Visual Acuity after Retinal Gene Therapy for Choroideremia.
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ABSTRACT:
SUBMITTER: Edwards TL
PROVIDER: S-EPMC4996318 | biostudies-literature | 2016 May
REPOSITORIES: biostudies-literature
Publications
Visual Acuity after Retinal Gene Therapy for Choroideremia.
Edwards Thomas L TL Jolly Jasleen K JK Groppe Markus M Barnard Alun R AR Cottriall Charles L CL Tolmachova Tanya T Black Graeme C GC Webster Andrew R AR Lotery Andrew J AJ Holder Graham E GE Xue Kanmin K Downes Susan M SM Simunovic Matthew P MP Seabra Miguel C MC MacLaren Robert E RE
The New England journal of medicine 20160427 20
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Project description: Not available
| S-EPMC8478312 | biostudies-literature
Project description:Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology1-5. Choroideremia is a chronic X-linked retinal degeneration that was first described in 18726. It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P = 0.04), with 6 treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted.
| S-EPMC7032956 | biostudies-literature
Project description:BackgroundChoroideremia is a rare inherited retinal disease that leads to blindness. Visual acuity (VA) is a key outcome measure in choroideremia treatment studies, but VA decline rates change with age. An accurate understanding of the natural deterioration of VA in choroideremia is important to assess the treatment effect of new therapies in which VA is the primary outcome measure. We conducted a meta-analysis of data on individuals with choroideremia to determine the rate of VA deterioration between the better- and worse-seeing eye (BSE and WSE, respectively).MethodsData were collected from the prospective Natural History of the Progression of Choroideremia (NIGHT) study (613 eyes, baseline data only), studies included in a recent meta-analysis, and studies identified in a targeted literature search performed on March 25, 2020, including individual best-corrected VA (BCVA) and age data in male individuals with choroideremia. Best-corrected VA decline rates (measured by logMAR units) by age and trends in BCVA decline rates in the BSE and WSE were evaluated. RESULTS: Data from 1037 males (1602 eyes; mean age, 41.8 years) were included. Before and after an age cutoff of 33.8 years, BCVA decline rates for the WSE were 0.0086 and 0.0219 logMAR per year, respectively. Before and after an age cutoff of 39.1 years, BCVA decline rates for the BSE were 0.00001 and 0.0203 logMAR per year, respectively. Differences in absolute BCVA and decline rates increased between the 2 eyes until age ~ 40; thereafter, differences in absolute BCVA and decline rates were similar between eyes.ConclusionsUsing the largest choroideremia data set to date, this analysis demonstrates accelerated BCVA decline beginning between 30 and 40 years of age. Disparate interocular progression rates were observed before the transition age, with similar interocular progression rates after the transition age.
| S-EPMC8762852 | biostudies-literature
Project description:Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5-3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence and impaired adaptive behavior, frequently as well as visual impairments. Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an interacting partner of fragile X mental retardation protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants were found in patients with early-onset epileptic encephalopathy, developmental delay, and ID. Individuals with these CYFIP2 variants often exhibit visual impairments, however, the underlying mechanism is poorly understood. In the current study, we investigated the role of Cyfip2 in retinal and visual function by generating and analyzing mice in which Cyfip2 is depleted in the retina (Cyfip2 CKO mice). We found no major difference in the layer structure and cell composition between control and Cyfip2 CKO retinas, whereas a subset of genes associated with transporter and channel activity was differentially expressed in the Cyfip2 CKO retina. Multi-electrode array recordings showed more sustained and stronger response to positive flashes of ON ganglion cells in the Cyfip2 CKO retina, although we did not observe that Cyfip2 deficiency affects photoreceptor and ON bipolar cell functions by electroretinogram analysis. Furthermore, initial and late phase OKR analysis demonstrated that Cyfip2 deficiency impairs visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying visual impairments observed in individuals with CYFIP2 variants and, more generally, in patients with neurodevelopmental disorders including ID.
2021-09-12 | GSE176528 | GEO
Project description:IntroductionChoroideremia and RPGR-associated retinitis pigmentosa (RP) are two distinct inherited rod-cone degenerations, where good visual acuity (VA) is maintained until late disease stages, limiting its usefulness as a disease marker. Low luminance VA and low luminance deficit (standard VA minus low luminance VA) may be more sensitive visual function measures.MethodsStandard VA was obtained using Early Treatment Diabetic Retinopathy Study letter charts (Precision Vision, Bloomington, IL, USA). Low luminance VA was assessed using a 2.0-log unit neutral density filter, with the same chart setup, without formal dark adaptation. Mean central retinal sensitivity was assessed using MAIA microperimetry (Centervue SpA, Padova, Italy). Optical coherence tomography imaging was attained with Heidelberg Eye Explorer software (Heidelberg Engineering, Heidelberg, Germany).ResultsTwenty-four male participants with confirmed pathogenic RPGR mutations, 44 male participants with confirmed pathogenic CHM mutations, and 62 age-matched controls underwent clinical assessment prior to clinical trial recruitment. Low luminance VA was significantly reduced in both disease groups compared to controls. The low luminance deficit correlated with microperimetry retinal sensitivity and ellipsoid zone width. Eleven participants with moderate VA had poor low luminance VA (subsequently a large low luminance deficit), no detectable microperimetry sensitivity, and severely constricted ellipsoid zone widths.ConclusionsLow luminance VA and subsequently low luminance deficit are useful markers of central macular visual function in both choroideremia and RPGR-associated RP, when standard VA is preserved.Translational relevanceLow luminance visual acuity and low luminance deficit are useful vision measures in two distinct rod-cone degenerations and may be useful in other retinal degenerations.
| S-EPMC7900861 | biostudies-literature
Project description:Choroideremia (CHM) is an incurable progressive chorioretinal dystrophy. Little is known about the natural disease course of visual acuity in the Japanese population. We aimed to investigate the genetic spectrum of the CHM gene and visual acuity outcomes in 24 CHM patients from 16 Japanese families. We measured decimal best-corrected visual acuity (BCVA) at presentation and follow-up, converted to logMAR units for statistical analysis. Sanger and/or whole-exome sequencing were performed to identify pathogenic CHM variants/deletions. The median age at presentation was 37.0 years (range, 5-76 years). The mean follow-up interval was 8.2 years. BCVA of the better-seeing eye at presentation was significantly worsened with increasing age (r = 0.515, p < 0.01), with a high rate of BCVA decline in patients > 40 years old. A Kaplan-Meier survival curve suggested that a BCVA of Snellen equivalent 20/40 at follow-up remains until the fifties. Fourteen pathogenic variants, 6 of which were novel [c.49 + 5G > A, c.116 + 5G > A, p.(Gly176Glu, Glu177Ter), p.Tyr531Ter, an exon 2 deletion, and a 5.0-Mb deletion], were identified in 15 families. No variant was found in one family only. Our BCVA outcome data are useful for predicting visual prognosis and determining the timing of intervention in Japanese patients with CHM variants.
| S-EPMC7522719 | biostudies-literature
Project description:BackgroundChoroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease.MethodsIn a multicentre clinical trial, six male patients (aged 35-63 years) with choroideremia were administered AAV.REP1 (0·6-1·0×10(10) genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213.FindingsDespite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23·0 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment (increase 2·3 dB [95% CI 0·8-3·8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm(2) of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (-0·8 dB [1·5]) and mean sensitivity (-1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector.InterpretationThe initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning.FundingUK Department of Health and Wellcome Trust.
| S-EPMC4171740 | biostudies-literature
Project description:While albino mice are widely used in research which includes the use of visually guided behavioral tests, information on their visual capability is scarce. We compared the spatial resolution (acuity) of albino mice (BALB/c) with that of pigmented mice (C57BL/6J). We used a high-throughput pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) method for objective assessment of retinal and cortical acuity, as well as optomotor head-tracking response/ reflex (OMR). We found that PERG, PVEP, and OMR acuities of C57BL/6J mice were all in the range of 0.5-0.6 cycles/degree (cyc/deg). BALB/c mice had PERG and PVEP acuities in the range of 0.1-0.2 cyc/deg but were unresponsive to OMR stimulus. Results indicate that retinal and cortical acuity can be reliably determined with electrophysiological methods in BALB/c mice, although PERG/PVEP acuities are lower than those of C57BL/6J mice. The reduced acuity of BALB/c mice appears to be primarily determined at retinal level.
| S-EPMC8162811 | biostudies-literature
Project description:Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5-3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence, impaired adaptive behavior and often visual impairments. Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) is an interacting partner of the FMR protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants have been found in patients with early-onset epileptic encephalopathy, developmental delay and ID. Such individuals often exhibit visual impairments; however, the underlying mechanism is poorly understood. In the present study, we investigated the role of Cyfip2 in retinal and visual functions by generating and analyzing Cyfip2 conditional knockout (CKO) mice. While we found no major differences in the layer structures and cell compositions between the control and Cyfip2 CKO retinas, a subset of genes associated with the transporter and channel activities was differentially expressed in Cyfip2 CKO retinas than in the controls. Multi-electrode array recordings showed more sustained and stronger responses to positive flashes of the ON ganglion cells in the Cyfip2 CKO retina than in the controls, although electroretinogram analysis revealed that Cyfip2 deficiency unaffected the photoreceptor and ON bipolar cell functions. Furthermore, analysis of initial and late phase optokinetic responses demonstrated that Cyfip2 deficiency impaired the visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying the visual impairments observed in individuals with CYFIP2 variants and, more generally, in patients with neurodevelopmental disorders, including ID.
| S-EPMC8863419 | biostudies-literature
Project description:PurposeThis study explored whether visual acuity (VA) can be inferred from self-reported ability to recognize everyday objects using a set of yes/no questions.MethodsParticipants answered 100 yes/no questions designed to assess their ability to recognize familiar objects at typical viewing distances, such as distinguishing between a full moon and a half moon on a clear night. The questions demanded VA ranging from normal to severe vision impairment. Responses were analyzed using item response theory, and the results were compared with participants' VA values.ResultsWe recruited 385 participants from 4 sites in the United States. Participants had a mean age of 56.7 years with VA ranging from -0.3 to 2.0 logarithm of the minimum angle of resolution (logMAR) (mean = 0.58). A strong relationship was observed between participants' estimated vision ability and their VA (r = -0.72). The linear relationship can be used to predict each participant's VA based on their estimated vision ability. The average signed and unsigned prediction errors were 0 and 0.24 logMAR, respectively, with a coefficient of repeatability of 0.59 logMAR between the estimated VA and measured VA. The same linear function was used to determine the VA limit required for each question. For instance, the VA limit for the moon question was 1.0 logMAR.ConclusionsYes/no questions about everyday visual activities have the potential to estimate an individual's VA. Future refinements may enhance reliability.Translational relevanceThe survey provides insights into the real-world visual capabilities of people with low vision, making it potentially useful for telehealth applications.
| S-EPMC11412607 | biostudies-literature