RESUMEN
In everyday practice, intravitreal therapy in an "as needed" regimen (pro re nata, PRN) is less predictable and requires more visits (monitoring and injections taken together) with poorer functional results than with the treat and extend (T&E) regimen. Current literature supports the benefit of a switch. However, practical advice is still missing. This article provides "best practice" recommendations for private practice or smaller institutions for the change from PRN to T&E. The requirements are organisational adjustments, staff training, definition of the scenario triggering the switch (A - functional or anatomical deterioration; B - general switch at a predefined date), counselling of the patients, defining benchmarks for the follow-up of the switch and preparing for higher capacity utilisation during the transition (shorter treatment intervals during the switching phase). Guidance is provided for each phase (a, preparation; b, transition; and c, follow-up).
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Retinopatía Diabética/tratamiento farmacológico , Inyecciones Intravítreas , Edema Macular/tratamiento farmacológico , Ranibizumab/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Oclusión de la Vena Retiniana/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Degeneración Macular Húmeda/tratamiento farmacológico , Esquema de Medicación , Humanos , Práctica Privada , Garantía de la Calidad de Atención de Salud , Ranibizumab/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: In severe forms of ocular surface disorders keratoprostheses provide the ultimate possibility to restore vision. They are made of an optical cylinder integrated with a supporting biocompatible or biological haptic. CASE REPORT: We report on two patients with different types of keratoprostheses. An 88-year-old woman with ocular pemphigoid received in 1970 a bilateral osteo-odonto-keratoprosthesis (Strampelli). A 59-year-old man with refractory corneal ulcer after corneal grafting received in 2003 a keratoprosthesis with supporting Dacron tissue (Pintucci). RESULTS: The course 35 years after implantation of the osteo-odonto-keratoprosthesis was uneventful. Histologically there were no signs of loosening, rejection or infection. The autologous dentin, which was used for the fixation, was still present. The eye with the Dacron fixated prosthesis (Pintucci) had to be enucleated due to a loosening with endophthalmitis one and a half year after implantation. CONCLUSIONS: Keratoprostheses with autologous fixation often show good long-term results. On the other hand, prostheses with synthetic material are more often complicated by dislocation and inflammation.
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Órganos Artificiales , Materiales Biocompatibles , Enfermedades de la Córnea/cirugía , Trasplante de Córnea/instrumentación , Prótesis e Implantes , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Diseño de Prótesis , Resultado del TratamientoRESUMEN
PURPOSE: To describe conjunctival histopathologic alterations induced by excessive chronic astringent use. METHODS: Report of a case with clinical picture, epicutane test results, histologic workup of conjunctival biopsy using conventional staining, and immunohistochemical markers. RESULTS: A 45-year-old man using a phenylephrine preparation hourly for years presented with grotesque eye redness, fornix shortening, and scarring of puncta lacrimalia. Direct and indirect immunofluorescence were negative for ocular pemphigoid. Histology revealed signs of chronic inflammation and neovascularization in the conjunctiva. Symptoms resolved after cessation of therapy. CONCLUSIONS: Chronic abuse of decongestant eyedrops can produce a clinical picture resembling an ocular pemphigoid. Histology suggests that late onset immunoreaction and chronic vasoconstriction cause chronic inflammation and neovascularization, respectively.
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Conjuntivitis/diagnóstico , Azul de Metileno/efectos adversos , Soluciones Oftálmicas/efectos adversos , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Fenilefrina/efectos adversos , Vasoconstrictores/efectos adversos , Conjuntivitis/inducido químicamente , Diagnóstico Diferencial , Combinación de Medicamentos , Humanos , Masculino , Azul de Metileno/administración & dosificación , Persona de Mediana Edad , Medicamentos sin Prescripción , Soluciones Oftálmicas/administración & dosificación , Penfigoide Benigno de la Membrana Mucosa/inducido químicamente , Fenilefrina/administración & dosificación , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/etiología , Vasoconstrictores/administración & dosificaciónRESUMEN
Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.
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Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , VIH-1/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Interleucina-10/genética , Uveítis/terapia , Animales , Femenino , Expresión Génica , Vectores Genéticos/genética , Humanos , Inyecciones , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Lipopolisacáridos , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Transducción Genética/métodos , Transgenes , Úvea/inmunología , Uveítis/inmunologíaRESUMEN
AIMS: To characterize genotype, phenotype, and age-related penetrance in a Swiss pedigree with juvenile open-angle glaucoma (JOAG). METHODS: In a large Swiss family with history of glaucoma and 82 living members of four generations, we conducted molecular analysis and a detailed phenotype characterization in 52 family members. Mutation analysis was carried out using single-strand conformation polymorphism and DNA sequence analyses of the suspected candidate gene, myocilin (MYOC). RESULTS: We detected a Gly367Arg mutation in the MYOC gene of 13 family members. Nine of them (69.2%) had glaucoma: mean IOP 35.3 mm Hg, range 24-50 mm Hg; mean age at diagnosis 34.9 years, range 28-51 years. Two mutation carriers were glaucoma suspects, one (age 15) was unaffected, and one (age 16) not available for clinical examinations. Age-related glaucoma penetrance was 50% at 30 and 78% at 40. Untreated IOP resulted in rapid disease progression, whereas good IOP control, usually only by means of filtration surgery, could stabilize the disease. None of the wild-type members had glaucoma. CONCLUSIONS: This Swiss family is the largest reported Gly367Arg pedigree to date. The exact genotype and phenotype characterization allowed a reliable risk and prognosis assessment and targeted eye-care planning for the family. The study demonstrates the importance of genetic investigations in glaucoma families, carrying the potential of long-term socio-economic benefits.
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Proteínas del Citoesqueleto/genética , Proteínas del Ojo/genética , Glaucoma de Ángulo Abierto/genética , Glicoproteínas/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Pronóstico , Adulto JovenRESUMEN
INTRODUCTION: Adult patients with acute myeloid leukemia (AML) frequently present retinal abnormalities. We tried to find a relationship between fundus lesions and treatment responsiveness, prognosis, and several hematologic parameters. PATIENTS AND METHODS: We examined 178 adult patients with newly diagnosed AML. All patients were assigned to two groups regarding retinal parameters (1 or 2) and age (A or B). Group 1 included cases with retinal dysfunction classified as retinal abnormalities with impaired visual acuity; group 2 included cases with no or only minor retinal changes. Subgroup A included patients younger than 60 years (n=97), subgroup B patients older than 60 years (n=81). RESULTS: In this study, higher age and a lower Hb value were associated with retinal findings (group 1). Among the younger patients (subgroup A), 78% of those with complete remission had no retinal findings (group 2) compared to 18% of the nonresponders. In the elderly population (subgroup B), this ratio was 58% versus 19%. In the younger patients (subgroup A), the mean overall survival was 50 months if they had no retinal abnormalities (group 2) and 7 months in the case of retinal changes (group 1). In the older population (subgroup B), the ratio was 15 months versus 3 months, respectively. CONCLUSION: Retinal abnormalities in AML are generally associated with higher age, although they correlate with a shorter survival in both age groups. This association is stronger in younger patients.
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Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/terapia , Enfermedades de la Retina/epidemiología , Adulto , Anciano , Envejecimiento/fisiología , Humanos , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: The low diagnostic yield of vitrectomy specimen analysis in chronic idiopathic uveitis (CIU) has been related to the complex nature of the underlying disease and to methodologic and tissue immanent factors in older studies. In an attempt to evaluate the impact of recently acquired analytic methods, the authors assessed the current diagnostic yield in CIU. METHODS: Retrospective analysis of consecutive vitrectomy specimens from patients with chronic endogenous uveitis (n = 56) in whom extensive systemic workup had not revealed a specific diagnosis (idiopathic) and medical treatment had not resulted in a satisfying clinical situation. Patients with acute postoperative endophthalmitis served a basis for methodologic comparison (Group 2; n = 21). RESULTS: In CIU, a specific diagnosis provided in 17.9% and a specific diagnosis excluded in 21.4%. In 60.7% the laboratory investigations were inconclusive. In postoperative endophthalmitis, microbiological culture established the infectious agent in 47.6%. In six of eight randomly selected cases, eubacterial PCR identified bacterial DNA confirming the culture results in three, remaining negative in two with a positive culture and being positive in three no growth specimens. A double negative result never occurred, suggesting a very high detection rate, when both tests were applied. CONCLUSIONS: The diagnostic yield of vitrectomy specimen analysis has not been improved by currently routinely applied methods in recent years in contrast to the significantly improved sensitivity of combined standardized culture and PCR analysis in endophthalmitis. Consequently, the low diagnostic yield in CIU has to be attributed to insufficient understanding of the underlying pathophysiologic mechanisms.
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Infecciones del Ojo/diagnóstico , Uveítis/diagnóstico , Vitrectomía , Cuerpo Vítreo/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Enfermedad Crónica , ADN Bacteriano/análisis , ADN Protozoario/análisis , ADN Viral/análisis , Infecciones del Ojo/microbiología , Infecciones del Ojo/parasitología , Infecciones del Ojo/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Uveítis/microbiología , Uveítis/parasitología , Uveítis/virología , Cuerpo Vítreo/microbiología , Cuerpo Vítreo/parasitología , Cuerpo Vítreo/virologíaRESUMEN
PURPOSE: This study evaluated the long-term effect of pars plana vitrectomy (PPV) in children and adolescents with chronic uveitis on visual function, anatomical outcome, and the requirement of systemic treatment. Further, predictive preoperative factors associated with a beneficial visual outcome were assessed. METHODS: Retrospective review of 29 eyes of 23 consecutive paediatric and juvenile patients below 20 years of age with chronic uveitis who underwent a PPV for visually significant opacities in 25 eyes, vitreous haemorrhage in three eyes, and retinal detachment in one eye. The clinical diagnosis was chronic intermediate uveitis in 22 eyes and retinal vasculitis of different origin in seven eyes. RESULTS: LogMAR visual acuity improved from an average of 0.91 to 0.33 (P<0.001). Cystoid macular oedema (CME) was significantly reduced in eight of 10 eyes postoperatively (P=0.021). In the multiple regression analysis, a low preoperative logMAR visual acuity and the presence of a CME had a negative influence on the final logMAR visual acuity. Furthermore, the appearance of chronic uveitis relapses was significantly reduced from 15 eyes before to seven eyes after surgery (P=0.042). CONCLUSIONS: PPV has a beneficial effect on the course and the complications of chronic uveitis in paediatric and juvenile patients with respect to the anatomical and visual outcome. Preoperative logMAR visual acuity and clinically significant CME were the most accurate predictors for the functional outcome.
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Uveítis Intermedia/cirugía , Vitrectomía , Adolescente , Adulto , Extracción de Catarata , Niño , Enfermedad Crónica , Femenino , Humanos , Edema Macular/cirugía , Masculino , Pronóstico , Recurrencia , Análisis de Regresión , Estudios Retrospectivos , Resultado del Tratamiento , Uveítis Intermedia/fisiopatología , Agudeza Visual , Vitrectomía/efectos adversosRESUMEN
BACKGROUND: In hereditary retinal degeneration, microglia cells become activated, migrate through the outer nuclear layer (ONL) and accumulate in the subretinal space. Although this inflammatory process is not likely to be responsible for the onset of photoreceptor apoptosis, cytotoxic substances secreted by activated microglia could potentially accelerate and perpetuate the degenerative process. Anti-inflammatory drugs have been shown to modulate the microglia response in neurodegenerative disorders and potentially ameliorate the disease progression in various animal model systems. In this study we wanted to test the impact of the most commonly used anti-inflammatory drugs (acetylsalicylate and prednisolone) on the microglia activation pattern, the rate of caspase-3-dependent photoreceptor apoptosis and the course of the degeneration in the retinal degeneration slow (rds) mouse retina. METHODS: 169 pigmented rds mice and 30 CBA wild-type mice were used for this study. The treatment groups were injected daily with either acetylsalicylate (200 mg/kg) or prednisolone (2 mg/kg) i.p. from day 0 up to 3 months. Animals were sacrificed at days 10, 14, 16, 18, 20, 30, 40, 60 and 90. Cryoprotected frozen sections were immunostained with F4/80 and cleaved caspase-3 antibodies. The main outcome measures were the total microglia count in the subretinal space, the total cleaved caspase-3-positive cells in the ONL and the averaged number of photoreceptor rows in the midperipheral retina. RESULTS: Neither acetylsalicylate nor prednisolone reduced subretinal microglia accumulation in the rds mouse degeneration model. Moreover, they aggravated migration and accumulation in the early time course. The apoptotic cascade started earlier and was more pronounced in both treatment groups compared to the control group. The pace of retinal degeneration was not reduced in the treatment groups compared to the untreated control. In contrast, acetylsalicylate did significantly accelerate the photoreceptor cell degeneration in comparison to the prednisolone (p < 0.001) and to the control group (p < 0.001). CONCLUSIONS: Acetylsalicylate and prednisolone do not decrease the microglia response in the rds mouse and are not neuroprotective. More research is needed to clarify the molecular mechanisms which lead to photoreceptor cell death and to elucidate the complex role of microglia in inherited retinal degeneration.
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Antiinflamatorios no Esteroideos/farmacología , Glucocorticoides/farmacología , Microglía/efectos de los fármacos , Degeneración Retiniana/metabolismo , Animales , Antígenos de Diferenciación/metabolismo , Apoptosis/efectos de los fármacos , Aspirina/farmacología , Caspasa 3 , Caspasas/metabolismo , Recuento de Células , Movimiento Celular/efectos de los fármacos , Técnicas para Inmunoenzimas , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos CBA , Ratones Mutantes , Microglía/patología , Microscopía Confocal , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patología , Prednisolona/farmacología , Degeneración Retiniana/patologíaRESUMEN
BACKGROUND: Incomplete removal of the viscoelastic material during cataract surgery may lead to the early postoperative capsular block syndrome. In this retrospective case series, postoperative capsular bag distention after implantation of a foldable acrylic lens is reported and the sequelae are analyzed. PATIENTS AND METHOD: In a retrospective case series, 10 eyes of altogether 1674 eyes that underwent cataract surgery in the years 2001 and 2002 were identified with early postoperative capsular block syndrome. All 10 eyes had cataract removal with continuous curvilinear capsulorhexis, phacoemulsification and a foldable acrylic lens was placed in the capsular bag. In 4 of 10 eyes cataract extraction was combined with trabeculectomy. All patients had posterior Nd:YAG capsulotomy. Refraction was performed before and after capsulotomy. RESULTS: Postoperative examination showed capsular bag distention in all eyes. The mean postoperative spherical equivalent was -3.9 +/- 1.6 Dpt. As the target refraction was -1.2 +/- 1.0 Dpt there was an average of -2.7 +/- 1.4 Dpt of induced myopia. A mild increase in postoperative anterior chamber inflammation was noted only in 1 patient and shallowing of the anterior chamber was observed in another patient. Posterior Nd:YAG capsulotomy was performed 4.5 +/- 4.3 months after surgery. The mean refractive shift after Nd:YAG capsulotomy was 1.9 +/- 1.9 Dpt. CONCLUSIONS: Unexpected postoperative myopic correction was the main manifestation of capsular block syndrome in this series. Intraoperative use of miotics prohibiting optical control of complete viscoelastic removal may explain the high proportion of combined procedures. In the case of unexpected postoperative myopia the position of the intraocular lens within the bag should be checked and attention should be paid to possibly incompletely removed viscoelastic material.
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Acrilatos , Capsulorrexis , Edema/etiología , Cápsula del Cristalino , Lentes Intraoculares , Complicaciones Posoperatorias/etiología , Trabeculectomía , Edema/cirugía , Estudios de Seguimiento , Humanos , Terapia por Láser , Cápsula del Cristalino/cirugía , Facoemulsificación , Complicaciones Posoperatorias/cirugía , Refracción Ocular , Reoperación , Estudios RetrospectivosRESUMEN
BACKGROUND: While cataract surgery is nowadays performed routinely as an outpatient procedure, performing filtering glaucoma surgery under these conditions remains questionable due to the more demanding perioperative management. PATIENTS AND METHODS: Outpatient filtering glaucoma surgery (trabeculectomy and combined phakoemulsification and trabeculectomy (phakotrab)) is performed at the Ophthalmology Department of Kantonsspital Winterthur when requested by the patient. This paper provides a retrospective review of all outpatient filtering glaucoma procedures performed in the last three and a half years. RESULTS: Forty-six filtering procedures (21 trabeculectomies and 25 phakotrabs) were performed in 45 eyes of 40 patients (50 - 84 years) as outpatient procedures. Mitomycin C was administered in 16/21 trabeculectomies and in 7/25 combined procedures. In the trabeculectomy group, intraocular pressure (IOP) was surgically lowered from 23.3 +/- 7.2 mm Hg (under 2.4 +/- 0.8 IOP-lowering medications) to 12.7 +/- 3.5 mm Hg (20/21 patients without medication). In the combined group, IOP was lowered from 20.8 +/- 6.3 (under 2.0 +/- 0.7 medications) to 13.7 +/- 2.7 mm Hg (only 5/25 patients still requiring IOP-lowering medications). In the latter group, the best corrected visual acuity was below 20/40 only in 2 eyes due to advanced glaucomatous optic atrophy. One patient developed relative intraocular hypotony (IOP 6 mm Hg), one patient required needling + 5-fluorouracil injection and one patient required surgical revision of the trabeculectomy after 14 months. DISCUSSION: Adequate patient selection and refined surgical technique (tight wound closure and releasable sutures or argon laser suturolysis) allow performing filtering glaucoma surgery as an outpatient procedure. Extended post-operative care during the first 2 months is the key for IOP-lowering success.
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Procedimientos Quirúrgicos Ambulatorios , Facoemulsificación , Trabeculectomía , Anciano , Anciano de 80 o más Años , Terapia Combinada , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Presión Intraocular/fisiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatología , Complicaciones Posoperatorias/cirugía , Reoperación , Técnicas de Sutura , Agudeza Visual/fisiologíaRESUMEN
More than 60 genes responsible for human retinal dystrophies have already been identified. Most of them are either expressed in the photoreceptor or in the retinal pigment epithelium (RPE). Therefore these cells have become the target of new therapeutical strategies on a molecular level. The most promising approach at present is somatic gene therapy, which has been developed over the last years and the principle has now been established in animal models. For gene therapy of inherited retinal degeneration, as for gene therapy in general, gene transfer has to be proven to be not only efficient but also safe. This has recently been achieved using the adeno-associated virus (AAV) as a vector to express a therapeutic gene within the photoreceptor cell. It could be demonstrated in mouse and dog models of retinal degeneration that expression of the therapeutic transgene leads to anatomical and functional restitution of degenerating photoreceptors. A significant immune response to AAV has not been detected so far. In this paper the recent success of gene therapy of retinal degeneration in animal models is reviewed.
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Terapia Genética/métodos , Degeneración Retiniana/terapia , Adenoviridae/genética , Animales , Gatos , Modelos Animales de Enfermedad , Perros , Técnicas de Transferencia de Gen , Humanos , Ratones , Células Fotorreceptoras/patología , Epitelio Pigmentado Ocular/patología , Degeneración Retiniana/genética , Degeneración Retiniana/patología , PorcinosRESUMEN
Using confocal microscopy we have examined in detail the temporal and spatial pattern of green fluorescent protein expression following sub-retinal injection of recombinant adeno-associated virus (rAAV) in the mouse and have determined the effect of viral titre on the number and type of cells transduced. Our results suggest that some transgene expression occurs as early as three days after injection, and that transgene expression occurs beyond the area of retinal detachment. Vector titre appears to have a substantial effect on both transduction efficiency and the speed of onset of photoreceptor cell transduction. Our data suggests that we have not yet reached the limits of photoreceptor transduction efficiency using AAV vectors. An increase in titre could still lead to an improved transduction efficiency and faster onset of photoreceptor transduction. We failed to detect transfected cones even in areas where nearly 100% of the rods were transduced, but we found efficient and sustained RPE transduction.
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Terapia Genética/métodos , Modelos Animales , Retina/metabolismo , Retinitis Pigmentosa/terapia , Transfección/métodos , Transgenes , Animales , Citomegalovirus/genética , Dependovirus/genética , Expresión Génica , Vectores Genéticos/administración & dosificación , Proteínas Fluorescentes Verdes , Inyecciones , Proteínas Luminiscentes/genética , Ratones , Ratones Endogámicos CBA , Epitelio Pigmentado Ocular/metabolismo , Distribución AleatoriaRESUMEN
The retinal degeneration slow (rds or Prph2(Rd2/Rd2)) mouse, a model of recessive retinitis pigmentosa, lacks a functional gene encoding peripherin 2. This membrane glycoprotein is required for the formation of photoreceptor outer segment discs. The striking feature of the rds mouse is the complete failure to develop outer segments. We have previously examined the short-term effect of gene replacement therapy using an adeno-associated (AAV) vector and demonstrated induction of outer segments and improvement of photoreceptor function. Here we have extended our analysis and have demonstrated that the potential for ultrastructural improvement is dependent upon the age at which animals are treated, but the effect of a single injection on photoreceptor ultrastructure may be long-term. However, there was no significant effect on photoreceptor cell loss, irrespective of the date of administration, despite the improvements in morphology and function. Our investigation excluded procedure-related damage, vector toxicity and immune responses as major factors which might counteract the benefits of photoreceptor restoration, but suggested that transgene over-expression is of significance. These findings suggest that successful gene therapy in patients with photoreceptor defects may ultimately depend upon intervention in early stages of disease and upon accurate control of transgene expression.
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Terapia Genética , Proteínas de Filamentos Intermediarios/genética , Glicoproteínas de Membrana , Proteínas del Tejido Nervioso/genética , Degeneración Retiniana/terapia , Animales , Animales Recién Nacidos , Dependovirus/genética , Modelos Animales de Enfermedad , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes , Humanos , Proteínas de Filamentos Intermediarios/administración & dosificación , Proteínas Luminiscentes/administración & dosificación , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Endogámicos CBA , Ratones Mutantes , Microscopía Electrónica , Microscopía Electrónica de Rastreo , Proteínas del Tejido Nervioso/administración & dosificación , Periferinas , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/patología , Epitelio Pigmentado Ocular/metabolismo , Epitelio Pigmentado Ocular/patología , Epitelio Pigmentado Ocular/ultraestructura , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Retina/metabolismo , Retina/patología , Retina/ultraestructura , Degeneración Retiniana/genética , Retinitis Pigmentosa/genética , Factores de Tiempo , TransfecciónRESUMEN
The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein, peripherin-2 (also known as peripherin/rds), which is inserted into the rims of photoreceptor outer segment discs in a complex with rom-1 (ref. 2). The complex is necessary for the stabilization of the discs, which are renewed constantly throughout life, and which contain the visual pigments necessary for photon capture. Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy. A common feature of these diseases is the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or Prph2 Rd2/Rd2) mouse, which is homozygous for a null mutation in Prph2. It is characterized by a complete failure to develop photoreceptor discs and outer segments, downregulation of rhodopsin and apoptotic loss of photoreceptor cells. The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months. Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments. Moreover, the re-establishment of the structural integrity of the photoreceptor layer also results in electrophysiological correction. These studies demonstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer.