleaching, or cone-driven responses. CONCLUSIONS: R6G can be safely injected in doses of up to 0.02% in rats, but has a toxic effect on retinal ganglion cells at higher concentrations. Accumulation of R6G may be a problem at higher concentrations, particularly at the injection site.     

Increased sensitivity to light-induced damage in a mouse model of autosomal dominant retinal disease

PURPOSE: To describe a sensitivity to light-induced damage associated with expression of a T17M mutant human rhodopsin (hT17M) transgene in mice, with the goal of minimizing retinal injury during the subretinal delivery of rAAV-mediated gene therapy. METHODS: Mice were bred to express the hT17M rhodopsin transgene in a line that was hemizygous null for wild-type mouse rhodopsin (mrho(+/-)), and the eyes of transgenic mice and nontransgenic littermates were exposed for 2.5 minutes to unilateral illumination with fiber-optic light ranging from 5,000 to 10,000 lux. Funduscopic images were made with a handheld camera (Genesis; Kowa Company, Ltd., Tokyo, Japan). Full-field scotopic electroretinographic analysis (ERG) was performed to measure loss of retinal function. Morphometry in the light microscope was used to measure loss of rod photoreceptors. TUNEL staining and a nucleosome release assay were used to measure levels of apoptosis in retinal specimens. RESULTS: mrho(+/-);hT17M mice exhibited a sensitivity to light-induced damage that caused severe loss of a- and b-wave ERG responses. hT17M transgenic mice on the mrho(+/+) background were equally sensitive to light-induced damage. Histologic analysis showed a concomitant loss of photoreceptors and TUNEL labeling of fragmented DNA in rod photoreceptor cells, demonstrating that the damage occurred via an apoptotic pathway. Nontransgenic littermate mice were not affected by this exposure to light. Mice expressing an hP23H mutant human rhodopsin transgene were minimally sensitive to light-induced damage at these intensities, in comparison to hT17M mice. Treating the hT17M mice with an equivalent regimen of exposure to red light was less damaging to the retina, as measured by ERG and histology. CONCLUSIONS: Expression of a human hT17M mutant rhodopsin transgene in mice is associated with photoreceptor apoptosis in response to moderate exposure to light. This phenotype was not observed in nontransgenic littermates or in mice expressing an hP23H mutant human rhodopsin transgene. The results suggest that elimination of the glycosylation site at N15 is associated with increased sensitivity to light-induced damage.     

Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund

PURPOSE: To characterize the electrophysiological and histopathological features of a retinal degenerative disease in a colony of miniature longhaired dachshunds known to have a form of progressive retinal atrophy (PRA). METHODS: Serial electroretinograms were recorded from affected homozygous (n = 36) and heterozygous (n = 15) dogs. Morphologic investigations including immunohistochemistry and lectin histochemistry were performed on selected homozygous animals (n = 15). RESULTS: Clinical findings included loss of tapetal hyperreflectivity. The mode of inheritance was autosomal recessive. An early dramatic reduction of cone-specific ERG amplitude with a more modest reduction in rod b-wave amplitude was demonstrated. Progressively, rod specific responses diminished until there were no recordable responses to the ERG stimuli at 40 weeks of age. Morphologic changes confirmed early cone inner and outer segment loss. Other abnormalities included opsin mislocalization and outer nuclear layer thinning due to the subsequent loss of rod photoreceptors. CONCLUSIONS: A novel canine cone-rod dystrophy has been identified.     

Granulocyte colony-stimulating factor facilitates recovery of retinal function following retinal ischemic injury

The purpose of the present study was to investigate whether systemically administered granulocyte colony-stimulating factor (G-CSF) can protect against acute ischemic reperfusion injury. Two groups of anesthetized adult male Lewis rats (n = 8 per group) were subjected to an acute (45 min) episode of retinal ischemic injury followed by subcutaneous administration of vehicle (5% dextrose) or G-CSF (0.1 mg/kg/day) once per day × 5 days. Prior to and one week following ischemic insult, retinal function was measured by scotopic electroretinography (ERG). Retinas were harvested and morphologically analyzed one week after ischemic insult. ERG a- and b-wave amplitudes were significantly reduced following ischemic reperfusion injury. G-CSF treatment attenuated ischemic-induced loss of retinal function. In control vehicle-treated rats, ischemic reperfusion injury elicited marked and selective thinning of inner retinal layers while only minimally affecting outer retinal layers. Therapeutically administered G-CSF minimized ischemic-mediated thinning of whole retina and inner retinal layers. G-CSF may be of therapeutic interest for the management of retinal ischemic disorders.     

Trophic factors in the pathogenesis and therapy for retinal degenerative diseases

Trophic factors are endogenously secreted proteins that act in an autocrine and/or paracrine fashion to affect vital cellular processes such as proliferation, differentiation, and regeneration, thereby maintaining overall cell homeostasis. In the eye, the major contributors of these molecules are the retinal pigment epithelial (RPE) and Müller cells. The primary paracrine targets of these secreted proteins include the photoreceptors and choriocapillaris. Retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa are characterized by aberrant function and/or eventual death of RPE cells, photoreceptors, choriocapillaris, and other retinal cells. We discuss results of in vitro and in vivo animal studies in which candidate trophic factors, either singly or in combination, were used in an attempt to ameliorate photoreceptor and/or retinal degeneration. We also examine current trophic factor therapies as they relate to the treatment of retinal degenerative diseases in clinical studies.     

Longitudinal measures in children receiving ENCAD for hereditary retinal degeneration

A hydrolysate of yeast RNA (ENCAD) is used in the Soviet Union for the treatment of hereditary retinal degenerations. We report longitudinal data from three young patients who have made at least two visits to the Soviet Union over a five-year period to receive treatment with ENCAD. Two children were diagnosed with cone-rod degeneration and the third has an isolated (simplex) form of retinitis pigmentosa. Visual function measurements were obtained before and after each visit to Moscow. In the comparison of previsit and postvisit visual acuity, 30 Hz flicker amplitude, and visual fields, ENCAD treatment had no significant short-term effect. Despite treatment with ENCAD, each patient has shown a significant decrease in visual function over the 5-year period. The rate of progression in these patients appears similar to previously published data on the natural history of their retinal degenerative disorders.Abbreviations ENCAD a hydrolysate of yeast RNA - RP retinitis pigmentosa     

Progressive retinal atrophy in the Abyssinian cat: studies of the DC-recorded electroretinogram and the standing potential of the eye.

DC-recorded electroretinography (ERG) and direct recordings of the standing potential (SP) were performed on a group of normal cats and Abyssinian cats affected by a hereditary retinal degenerative disease with similarities to human retinitis pigmentosa. A significant reduction of a- and b-wave amplitudes was found at an early stage of disease at a time when there were no major alterations in the c-wave and SP. At later stages both the c-wave and the SP oscillations were significantly reduced or absent. These findings indicate a primary photo-receptor disorder. Threshold studies for the scotopic b-wave showed a loss of retinal sensitivity early in the disease at a time when 30 Hz flicker responses were normal, which could indicate an earlier involvement of the rods than of the cones. There were no major alterations in the timing of the ERG in the affected animals tested.     

ZX-5及其光学异构体对兔眼血流和大鼠视网膜功能恢复的影响

目的:研究ZX-5对缺血后视网膜功能的恢复作用,并比较其光学异构体(R,R)-ZX-5和(S,S)-ZX-5对脉络膜血流及缺血后视网膜功能恢复的影响。方法:用彩色微球技术研究兔高眼压下(40mmHg)脉络膜血流的变化。用视网膜电生理仪测量b波,评价大鼠缺血后视网膜功能的恢复情况。结果:10g/L(R,R)-ZX-5滴眼液50μL能在不同时间点提高脉络膜血流(P<0.05),而(S,S)-ZX-5在相同条件下对提高脉络膜血流没有影响。ZX-5和(R,R)-ZX-5在不同时间点对视网膜缺血后功能恢复作用明显(P<0.05),(R,R)-ZX-5的作用优于ZX-5;而(S,S)-ZX-5对缺血后视网膜功能的恢复作用不明显。结论:ZX-5和(R,R)-ZX-5对增加脉络膜血流量和促进视网膜功能的恢复有显著功效,(R,R)-ZX-5恢复视网膜功能的作用更强,有可能进一步开发成有效防治眼血流障碍相关性眼病的药物。     

Pigmented paravenous retinochorodial atrophy.

Three male patients had paravenous pigmented retinochoroidal atrophy. Extensive retinal function tests showed characteristic retinal pigment epithelial abnormalities on fluorescein angiography, loss of peripheral visual field, diminution of the electroretinographic b-wave, and elevated rod threshold on dark adaptometry. The disease appears to be more progressive than previously indicated, and in late stages, may cause legal blindness through involvement of the posterior pole. No treatment is known.     

Age-related changes in retinal sensitivity, rhodopsin content and rod outer segment length in hooded rats following low-level lead exposure during development

Electroretinographic, morphometric and cyclic nucleotide metabolism studies in adult hooded rats have established that low-level lead exposure during early postnatal development (postnatal days 0-21) causes long-term selective rod deficits and degeneration. To determine if this same low-level lead exposure during early postnatal development produces immediate and/or long-term alterations in retinal sensitivity we examined ERG b-wave threshold responses in dark-adapted control and lead-exposed rats at 1-, 3- and 12 months of age. In addition, to determine possible sites and mechanisms of action responsible for the observed decreases in retinal sensitivity we analyzed the rhodopsin content per eye, the lambda max of rhodopsin and rod outer segment (ROS) length in superior and inferior posterior retina at 1-, 3- and 12 months of age. Relative to adult (3-month-old) controls whose log threshold was arbitrarily set at 0 log units, the mean log relative threshold in control rats was 0.4 log units at 1 month of age and 0.2 log units at 1 yr of age. In contrast, the mean log relative threshold in lead-exposed rats was 1.3 log units at 1 month of age and 1.1-1.2 log units at 3- and 12 months of age. Thus, compared with controls, retinal sensitivity in lead-exposed rats was decreased approx. 1 log unit at all ages examined. The rhodopsin content per eye in control rats increased 13% between 1- and 3 months of age, reaching an adult value of 1.99 nmol per eye, and then decreased 8% by 1 yr of age. In contrast, the eyes from lead-exposed rats contained 30-34% less rhodopsin at all ages examined. No change in the lambda max of rhodopsin was observed in the retinas from the lead-exposed rats. In both controls and lead-exposed rats, the developmental changes in log b-wave relative threshold were paralleled by linear increases and decreases in rhodopsin content per eye such that a log-linear relation between retinal sensitivity and rhodopsin content per eye existed between 1- and 12 months of age. The developmental changes in the superior and inferior retinal ROS length were similar in control and lead-exposed rats: ROSs were at their adult length at 1 month of age and then slightly decreased by 1 yr of age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retinal remodeling

Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3',5'-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and optogenetic approaches that target appropriate classes of neurons in the remnant neural retina.     

Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa

We studied the potential of systemically administered aminoglycosides as a therapy for retinal degeneration resulting from premature termination codon (PTC) mutations. Aminoglycosides were systemically delivered to two rodent models of retinal degeneration: a transgenic rat model of dominant disease caused by a PTC in rhodopsin (S334ter); and a mouse model of recessive disease (rd12) caused by a PTC in the retinoid isomerase Rpe65. Initial luciferase reporter assays were undertaken to measure the efficiency of gentamicin-induced read-through in vitro. These experiments indicated that gentamicin treatment induced on average a 5.3% extra read-through of the S334ter PTC in vitro, but did not affect the rd12 PTC. Beginning at postnatal day 5, animals received daily subcutaneous injections of gentamicin or geneticin at a range of doses. The effect of the treatment on retinal degeneration was examined by histopathology and electroretinography (ERG). Systemic treatment with aminoglycoside significantly increased the number of surviving photoreceptors in the S334ter rat model over several weeks of treatment, but was not effective in slowing the retinal degeneration in the rd12 mouse model. Similarly, ERG recordings indicated better preservation of retinal function in the treated S334ter rats, but no difference was observed in the rd12 mice. Daily subcutaneous injection of 12.5mug/g gentamicin was the only regimen that inhibited retinal degeneration without apparent adverse systemic side effects. Reduced effectiveness beyond postnatal day 50 correlated with reduced ocular penetration of drug as seen in gentamicin-Texas red (GTTR) conjugation experiments. We conclude that, in the rat model, an approximately 5% reduction of abnormal truncated protein is sufficient to enhance photoreceptor survival. Such a change in truncated protein is consistent with beneficial effects seen when aminoglycosides has been used in other, non-ocular animal models. In the rd12 mouse, lack of efficacy was seen despite this particular PTC being theoretically more sensitive to aminoglycoside modification. We conclude that aminoglycoside read-through of PTCs in vitro and in vivo cannot be predicted just from genomic context. Because there is considerable genetic heterogeneity amongst retinal degenerations, pharmacologic therapies that are not gene-specific have significant appeal. Our findings suggest that if adverse issues such as systemic toxicity and limited ocular penetration can be overcome, small molecule therapeutics, such as aminoglycosides, which target classes of mutation could hold considerable potential as therapies for retinal disease.