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Background and Objectives: The role and the levels of ghrelin in diabetes-induced retinal damage have not yet been explored. The present study aimed to measure the serum levels of total ghrelin (TG), and its acylated (AG) and des-acylated (DAG) forms in patients with the two stages of diabetic retinopathy (DR), non-proliferative (NPDR) and proliferative (PDR). Moreover, the correlation between serum ghrelin and neutrophil elastase (NE) levels was investigated. Materials and Methods: The serum markers were determined via enzyme-linked immunosorbent assays in 12 non-diabetic subjects (CTRL), 15 diabetic patients without DR (Diabetic), 15 patients with NPDR, and 15 patients with PDR. Results: TG and AG serum levels were significantly decreased in Diabetic (respectively, p < 0.05 and p < 0.01 vs. CTRL), NPDR (p < 0.01 vs. Diabetic), and in PDR patients (p < 0.01 vs. NPDR). AG serum levels were inversely associated with DR abnormalities (microhemorrhages, microaneurysms, and exudates) progression (r = -0.83, p < 0.01), serum neutrophil percentage (r = -0.74, p < 0.01), and serum NE levels (r = -0.73, p < 0.01). The latter were significantly increased in the Diabetic (p < 0.05 vs. CTRL), NPDR (p < 0.01 vs. Diabetic), and PDR (p < 0.01 vs. PDR) groups. Conclusions: The two DR stages were characterized by decreased AG and increased NE levels. In particular, serum AG levels were lower in PDR compared to NPDR patients, and serum NE levels were higher in the PDR vs. the NPDR group. Together with the greater presence of retinal abnormalities, this could underline a distinctive role of AG in PDR compared to NPDR.
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Diabetes Mellitus , Retinopatía Diabética , Humanos , Elastasa de Leucocito , Ghrelina , Ensayo de Inmunoadsorción Enzimática , Exudados y TransudadosRESUMEN
Carnosol is a natural compound with antioxidant properties. Based on this evidence, in the present study we investigated whether this compound can protect retinal vascular endothelium from hyperglycemic insult responsible for diabetic retinopathy development. We performed in vitro study on human retinal endothelial cells (HREC) cultured both in normal and high glucose conditions to assess the effects of carnosol on cell viability, Nrf2 expression, HO-1 activity, and ERK1/2 expression. HREC exposed to high glucose insult were treated with carnosol. Data indicated that carnosol treatment is able to induce HO-1 expression via Nrf2 activation and counteracts the damage elicited by high glucose. Further, carnosol activation of Nrf2/HO-1 signaling axis involves ERK1/2 pathway. These data confirm the therapeutic value of carnosol by suggesting its use to treat diabetic retinopathy.
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Diabetic retinopathy (DR) is the most frequent microvascular retinal complication of diabetic patients, contributing to loss of vision. Recently, retinal neuroinflammation and neurodegeneration have emerged as key players in DR progression, and therefore, this review examines the neuroinflammatory molecular basis of DR. We focus on four important aspects of retinal neuroinflammation: (i) the exacerbation of endoplasmic reticulum (ER) stress; (ii) the activation of the NLRP3 inflammasome; (iii) the role of galectins; and (iv) the activation of purinergic 2X7 receptor (P2X7R). Moreover, this review proposes the selective inhibition of galectins and the P2X7R as a potential pharmacological approach to prevent the progression of DR.
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Diabetes Mellitus , Retinopatía Diabética , Humanos , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/etiología , Enfermedades Neuroinflamatorias , Galectinas/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamasomas/metabolismo , Receptores Purinérgicos P2X7 , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
Background and Objectives: To report the real-life Brolucizumab therapeutical outcomes of treatment-naïve and non-treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) and to analyze the incidence of therapy-related adverse events. Materials and Methods: A total of 56 eyes of 54 patients diagnosed with nAMD were retrospectively evaluated over a 3-month follow-up. Naïve eyes received a 3-month loading phase, whereas non-naïve eyes were treated with one intravitreal injection + ProReNata scheme. The main outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) change. In addition, patients were stratified on the basis of fluid accumulation site, whether intra-retinal (IRF), sub-retinal (SRF), or sub-retinal pigmented epithelium (SRPE), to separately assess the eventual BCVA change in each subgroup. Finally, the incidence of ocular adverse events was evaluated. Results: In naïve eyes, a significant improvement of BCVA (LogMar) was observed at all timepoints from baseline (1 month-Mean Difference (MD): -0.13; 2 months MD: -0.17; 3 months MD: -0.24). In non-naïve eyes, a significant mean change was observed at all timepoints, with the exception of 1-month follow-up (2 months MD: -0.08; 3 months MD: -0.05). CRT significantly changed in both groups at all timepoints at a similar pace within the first two months, with naïve eyes displaying a larger overall thickness decrease at the end of the follow-up (Group 1 = MD: -123.91 µm; Group 2 = MD: -110.33 µm). With respect to the location of the edema, a significant BCVA change was observed in naïve patients with fluid in all three sites at the end of the follow-up (SRPE = MD: -0.13 (p = 0.043); SR = MD: -0.15 (p = 0.019); IR = MD: -0.19 (p = 0.041). Non-naïve patients exhibited significant mean BCVA changes only with respect to SR and IR fluid presence (SRPE = MD: -0.13 (p = 0.152); SR = MD: -0.15 (p = 0.007); IR = MD: -0.06 (p = 0.011). One naïve patient experienced acute-onset anterior and intermediate uveitis which completely resolved after therapy. Conclusions: Brolucizumab was demonstrated to be a safe and efficient alternative in improving both the anatomical and functional parameters of eyes with nAMD in this small, uncontrolled, series of patients.
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Tomografía de Coherencia Óptica , Degeneración Macular Húmeda , Humanos , Inyecciones Intravítreas , Estudios Retrospectivos , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
The most frequent retinal diseases, such as diabetic retinopathy, age-related macular degeneration and posterior uveitis, are underlined by oxidative stress or aging-induced retinal inflammation, which contributes to vision impairing or loss. Resolution of inflammation is emerging as a critical phase able to counteract the inflammatory process leading to the progression of retinal damage. Particularly, pro-resolving mediators (PMs) play a key role in the modulation of inflammatory exudates and could be considered a new target to be investigated in different inflammatory-autoimmune pathologies. Here, we highlight the most recent studies concerning the role of the main PMs (lipoxins, resolvins, prtectins, maresins and annexins) in retinal inflammation, in order to collect the best evidence in the field of inflammatory retinal damage resolution and to propose novel pharmacological approaches in the management of the most common retinal diseases.
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Lipoxinas , Enfermedades de la Retina , Ácidos Docosahexaenoicos , Humanos , Inflamación/patología , Mediadores de InflamaciónRESUMEN
Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25−50−100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome−lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration.
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Diabetes Mellitus Experimental , Retinopatía Diabética , Ácido 3-Hidroxibutírico/farmacología , Animales , Autofagia , Factor Neurotrófico Derivado del Encéfalo , Conexina 43 , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Retinopatía Diabética/complicaciones , Retinopatía Diabética/etiología , Ratones , Ratones Endogámicos C57BL , RetinaRESUMEN
Diabetic retinopathy (DR) is a neurovascular disease characterized by the reduction of retina integrity and functionality, as a consequence of retinal pigment epithelial cell fibrosis. Although galectin-1 (a glycan-binding protein) has been associated with dysregulated retinal angiogenesis, no evidence has been reported about galectin-1 roles in DR-induced fibrosis. ARPE-19 cells were cultured in normal (5 mM) or high glucose (35 mM) for 3 days, then exposed to the selective galectin-1 inhibitor OTX008 (2.5-5-10 µM) for 6 days. The determination of cell viability and ROS content along with the analysis of specific proteins (by immunocytochemistry, Western blotting, and ELISA) or mRNAs (by real time-PCR) were performed. OTX008 5 µM and 10 µM improved cell viability and markedly reduced galectin-1 protein expression in cells exposed to high glucose. This was paralleled by a down-regulation of the TGF-ß/, NF-kB p65 levels, and ROS content. Moreover, epithelial-mesenchymal transition markers were reduced by OTX008 5 µM and 10 µM. The inhibition of galectin-1 by OTX008 in DR may preserve retinal pigment epithelial cell integrity and functionality by reducing their pro-fibrotic phenotype and epithelial-mesenchymal transition phenomenon induced by diabetes.
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Retinopatía Diabética , Galectina 1 , Calixarenos , Retinopatía Diabética/metabolismo , Células Epiteliales , Transición Epitelial-Mesenquimal , Fibrosis , Glucosa/metabolismo , Glucosa/farmacología , Humanos , Fenoles , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Pigmentos Retinianos/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Fingolimod (FNG) is associated with the development of symptomatic macular edema (ME) in a small subset of multiple sclerosis (MS) patients. By using spectral domain optical coherence tomography (SD-OCT), an increase in the total macular volume (TMV) was rarely detected during the first months of treatment. OBJECTIVES: The objective of this study is to assess whether FNG treatment leads to long-term macular changes in a real-life setting. METHODS: Sixty RRMS patients starting FNG, according to therapeutic indication, were enrolled at three Italian MS centers and followed for 2 years. RESULTS: The mean TMV did not change between baseline and the follow-up. No patients experienced visual acuity drop during the follow-up. CONCLUSIONS: Initiation of FNG in MS is associated with a modest, not significant, increase in macular volume followed by no further significant changes over 2 years, highlighting the good safety profile of such treatment in MS.
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Edema Macular , Esclerosis Múltiple , Clorhidrato de Fingolimod/efectos adversos , Humanos , Edema Macular/diagnóstico por imagen , Edema Macular/tratamiento farmacológico , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Tomografía de Coherencia Óptica , Agudeza VisualRESUMEN
(1) Background: The pro-resolving lipid mediator Resolvin D1 (RvD1) has already shown protective effects in animal models of diabetic retinopathy. This study aimed to investigate the retinal levels of RvD1 in aged (24 months) and younger (3 months) Balb/c mice, along with the activation of macro- and microglia, apoptosis, and neuroinflammation. (2) Methods: Retinas from male and female mice were used for immunohistochemistry, immunofluorescence, transmission electron microscopy, Western blotting, and enzyme-linked immunosorbent assays. (3) Results: Endogenous retinal levels of RvD1 were reduced in aged mice. While RvD1 levels were similar in younger males and females, they were markedly decreased in aged males but less reduced in aged females. Both aged males and females showed a significant increase in retinal microglia activation compared to younger mice, with a more marked reactivity in aged males than in aged females. The same trend was shown by astrocyte activation, neuroinflammation, apoptosis, and nitrosative stress, in line with the microglia and Müller cell hypertrophy evidenced in aged retinas by electron microscopy. (4) Conclusions: Aged mice had sex-related differences in neuroinflammation and apoptosis and low retinal levels of endogenous RvD1.
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Envejecimiento/patología , Ácidos Docosahexaenoicos/farmacología , Inflamación/patología , Retina/patología , Caracteres Sexuales , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Células Ependimogliales/efectos de los fármacos , Células Ependimogliales/metabolismo , Células Ependimogliales/patología , Células Ependimogliales/ultraestructura , Femenino , Masculino , Ratones Endogámicos BALB C , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Microglía/ultraestructura , FN-kappa B/metabolismo , Retina/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
BACKGROUND: Sialidosis is a rare genetic lysosomal storage disorder caused by a deficit of neuraminidase enzyme activity. Patients with sialidosis present various neurological disorders such as: myoclonic epilepsy and hypotonia, often associated with visual impairment. A typical aspect of sialidosis is the finding of a macular cherry-red spot on ocular fundus examination. In this paper we describe a unilateral case of Bergmeister's papilla (BP) in a young female patient suffering from type 1 sialidosis. CASE PRESENTATION: A 28-year-old young woman suffering from type 1 sialidosis, confirmed by previously described compound heterozigosity Leu91Arg and Gly328Ser on N-acetyl-alpha-neuraminidase - 1 (NEU1) gene, underwent an opthalmological examination at the Eye Clinic of the University of Campania L. Vanvitelli, for bilateral visual deterioration. The patient was suffering from myoclonic epilepsy with hypotonia and severe motor disability. Fundoscopic examination showed a typical macular cherry-red spot with retinal pigment epithelium dystrophy in the middle periphery, in both eyes. Furthermore, in the left eye (OS), a vitreous thickening was observed in the nasal sector of the optic disc, remnant of fetal vasculature on the optic disc (Bergmeister's papilla). Optical coherence tomography (OCT) showed, in both eyes, a thickening of the ganglion cell layer (GCL) with a hyperreflective opacity as a cap on the left optic disc. CONCLUSIONS: In our paper we have described, for the first time in literature, a case of BP in a patient with type 1 sialidosis. The detection of BP with thickening of the peripapillary vitreous by SD-OCT is useful in monitoring any vitreo-retinal change that could cause future visual deterioration.
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Personas con Discapacidad , Trastornos Motores , Mucolipidosis , Disco Óptico , Adulto , Femenino , Humanos , Mucolipidosis/diagnóstico , Mucolipidosis/genética , Tomografía de Coherencia ÓpticaRESUMEN
Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alström syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected full-length products along a number of aberrant transcripts. However, only the full-length transcripts are efficiently translated in vivo. We additionally showed that approximately 4% of mouse photoreceptors are transduced by triple AAV vectors and showed correct localization of recombinant ALMS1. The low-photoreceptor transduction levels might justify the modest and transient improvement we observe in the retina of a mouse model of ALMS. However, the levels of transduction mediated by triple AAV vectors in pig retina reached 40% of those observed with single vectors, and this bodes well for further improving the efficiency of triple AAV vectors in the retina.
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Dependovirus/genética , Vectores Genéticos/genética , Recombinación Genética , Retina/metabolismo , Transducción Genética , Animales , Cadherinas/genética , Cadherinas/metabolismo , Expresión Génica , Regulación Viral de la Expresión Génica , Técnicas de Transferencia de Gen , Genes Reporteros , Terapia Genética , Vectores Genéticos/administración & dosificación , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Porcinos , Transcripción Genética , TransgenesRESUMEN
PURPOSE: To investigate the natural history of Stargardt disease over a multiyear follow-up. METHODS: We reviewed medical records of Stargardt disease patients, with clinical diagnosis of Stargardt disease at a single institution, which was also supported by molecular diagnosis. All patients underwent best-corrected visual acuity, fundus photography, optical coherence tomography, and full-field electroretinography. RESULTS: The study cohort consisted of 157 Stargardt disease patients aged 30.4 ± 1.1 years. Longitudinal analysis (mean follow-up: 3 years) showed a significant worsening of best-corrected visual acuity at an average rate of 1.5 Early Treatment Diabetic Retinopathy Study letters/year (P < 0.001), an enlargement of retinal pigment epithelium lesion area by optical coherence tomography at an average linear rate of 0.10 mm/year (P < 0.001), and a thinning of central macular thickness at a mean rate of -1.42 µm/year (P < 0.001). Survival analysis showed that patients with 2 alleles harboring likely-null variants, on average, reached most severe disease stage, i.e., legal blindness, alteration in both dark-adapted and light-adapted electroretinographic responses, and retinal pigment epithelium lesion area larger than 2.5 mm significantly earlier than patients with at least one allele harboring a missense variant. CONCLUSION: The current longitudinal study showed a significant genotype-phenotype correlation characterization, because patients harboring 2 likely-null alleles reach a severe disease stage about 10 years earlier than patients with at least one missense allele.
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Angiografía con Fluoresceína/métodos , Predicción , Oftalmoscopía/métodos , Epitelio Pigmentado de la Retina/patología , Enfermedad de Stargardt/diagnóstico , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Transportadoras de Casetes de Unión a ATP/genética , Adulto , Progresión de la Enfermedad , Electrorretinografía , Femenino , Estudios de Seguimiento , Fondo de Ojo , Estudios de Asociación Genética , Humanos , Incidencia , Italia/epidemiología , Masculino , Mutación , Estudios Retrospectivos , Enfermedad de Stargardt/epidemiología , Enfermedad de Stargardt/genéticaRESUMEN
BACKGROUND: To evaluate the clinical results of standard, transepithelial (TE) and iontophoresis (I) corneal cross-linking (CXL), in patients with progressive keratoconus. METHODS: Thirty eyes of 30 patients with progressive keratoconus treated by CXL (10 by standard-CXL, 10 by TE-CXL and 10 by I-TE-CXL) with 12 months of follow-up. Pre- and postoperative ophthalmologic testing were: uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive examination (spherical error, spherical equivalent), corneal topography (corneal astigmatism, simulated maximum, minimum and average keratometry), aberrometry (coma and spherical aberration), pachymetry and endothelial cell density. RESULTS: In all groups, UDVA and CDVA improved significantly after treatment. Furthermore, a significant improvement in spherical error, spherical equivalent, topographic and aberrometric outcomes was observed in 3 groups at 1 year posttreatment. No significant variations were recorded in corneal thickness and endothelial cellular density. CONCLUSION: Our results showed efficacy, clinical and refractive stability after standard-CXL, TE-CXL and iontophoresis-CXL.
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Córnea/cirugía , Iontoforesis/métodos , Queratocono/cirugía , Fotoquimioterapia/métodos , Adulto , Análisis de Varianza , Reactivos de Enlaces Cruzados/uso terapéutico , Desbridamiento/métodos , Femenino , Humanos , Queratocono/tratamiento farmacológico , Queratocono/fisiopatología , Masculino , Fármacos Fotosensibilizantes/uso terapéutico , Refracción Ocular/fisiología , Agudeza Visual/fisiología , Adulto JovenRESUMEN
Retinal photoreceptors are particularly vulnerable to local high-glucose concentrations. Oxidative stress is a risk factor for diabetic retinopathy development. Melanocortin receptors represent a family of G-protein-coupled receptors classified in five subtypes and are expressed in retina. Our previous data indicate that subtypes 1 and 5 receptor agonists exert a protective role on experimental diabetic retinopathy. This study focuses on their role in primary retinal cell cultures in high-glucose concentrations. After eye enucleation from wild-type male C57BL/6 mice, retinal cells were isolated, plated in high-glucose concentration and treated with melanocortin receptors 1 and 5 agonists and antagonists. Immunocytochemical and biochemical analysis showed that treatment with melanocortin receptors 1 and 5 agonists reduced anti-inflammatory cytokines and chemokines and enhanced manganese superoxide dismutase and glutathione peroxidase levels, preserving photoreceptor integrity. According with these evidences, we propose a major role of melanocortin receptors 1 and 5 on primary retinal cell response against high glucose or oxidative insults.
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Antioxidantes/metabolismo , Glucosa/toxicidad , Neuroprotección/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/enzimología , Células Fotorreceptoras de Vertebrados/patología , Receptores de Melanocortina/agonistas , Animales , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Opsinas/metabolismo , Cultivo Primario de Células , Receptores de Melanocortina/metabolismo , Coloración y Etiquetado , Superóxido Dismutasa/metabolismoRESUMEN
Stargardt disease (STGD1) due to mutations in the large ABCA4 gene is the most common inherited macular degeneration in humans. We have shown that dual adeno-associated viral (AAV) vectors effectively transfer ABCA4 to the retina of Abca4-/- mice. However, they express both lower levels of transgene compared with a single AAV and truncated proteins. To increase productive dual AAV concatemerization, which would overcome these limitations, we have explored the use of either various regions of homology or heterologous inverted terminal repeats (ITR). In addition, we tested the ability of various degradation signals to decrease the expression of truncated proteins. We found the highest levels of transgene expression using regions of homology based on either alkaline phosphatase or the F1 phage (AK). The use of heterologous ITR does not decrease the levels of truncated proteins relative to full-length ABCA4 and impairs AAV vector production. Conversely, the inclusion of the CL1 degradation signal results in the selective degradation of truncated proteins from the 5'-half without affecting full-length protein production. Therefore, we developed dual AAV hybrid ABCA4 vectors including homologous ITR2, the photoreceptor-specific G protein-coupled receptor kinase 1 promoter, the AK region of homology and the CL1 degradation signal. We show that upon subretinal administration these vectors are both safe in pigs and effective in Abca4-/- mice. Our data support the use of improved dual AAV vectors for gene therapy of STGD1.
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Transportadoras de Casetes de Unión a ATP/genética , Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos , Degeneración Macular/congénito , Administración Oftálmica , Animales , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos/administración & dosificación , Células HEK293 , Humanos , Degeneración Macular/genética , Degeneración Macular/terapia , Ratones , Retina/metabolismo , Enfermedad de Stargardt , Porcinos , Secuencias Repetidas Terminales , TransgenesRESUMEN
BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. METHODS: We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. RESULTS: At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. CONCLUSION: BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.
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Síndrome de Bardet-Biedl/genética , Ojo/fisiopatología , Riñón/fisiopatología , Población Blanca/genética , Adolescente , Adulto , Anciano , Umbral Auditivo , Síndrome de Bardet-Biedl/patología , Chaperoninas , Niño , ADN/química , ADN/aislamiento & purificación , ADN/metabolismo , Análisis Mutacional de ADN , Ojo/diagnóstico por imagen , Femenino , Estudios de Asociación Genética , Genotipo , Chaperoninas del Grupo II/genética , Humanos , Italia , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Proteínas/genética , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
PURPOSE: To evaluate differences in the visual phenotype and natural history of Usher syndrome caused by mutations in MYO7A or USH2A, the most commonly affected genes of Usher syndrome Type I (USH1) and Type II (USH2), respectively. METHODS: Eighty-eight patients with a clinical diagnosis of USH1 (26 patients) or USH2 (62 patients) were retrospectively evaluated. Of these, 48 patients had 2 disease-causing mutations in MYO7A (10 USH1 patients), USH2A (33 USH2 patients), and other USH (5 patients) genes. Clinical investigation included best-corrected visual acuity, Goldmann visual field, fundus photography, electroretinography, and audiologic and vestibular assessments. Longitudinal analysis was performed over a median follow-up time of 3.5 years. RESULTS: Patients carrying mutations in MYO7A had a younger age of onset of hearing and visual impairments than those carrying mutations in USH2A, leading to an earlier diagnosis of the disease in the former patients. Longitudinal analysis showed that visual acuity and visual field decreased more rapidly in subjects carrying MYO7A mutations than in those carrying USH2A mutations (mean annual exponential rates of decline of 3.92 vs. 3.44% and of 8.52 vs. 4.97%, respectively), and the former patients reached legal blindness on average 15 years earlier than the latter. CONCLUSION: The current study confirmed a more severe progression of the retinal disease in USH1 patients rather than in USH2 patients. Furthermore, most visual symptoms (i.e., night blindness, visual acuity worsening) occurred at an earlier age in USH1 patients carrying mutations in MYO7A.
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ADN/genética , Proteínas de la Matriz Extracelular/genética , Mutación , Miosinas/genética , Síndromes de Usher/genética , Agudeza Visual , Campos Visuales , Adolescente , Adulto , Análisis Mutacional de ADN , Progresión de la Enfermedad , Electrorretinografía , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Miosina VIIa , Miosinas/metabolismo , Fenotipo , Retina/diagnóstico por imagen , Retina/fisiopatología , Estudios Retrospectivos , Factores de Tiempo , Tomografía de Coherencia Óptica , Síndromes de Usher/diagnóstico , Síndromes de Usher/fisiopatología , Adulto JovenRESUMEN
In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came to our observation in January 2013 claiming a severe uveitis attack that involved the right eye. During the acute attack of uveitis, this woman had normal serum biochemical parameters but higher levels of serum ubiquitin and proteasome 20S subunit, with respect to a healthy volunteer matched for age and sex. These levels correlated well with the clinical score attributed to uveitis. After the patient was admitted to therapy, she received oral prednisone in a de-escalation protocol (doses from 50 to 5 mg/day) for four weeks. Following this therapy, she had an expected reduction of clinical signs and score for uveitis, but concomitantly she had a reduction of the serum levels of ubiquitin, poliubiquitinated proteins (MAb-FK1) and proteasome 20S activity. Therefore, a role for ubiquitin and proteasome in the development of human autoimmune uveitis has been hypothesized.
Asunto(s)
Antígeno HLA-B27/genética , Antígeno HLA-B27/inmunología , Complejo de la Endopetidasa Proteasomal/sangre , Ubiquitina/sangre , Uveítis/sangre , Uveítis/etiología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Persona de Mediana Edad , Fenotipo , Uveítis/diagnóstico , Uveítis/tratamiento farmacológicoRESUMEN
BACKGROUND: To evaluate the functional recovery of patients with symptomatic vitreomacular traction (VMT) after Ocriplasmin treatment. METHODS: Prospective, single centre, consecutive case series. Patients were treated with a single intravitreal injection of Ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU). The following outcome measures are considered: resolution of VMT, evaluated through the use of optical coherence tomography (SD-OCT), functional recovery evidenced by multifocal-electroretinogram (mfERG) and microperimetry (MP1) after treatment with Ocriplasmin. RESULTS: Four eyes of four patients were treated with Ocriplasmin injection. We observed a VMT non-surgical resolution in all patients. The longitudinal statistical analysis showed a significant improvement of best corrected visual acuity (BCVA) in the treated eye of about 0.97 letters/week (p = 0.033). No significant difference was observed in mean sensitivity (p > 0.05) assessed by MP1 in both eyes, while improvement in fixation stability was assessed in treated eyes (ß = 0.39; p = 0.029). In the four treated eyes mfERG revealed an increased foveal peak response over the follow-up. The longitudinal analysis of mfERG data shows a significant increase of N1 and P1 amplitude in the first rings and a significant decrease of N1 and P1 implicit time in most rings. CONCLUSIONS: We report on four cases with resolution of VMT after Ocriplasmin treatment. Our preliminary results demonstrate that Ocriplasmin is safe and effective in the treatment of VMT, because it not only leads to a morphological recovery but mostly to a restoration of macular functionality, evaluated through the use of different objective tests, such as MP1 and mfERG over a six-month follow-up.
Asunto(s)
Fibrinolisina/uso terapéutico , Fibrinolíticos/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Enfermedades de la Retina/tratamiento farmacológico , Anciano , Electrorretinografía/métodos , Femenino , Fijación Ocular/fisiología , Humanos , Inyecciones Intravítreas , Persona de Mediana Edad , Estudios Prospectivos , Enfermedades de la Retina/fisiopatología , Perforaciones de la Retina/tratamiento farmacológico , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Campos Visuales/fisiología , Desprendimiento del Vítreo/tratamiento farmacológicoRESUMEN
Gene therapy clinical trials with gene augmentation therapy for Leber Congenital Amaurosis have shown partial reversal of retinal dysfunction. Most studies described the effect of treatment in a single eye and limited evidence is reported in literature about patients treated in both eyes. In this chapter, we present the findings of a young patient treated in both eyes. Efficacy of the treatment was assessed with Best Corrected Visual Acuity, Goldman Visual Field testing, Esterman computerized binocular visual field and Microperimetric testing. Post-treatment results showed improvement of visual function in both eyes, in particular, a strong amelioration was observed after the first injection, by using conventional monocular tests. Moreover, the treatment in the second eye resulted in a further improvement of binocular visual functionality, as easily detected by computerized binocular visual field. In conclusion, our data suggest that gene therapy can inhibit retinal degeneration and can be safe and effective in restoring visual functionality in young subjects treated in both eyes. Finally, new outcome measurements, in particular binocular computerized visual field parameters, can therefore be useful to quantify overall visual gain in patients undergoing gene therapy in both eyes.