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Purpose: To define the clinical characteristics of centrosomal protein 290 (CEP290)-associated inherited retinal degeneration (IRD) and determine which assessments may provide reliable endpoints in future interventional trials. Design: Participants in this natural history study were enrolled into 2 best-corrected visual acuity (BCVA) cohorts: light perception to > 1.0 logarithm of the minimum angle of resolution (logMAR) and 1.0 logMAR to 0.4 logMAR. Each comprised 4 age cohorts (3-5, 6-11, 12-17, and ≥ 18 years). Participants: Patients with CEP290-associated IRD caused by the intron 26 c.2991+1655A>G mutation and BCVA ranging from light perception to 0.4 logMAR. Methods: Best-corrected visual acuity, full-field stimulus threshold (FST) sensitivity, Ora-Visual Navigation Challenge (Ora-VNC) composite score, and OCT-outer nuclear layer (OCT-ONL) average thickness were assessed at screening, baseline, 3 months, 6 months, and 12 months. Main Outcome Measures: Best-corrected visual acuity, FST sensitivity, Ora-VNC composite score, and OCT-ONL average thickness. Results: Twenty-six participants were included in this analysis. Nineteen were female. All participants were White and 4 reported Hispanic ethnicity. At screening, 13 of 16 adult and 9 of 10 pediatric participants had BCVA > 1.0 logMAR. Baseline BCVA was variable (median [range] = 2.0 [0.5, 3.9] logMAR) and was uncorrelated with age, as were VNC composite score, FST sensitivity, and OCT-ONL average thickness. Mean (95% confidence interval [CI]) test-retest variability was -0.04 (-0.09, 0.01) logMAR for BCVA (n = 25); 0.6 (-0.1, 1.3) for VNC composite score (n = 18); and 0.10 (-0.07, 0.27) log cd.s/m2 for red FST (n = 14). A greater than expected test-retest variability (5 [0, 10] µm, n = 14) was observed for OCT-ONL average thickness as nystagmus impacted ability to repeat measures at the same retinal location. Functional assessments were stable over 12 months. Mean (95% CI) change from baseline was 0.06 (-0.17, 0.29) logMAR for BCVA (n = 23); -0.1 (-1.2, 1.0) for VNC composite score (n = 21); and -0.15 (-0.43, 0.14) log cd.s/m2 for red FST (n = 16). Conclusions: Vision was stable over 12 months. Best-corrected visual acuity, FST, and VNC composite score are potentially viable endpoints for future studies in CEP290-associated IRD. Repeatability of OCT measures poses challenges for quantifying anatomical changes in this population. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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AIM: To describe the clinical, electrophysiological, and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant. METHODS: The patient underwent a complete ophthalmologic examination including best-corrected visual acuity, anterior segment and dilated fundus, visual field, spectral-domain optical coherence tomography (OCT) and electroretinogram (ERG). The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result. Then we reviewed the characteristics of the patients reported with the same variant. RESULTS: A 30-year male presented with severe early retinal degeneration who complained night blindness, decreased visual acuity, vitreous floaters and amaurosis fugax. The best corrected vision was 0.04 OD and 0.12 OS, respectively. The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye. Autofluorescence shows bilateral symmetrical hypo-autofluorescence. ERG revealed that the amplitudes of a- and b-wave were severely decreased. Multifocal ERG showed decreased amplitudes in the local macular area. A homozygous missense variant c.146C>T (chr14:68191267) was found. The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied. CONCLUSION: An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported. The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.
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BACKGROUND: To describe different clinical presentations of a same NR2E3 recessive mutation in two families and within one family. DESIGN: Interventional family study. RESULTS: Our first case was a one-year-old male child with high hyperopia and refractive accommodative esotropia. In retinal examination, peri-papillary sub-retinal fibrosis with a helicoid configuration was observed in both eyes. The parents and the only sibling had no pathologic findings in the eyes. The child showed to have severely reduced responses in both photopic and scotopic electroretinogram components. In the genetic investigation, a homozygous autosomal recessive mutation in the NR2E3 gene (IVS1-2A > C) was discovered in the affected child, while the other family members were heterozygous for this mutation. We followed up with the patient for 3 years and no new lesion developed during this period. The second case was a 13-year-old male child referred to the retina clinic for decreased vision in the right eye. In retina examination, there were nummular pigmentary changes at the level of retinal pigment epithelium and along the vascular arcades with foveo-schitic changes in both eyes. A choroidal neovascularization (CNV) was noticed in the macula of his right eye. The genetic evaluation proved the same mutation in the NR2E3 gene as in the first case. Family history was remarkable for an uncle, an aunt, and two cousins with night blindness. CONCLUSION: Same NR2E3 gene mutation can cause heterogeneous clinical manifestations such as slight retinal changes in the absence of any visual symptoms to high hyperopia associated with helicoid peri-papillary sub-retinal fibrosis.
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Biallelic variations in the aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) gene cause Leber congenital amaurosis subtype 4 (LCA4), an autosomal recessive early-onset severe retinal dystrophy that leads to the rapid degeneration of retinal photoreceptors and the severe impairment of sight within the first few years of life. Currently, there is no treatment or cure for AIPL1-associated LCA4. In this study, we investigated the potential of adeno-associated virus-mediated AIPL1 gene replacement therapy in two previously validated human retinal organoid (RO) models of LCA4. We report here that photoreceptor-specific AIPL1 gene replacement therapy, currently being tested in a first-in-human application, effectively rescued molecular features of AIPL1-associated LCA4 in these models. Notably, the loss of retinal phosphodiesterase 6 was rescued and elevated cyclic guanosine monophosphate (cGMP) levels were reduced following treatment. Transcriptomic analysis of untreated and AAV-transduced ROs revealed transcriptomic changes in response to elevated cGMP levels and viral infection, respectively. Overall, this study supports AIPL1 gene therapy as a promising therapeutic intervention for LCA4.
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Inherited retinal degeneration (IRD), a group of diseases often causing irreversible blindness, with multiple pathogenesis, still lacks effective treatments currently.Development of effective therapeutics is a primary research goal.Despite rapid advances in gene therapy during the past decades, the most challenging aspect of gene therapy in clinical applications for IRD is to deliver the curative molecules to achieve optimal expression levels in target cells safely.Apart from high gene transfection efficiency, there are still many limitations, such as immunogenicity, biosafety issue, etc.in the application of viral vectors, which drive the development of gene therapy based on non-viral vectors.As one of the hot research topics in non-viral vectors, encouraging progress has been made in DNA nanoparticles for IRD treatment.The polymer/DNA complex nanoparticle is compacted and encapsulated DNA via peptides, lipids, or polysaccharides.Besides, the non-viral delivery system shows cost, preparation, packaging capacity, and safety advantages, providing a promising non-viral platform for safe and effective treatment of IRD, such as retinitis pigmentosa, Stargardt disease, X-linked juvenile retinoschisis, Leber congenital amaurosis, and so on.In this article, advances in transfection efficiency, targeting ability and safety of non-viral gene therapy and its application in IRD were reviewed.
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A 2-year-old intact female Bengal cat was presented with a 6-month history of visual impairment. The cat manifested bilateral negative menace responses and dazzle reflexes and sluggish pupillary light reflexes. Bilateral fundus changes included generalized tapetal hyperreflectivity, advanced retinal vascular attenuation, and increased pallor of the optic disc. A diagnosis of bilateral retinal degeneration was made. The clinical findings suggest that the investigated Bengal cat was most likely to have an inherited retinal degeneration. Further studies of the Bengal cat breed are needed to determine the prevalence of inherited retinal degeneration in this breed in Korea.
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Animales , Gatos , Preescolar , Femenino , Humanos , Diagnóstico , Corea (Geográfico) , Palidez , Prevalencia , Reflejo , Degeneración Retiniana , Retinaldehído , Trastornos de la VisiónRESUMEN
Choroideremia is a rare X-linked disorder causing progressive chorioretinal atrophy. Affected patients develop night blindness with progressive peripheral vision loss and eventual blindness. Herein, we report two Korean families with choroideremia. Multimodal imaging studies showed that the probands had progressive loss of visual field with characteristic chorioretinal atrophy, while electroretinography demonstrated nearly extinguished cone and rod responses compatible with choroideremia. Sanger sequencing of all coding exons and flanking intronic regions of the CHM gene revealed a novel small deletion at a splice site (c.184_189+3delTACCAGGTA) in one patient and a deletion of the entire exon 9 in the other. This is the first report on a molecular genetic diagnosis of choroideremia in Korean individuals. Molecular diagnosis of choroideremia should be widely adopted for proper diagnosis and the development of new treatment modalities including gene therapy.
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Humanos , Atrofia , Ceguera , Coroideremia , Codificación Clínica , Diagnóstico , Electrorretinografía , Exones , Terapia Genética , Intrones , Biología Molecular , Imagen Multimodal , Ceguera Nocturna , Campos VisualesRESUMEN
Background Inherited retinal degeneration,one of the major causes of blindness worldwide,comprises a large number of disorders characterized by a slow and progressive retinal degeneration.Interleukin-1 (IL-1)was recognized to be involved in inherited retinal degeneration.Whether IL-1 receptor antagonist (IL-1ra) can arrest retinal degeneration is worthy of investigation.Objective This study was to investigate the effects of IL-1ra on photoreceptor apoptosis in Royal College of Surgeons (RCS) rats.Methods The use of the animals complied with the Regulations for the Administration of Affairs Concerning Experimental Animals by State Science and Technology Commission.The SPF RCS rats aged 9,15,16,25,30,35,40,50 and 60 postnatal days were collected,with 9 rats for each age group.Retinal sections were used for the TdT-mediated biotin-dUTP nick-end labeling (TUNEL) cell apoptosis assay.1 μl of IL-1ra (1.8 g/L) was intravitreally injected in the right eyes of 9 RCS rats aged 15 postnatal days and PBS was used in the same way in the fellow eyes.The injection procedure was repeated on the 20 th and 25 th day,respectively.The rats were sacrificed on the 30 th day and retinal sections were prepared for the TUNEL assay.The differences in the percentage of the positive cellular nuclei area among different ages of rats were compared by one-way ANOVA,and the differences in retinal layer thickness between IL-1ra injection group and PBS injection group were assessed by paired t test.Results Photoreceptor apoptosis appeared in 20-day-old RCS rats and progressed and peaked in 30 and 35-day-old rats and then reduced,showing a significant difference among rat of various age groups (F=28.020,P<0.01).Images from TUNEL assay showed a weaker and less TUNEL staining in the IL-1ra injected eyes than the PBS injected eyes in 30-day-old rats.The total area and relative area of TUNEL positive nuclei were (223.052±153.092) μm2 and (2.206±1.531) % in the IL-1ra injected group,and those in PBS injected group were (1235.050±359.767) μm2 and (7.269± 1.624) %,with a significant difference between them (t =4.370,t=3.250,P<0.01).The cone and rod thickness was (15.324±9.035) μm in the IL-1ra injected group and (49.566±4.605)μm in the PBS injected group,showing a significant difference (t =22.674,P<0.01).However,no significant difference was seen in the outer nuclear layer thickness between the two groups (t =0.268,P>0.05).Conclusions IL-1 participates in the pathogenesis and development of inherited retinal degeneration of RCS rats.The use of IL-1ra might be a potential approach in the treatment of inherited retinal degeneration.