RESUMEN
Ocular and specifically retinal toxicities of systemic medications are prevalent and encompass many disease modalities. For many of these pharmaceuticals, established follow-up protocols are in place to ensure timely detection and cessation of therapy. However, while for some disorders, cessation of therapy is a viable option due to existing treatment alternatives, for some others cessation of treatment can be life threatening and/or shorten the patient's life expectancy. Such is the case for iron chelating agents used in transfusion-dependent patients of Thalassemia, of which deferoxamine (DFO) is the most widely used. In their recent article in EMBO Molecular Medicine, Kong et al (2023) addressed the issue of DFO-induced retinal toxicity used both in vivo and in vitro techniques. Their study suggests a potentially protective role for α-ketoglutarate (AKG) supplementation against DFO toxicity.
Asunto(s)
Deferoxamina , Talasemia , Humanos , Deferoxamina/uso terapéutico , Elevación , Quelantes del Hierro/uso terapéutico , Talasemia/tratamiento farmacológicoRESUMEN
Inherited retinal diseases (IRD) are a group of heterogeneous disorders, most of which lead to blindness with limited therapeutic options. Pathogenic variants in RBP4, coding for a major blood carrier of retinol, retinol-binding protein 4, are responsible for a peculiar form of IRD. The aim of this study was to investigate if retinal function of an RBP4-related IRD patient can be improved by retinol administration. Our patient presented a peculiar white-dot retinopathy, reminiscent of vitamin A deficient retinopathy. Using a customized next generation sequencing (NGS) IRD panel we discovered a novel loss-of-function homozygous pathogenic variant in RBP4: c.255G >A, p.(Trp85*). Western blotting revealed the absence of RBP4 protein in the patient's serum. Blood retinol levels were undetectable. The patient was put on a high-dose oral retinol regimen (50,000 UI twice a week). Subjective symptoms and retinal function markedly and sustainably improved at 5-months and 1-year follow-up. Here we show that this novel IRD case can be treated by oral retinol administration.
Asunto(s)
Distrofias Retinianas , Vitamina A , Humanos , Retina/metabolismo , Distrofias Retinianas/tratamiento farmacológico , Distrofias Retinianas/genética , Proteínas Plasmáticas de Unión al Retinol/genética , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Vitamina A/uso terapéuticoRESUMEN
Visual prostheses aim at restoring useful vision to patients who have become blind. This useful vision should enable them to regain autonomy in society for navigation, face recognition or reading. Two retinal prostheses have already obtained market authorization for patients affected by retinal dystrophies while a new device is in clinical trials for patients affected by age-related macular degeneration. Various prostheses, in particular cortical prostheses, are currently in clinical trials for optic neuropathies (glaucoma). Optogenetic therapy, an alternative strategy, has now reached the stage of clinical trials at the retinal level while moving forward at the cortical level. Other innovating strategies have obtained proofs of concepts in rodents but require a further validation in large animals prior to their evaluation on patients. Restoring vision should therefore become a reality for many patients even if this vision will not be as extensive and perfect as natural vision.
TITLE: Restauration de la vision: Science-fiction ou réalité ? ABSTRACT: Les prothèses visuelles ont pour objet de redonner une vision utile aux patients devenus aveugles. Cette vision utile doit leur permettre de retrouver une autonomie dans la société pour leurs déplacements, la reconnaissance des visages ou la lecture. Plusieurs prothèses rétiniennes ont déjà obtenu l'autorisation de mise sur le marché pour les dystrophies rétiniennes alors qu'un nouveau dispositif est en essai clinique pour la dégénérescence maculaire liée à l'âge. D'autres prothèses, notamment corticales, sont en essai clinique pour les neuropathies optiques (glaucome). Des stratégies alternatives, comme la thérapie optogénétique, ont également atteint le stade des essais cliniques. D'autres ont été évaluées sur les rongeurs, attendant leur validation sur le gros animal. Revoir devrait donc prochainement devenir une réalité pour de nombreux patients, même si cette vision ne sera ni aussi étendue, ni aussi parfaite que la vision naturelle.
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Trastornos de la Visión/rehabilitación , Visión Ocular/fisiología , Prótesis Visuales , Animales , Humanos , Invenciones/tendencias , Magnetoterapia/instrumentación , Magnetoterapia/métodos , Magnetoterapia/tendencias , Nervio Óptico/patología , Nervio Óptico/fisiología , Optogenética/instrumentación , Optogenética/métodos , Optogenética/tendencias , Diseño de Prótesis , Regeneración/fisiología , Degeneración Retiniana/terapia , Trastornos de la Visión/terapia , Prótesis Visuales/química , Prótesis Visuales/clasificación , Prótesis Visuales/tendenciasRESUMEN
Atrophic A\age-related macular degeneration (AMD) and Stargardt disease (STGD) are major blinding diseases affecting millions of patients worldwide, but no treatment is available. In dry AMD and STGD oxidative stress and subretinal accumulation of N-retinylidene-N-retinylethanolamine (A2E), a toxic by-product of the visual cycle, causes retinal pigment epithelium (RPE) and photoreceptor degeneration leading to visual impairment. Acute and chronic retinal degeneration following blue light damage (BLD) in BALB/c mice and aging of Abca4-/- Rdh8-/- mice, respectively, reproduce features of AMD and STGD. Efficacy of systemic administrations of 9'-cis-norbixin (norbixin), a natural di-apocarotenoid, prepared from Bixa orellana seeds with anti-oxidative properties, was evaluated during BLD in BALB/c mice, and in Abca4-/- Rdh8-/- mice of different ages, following three experimental designs: "preventive", "early curative" and "late curative" supplementations. Norbixin injected intraperitoneally in BALB/c mice, maintained scotopic and photopic electroretinogram amplitude and was neuroprotective. Norbixin chronic oral administration for 6 months in Abca4-/- Rdh8-/- mice following the "early curative" supplementation showed optimal neuroprotection and maintenance of photoreceptor function and reduced ocular A2E accumulation. Thus, norbixin appears promising as a systemic drug candidate for both AMD and STGD treatment.
Asunto(s)
Carotenoides/farmacología , Degeneración Macular , Células Fotorreceptoras de Vertebrados , Retinoides , Enfermedad de Stargardt , Animales , Monitoreo de Drogas/métodos , Electrorretinografía/métodos , Inyecciones Intraperitoneales , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Degeneración Macular/prevención & control , Ratones , Fármacos Neuroprotectores/farmacología , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/metabolismo , Retinoides/antagonistas & inhibidores , Retinoides/metabolismo , Enfermedad de Stargardt/tratamiento farmacológico , Enfermedad de Stargardt/metabolismo , Enfermedad de Stargardt/prevención & control , Resultado del TratamientoRESUMEN
The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9'-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally-injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin-trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9'-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial.
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Carotenoides/administración & dosificación , Degeneración Macular/tratamiento farmacológico , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Retinoides/efectos adversos , Transportadoras de Casetes de Unión a ATP/genética , Oxidorreductasas de Alcohol/genética , Animales , Bixaceae/química , Carotenoides/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Técnicas In Vitro , Inyecciones Intravítreas , Degeneración Macular/inducido químicamente , Degeneración Macular/genética , Degeneración Macular/metabolismo , Ratones , Ratones Noqueados , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Epitelio Pigmentado de la Retina/citología , PorcinosRESUMEN
Targeting the photosensitive ion channel channelrhodopsin-2 (ChR2) to the retinal circuitry downstream of photoreceptors holds promise in treating vision loss caused by retinal degeneration. However, the high intensity of blue light necessary to activate channelrhodopsin-2 exceeds the safety threshold of retinal illumination because of its strong potential to induce photochemical damage. In contrast, the damage potential of red-shifted light is vastly lower than that of blue light. Here, we show that a red-shifted channelrhodopsin (ReaChR), delivered by AAV injections in blind rd1 mice, enables restoration of light responses at the retinal, cortical, and behavioral levels, using orange light at intensities below the safety threshold for the human retina. We further show that postmortem macaque retinae infected with AAV-ReaChR can respond with spike trains to orange light at safe intensities. Finally, to directly address the question of translatability to human subjects, we demonstrate for the first time, AAV- and lentivirus-mediated optogenetic spike responses in ganglion cells of the postmortem human retina.
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Terapia Genética/métodos , Fototerapia/métodos , Retina/fisiología , Degeneración Retiniana/terapia , Rodopsina/genética , Animales , Dependovirus/genética , Vectores Genéticos , Humanos , Lentivirus/genética , Luz , Macaca , Ratones , Rodopsina/metabolismo , Transducción Genética , Resultado del TratamientoRESUMEN
To investigate the complexity of alternative splicing in the retina, we sequenced and analyzed a total of 115,706 clones from normalized cDNA libraries from mouse neural retina (66,217) and rat retinal pigmented epithelium (49,489). Based upon clustering the cDNAs and mapping them with their respective genomes, the estimated numbers of genes were 9,134 for the mouse neural retina and 12,050 for the rat retinal pigmented epithelium libraries. This unique collection of retinal of messenger RNAs is maintained and accessible through a web-base server to the whole community of retinal biologists for further functional characterization. The analysis revealed 3,248 and 3,202 alternative splice events for mouse neural retina and rat retinal pigmented epithelium, respectively. We focused on transcription factors involved in vision. Among the six candidates suitable for functional analysis, we selected Otx2S, a novel variant of the Otx2 gene with a deletion within the homeodomain sequence. Otx2S is expressed in both the neural retina and retinal pigmented epithelium, and encodes a protein that is targeted to the nucleus. OTX2S exerts transdominant activity on the tyrosinase promoter when tested in the physiological environment of primary RPE cells. By overexpressing OTX2S in primary RPE cells using an adeno associated viral vector, we identified 10 genes whose expression is positively regulated by OTX2S. We find that OTX2S is able to bind to the chromatin at the promoter of the retinal dehydrogenase 10 (RDH10) gene.
Asunto(s)
Empalme Alternativo , Factores de Transcripción Otx/genética , Retina/citología , Epitelio Pigmentado de la Retina/citología , Oxidorreductasas de Alcohol/genética , Secuencia de Aminoácidos , Animales , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , ADN Complementario/genética , Biblioteca de Genes , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Monofenol Monooxigenasa/genética , Factores de Transcripción Otx/análisis , Factores de Transcripción Otx/metabolismo , Regiones Promotoras Genéticas , Isoformas de Proteínas/análisis , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , Ratas , Retina/metabolismo , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
OBJECTIVE: To investigate the ability of 28 blind subjects implanted with a 60-electrode Argus II (Second Sight Medical Products Inc) retinal prosthesis system to detect the direction of a moving object. METHODS: Blind subjects (bare light perception or worse in both eyes) with retinitis pigmentosa were implanted with the Argus II prosthesis as part of a phase 1/2 feasibility study at multiple clinical sites worldwide. The experiment measured their ability to detect the direction of motion of a high-contrast moving bar on a flatscreen monitor in 3 conditions: with the prosthesis system on and a 1-to-1 mapping of spatial information, with the system off, and with the system on but with randomly scrambled spatial information. RESULTS: Fifteen subjects (54%) were able to perform the task significantly better with their prosthesis system than they were with their residual vision, 2 subjects had significantly better performance with their residual vision, and no difference was found for 11 subjects. Of the 15 better-performing subjects, 11 were available for follow-up testing, and 10 of them had significantly better performance with normal rather than with scrambled spatial information. CONCLUSIONS: This work demonstrates that blind subjects implanted with the Argus II retinal prosthesis were able to perform a motion detection task they could not do with their native vision, confirming that electrical stimulation of the retina provides spatial information from synchronized activation of multiple electrodes. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00407602
Asunto(s)
Ceguera/fisiopatología , Terapia por Estimulación Eléctrica/instrumentación , Percepción de Movimiento/fisiología , Trastornos de la Percepción/fisiopatología , Retina/fisiopatología , Retinitis Pigmentosa/fisiopatología , Prótesis Visuales , Adulto , Anciano , Ceguera/cirugía , Electrodos Implantados , Estudios de Factibilidad , Femenino , Humanos , Masculino , Microelectrodos , Persona de Mediana Edad , Trastornos de la Percepción/rehabilitación , Implantación de Prótesis , Retinitis Pigmentosa/cirugía , Umbral Sensorial , Resultado del TratamientoRESUMEN
Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.
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Fármacos Neuroprotectores/farmacología , Células Ganglionares de la Retina/efectos de los fármacos , Taurina/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ratones , Ratones Endogámicos DBA , N-Metilaspartato/farmacología , Células Fotorreceptoras de Vertebrados/metabolismo , Células Ganglionares de la Retina/citologíaRESUMEN
PURPOSE: This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration. DESIGN: Single-arm, prospective, multicenter clinical trial. PARTICIPANTS: Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years. METHODS: The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface. MAIN OUTCOME MEASURES: The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks. RESULTS: Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications. CONCLUSIONS: The long-term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it.
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Ceguera/rehabilitación , Terapia por Estimulación Eléctrica/instrumentación , Electrodos Implantados , Degeneración Retiniana/rehabilitación , Agudeza Visual/fisiología , Prótesis Visuales , Adulto , Anciano , Ceguera/fisiopatología , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Microelectrodos , Persona de Mediana Edad , Estudios Prospectivos , Retina/cirugía , Degeneración Retiniana/fisiopatología , Esclerótica/cirugía , Esclerostomía , Umbral Sensorial , Tomografía de Coherencia Óptica , Percepción Visual/fisiología , VitrectomíaRESUMEN
Lateral interactions at the first retinal synapse have been initially proposed to involve GABA by transporter-mediated release from horizontal cells, onto GABA(A) receptors expressed on cone photoreceptor terminals and/or bipolar cell dendrites. However, in the mammalian retina, horizontal cells do not seem to contain GABA systematically or to express membrane GABA transporters. We here report that mouse retinal horizontal cells express GAD65 and/or GAD67 mRNA, and were weakly but consistently immunostained for GAD65/67. While GABA was readily detected after intracardiac perfusion, it was lost during classical preparation for histology or electrophysiology. It could not be restored by incubation in a GABA-containing medium, confirming the absence of membrane GABA transporters in these cells. However, GABA was synthesized de novo from glutamate or glutamine, upon addition of pyridoxal 5'-phosphate, a cofactor of GAD65/67. Mouse horizontal cells are thus atypical GABAergic neurons, with no functional GABA uptake, but a glutamate and/or glutamine transport system allowing GABA synthesis, probably depending physiologically from glutamate released by photoreceptors. Our results suggest that the role of GABA in lateral inhibition may have been underestimated, at least in mammals, and that tissue pre-incubation with glutamine and pyridoxal 5'-phosphate should yield a more precise estimate of outer retinal processing.
Asunto(s)
Retina/metabolismo , Células Horizontales de la Retina/metabolismo , Ácido gamma-Aminobutírico/fisiología , Animales , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Ácido Glutámico/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural/fisiología , Vías Nerviosas/citología , Vías Nerviosas/metabolismo , Fosfato de Piridoxal/metabolismo , ARN Mensajero/metabolismo , Retina/citología , Retina/enzimología , Células Horizontales de la Retina/citología , Transmisión Sináptica/fisiología , Visión Ocular/fisiología , Ácido gamma-Aminobutírico/biosíntesisRESUMEN
OBJECTIVE: To determine the protective action of hyaluronidase on peribulbar anesthesia-related diplopia in patients undergoing cataract surgery. DESIGN: Single-center observational case series. PARTICIPANTS: All patients undergoing elective phacoemulsification and intraocular lens implantation under peribulbar anesthesia between February 2001 and January 2003. METHODS: We compared the incidence of postoperative diplopia between 2 periods--February 2001 to January 2002 (P1) and February 2002 to January 2003 (P2)--which differed by the presence (P1) or absence (P2) of hyaluronidase in the anesthetic solution. MAIN OUTCOME MEASURES: All patients were examined on the first and fifth postoperative days during both periods. When diplopia was diagnosed, we recorded the characteristics of the patient, peribulbar anesthesia, and diplopia (orthoptic examination, and magnetic resonance imaging in some cases). RESULTS: Seven thousand two hundred five patients were studied. During P1, 3582 patients received peribulbar anesthesia, and no cases of diplopia occurred. During P2, 3623 patients received peribulbar anesthesia, and 27 cases of diplopia occurred (incidence, 0.75%; P = 0.0002 vs. P1). Diplopia involved the inferior rectus (40%) and the external rectus (37%) muscles. Diplopia was persistent in 54% of the cases. CONCLUSIONS: Peribulbar anesthesia-related diplopia was significantly more frequent when hyaluronidase was not added to the anesthetic solution.
Asunto(s)
Anestesia Local/métodos , Anestésicos Combinados/administración & dosificación , Anestésicos Locales/administración & dosificación , Diplopía/prevención & control , Hialuronoglucosaminidasa/fisiología , Implantación de Lentes Intraoculares , Facoemulsificación , Anciano , Anciano de 80 o más Años , Bupivacaína/administración & dosificación , Diplopía/fisiopatología , Femenino , Humanos , Lidocaína/administración & dosificación , Masculino , Persona de Mediana Edad , Músculos Oculomotores/fisiopatología , ÓrbitaRESUMEN
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerative diseases, characterized by the progressive death of rod and cone photoreceptors. A tremendous genetic heterogeneity is associated with the RP phenotype. Most mutations affect rods selectively and, through an unknown pathway, cause the rod cells to die by apoptosis. Cones, on the other hand, are seldom directly affected by the identified mutations, and yet, in many cases, they degenerate secondarily to rods, which accounts for loss of central vision and complete blindness. Many animal models of RP are available and have led to a better understanding of the disease and to the development of therapeutic strategies aimed at curing the specific genetic disorder (gene therapy), slowing down or even stopping the process of photoreceptor degeneration (growth factors or calcium blockers applications, vitamin supplementation), preserving the cones implicated in the central visual function (identification of endogenous cone viability factors) or even replacing the lost cells (transplantation, use of stem or precursor cells). Still, many obstacles will need to be overcome before most of these strategies can be applied to humans. In this review, we describe the different therapeutic strategies being studied worldwide and report the latest results in this field.