RESUMO
PURPOSE: Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities. METHODS: Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls. RESULTS: Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities. CONCLUSIONS: The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.
Assuntos
Degeneração Macular , Polimorfismo de Nucleotídeo Único , Humanos , Fator I do Complemento/genética , Genótipo , Acessibilidade aos Serviços de Saúde , Degeneração Macular/epidemiologia , Degeneração Macular/genética , Degeneração Macular/metabolismo , PrevalênciaRESUMO
Purpose: Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous showing progressive retinal cell death which results in vision loss. IRDs include a wide spectrum of disorders, such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and Stargardt disease (STGD1). Methods: In this study, we performed targeted next-generation sequencing based on molecular inversion probes (MIPs) that allowed the sequence analysis of 108 IRD-associated genes in 50 Iranian IRD probands. Results: The sequencing and variant filtering led to the identification of putative pathogenic variants in 36 out of 50 (72%) probands. Among 36 unique variants, we identified 20 novel variants in 15 genes. Four out of 36 probands carry compound heterozygous variants, and 32 probands carry homozygous variants. Conclusions: Employing a cost-effective targeted next-generation sequencing procedure, we identified the genetic causes of different retinal disorders in the majority of Iranian families in this study.
Assuntos
Distrofias de Cones e Bastonetes/genética , Proteínas do Olho/genética , Amaurose Congênita de Leber/genética , Degeneração Macular/congênito , Mutação , Retinose Pigmentar/genética , Adolescente , Adulto , Criança , Distrofias de Cones e Bastonetes/metabolismo , Distrofias de Cones e Bastonetes/patologia , Proteínas do Olho/metabolismo , Feminino , Expressão Gênica , Estudos de Associação Genética , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/economia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Homozigoto , Humanos , Irã (Geográfico) , Amaurose Congênita de Leber/metabolismo , Amaurose Congênita de Leber/patologia , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Linhagem , Fenótipo , Retina/metabolismo , Retina/patologia , Retinose Pigmentar/congênito , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Doença de StargardtRESUMO
Neovascular age-related macular degeneration (AMD) is treated with anti-VEGF intravitreal injections, which can cause geographic atrophy, infection, and retinal fibrosis. To minimize these toxicities, we developed a nanoparticle delivery system for recombinant Flt23k intraceptor plasmid (RGD.Flt23k.NP) to suppress VEGF intracellularly within choroidal neovascular (CNV) lesions in a laser-induced CNV mouse model through intravenous administration. In the current study, we examined the efficacy and safety of RGD.Flt23k.NP in mice. The effect of various doses was determined using fluorescein angiography and optical coherence tomography to evaluate CNV leakage and volume. Efficacy was determined by the rate of inhibition of CNV volume at 2 weeks post-treatment. RGD.Flt23k.NP had peak efficacy at a dose range of 30-60 µg pFlt23k/mouse. Using the lower dose (30 µg pFlt23k/mouse), RGD.Flt23k.NP safety was determined both in single-dose groups and in repeat-dose (three times) groups by measuring body weight, organ weight, hemoglobin levels, complement C3 levels, and histological changes in vital organs. Neither toxicity nor inflammation from RGD.Flt23k.NP was detected. No side effect was detected on visual function. Thus, systemic RGD.Flt23k.NP may be an alternative to standard intravitreal anti-VEGF therapy for the treatment of neovascular AMD.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neovascularização de Coroide/terapia , Portadores de Fármacos , Degeneração Macular/terapia , Plasmídeos/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Corioide/irrigação sanguínea , Corioide/metabolismo , Corioide/patologia , Neovascularização de Coroide/genética , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Complemento C3/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Regulação da Expressão Gênica , Hemoglobinas/metabolismo , Humanos , Injeções Intravenosas , Injeções Intravítreas , Lasers , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Plasmídeos/química , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: To determine the changes in the anterior chamber flare and central macular thickness (CMT) under topical antiglaucomatous therapy. METHODS: This study included 121 eyes of 73 patients and 36 eyes of 18 controls. Glaucoma patients were divided into 3 groups (timolol maleate, latanoprost, and bimatoprost). Control eyes did not receive any medications. Flare and CMT measurements were performed at baseline and follow-up visits (15th day, and 1st, 3rd, 6th, and 12th month). RESULTS: Statistically significant increases were detected in the flare values in the bimatoprost and latanoprost groups (P < 0.001, P = 0.011, respectively). Significant increases were also found in CMT values measured in these 2 groups (P < 0.001, P = 0.002, respectively). However, increased flare and CMT values were not clinically manifested as uveitis and macular edema. Flare and CMT values did not change statistically in the timolol maleate and control groups. CONCLUSIONS: Although the use of prostaglandin (PG) analogs was found to be associated with increased flare and CMT, these increases were not clinically significant. PG analog monotherapy may be safely and effectively used in the treatment of glaucoma.
Assuntos
Câmara Anterior/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Bimatoprost/farmacologia , Degeneração Macular/tratamento farmacológico , Prostaglandinas F Sintéticas/farmacologia , Timolol/farmacologia , Administração Tópica , Câmara Anterior/patologia , Anti-Hipertensivos/administração & dosagem , Bimatoprost/administração & dosagem , Feminino , Glaucoma/diagnóstico , Glaucoma/tratamento farmacológico , Humanos , Latanoprosta , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade , Prostaglandinas F Sintéticas/administração & dosagem , Timolol/administração & dosagemRESUMO
Intravitreal injection of ranibizumab, a VEGF inhibitor, is an option for patients with neovascular age-related macular degeneration (AMD). Because of its lower price, bevacizumab, a VEGF inhibitor closely related to ranibizumab and marketed for the treatment of various malignancies, is sometimes used off label for intravitreal injection in AMD. In 2011, the harm-benefit balance of bevacizumab in patients with AMD was uncertain. New data are available in 2015. In six randomised trials including a total of about 3200 patients, funded independently of the pharmaceutical industry, bevacizumab (1.25 mg per dose) was about as effective as ranibizumab (0.5 mg per injection): visual acuity stabilised or improved in 90% to 95% of patients after one to two years of treatment. During these trials, bevacizumab did not reduce the number of injections needed, as compared with ranibizumab. These trials confirmed the known adverse effect profile of bevacizumab, which is similar to that of ranibizumab and includes serious ocular as well as extraocular adverse effects, in particular cardiac disorders. Serious extraocular adverse events, especially gastrointestinal disorders, were more frequent with bevacizumab than with ranibizumab at one year (18% versus 14%). In early 2015, there are no bevacizumab products suitable for intravitreal injection. In 2011, cases of sight-threatening infectious endophthalmitis were reported in the United States, following contamination during syringe preparation for intravitreal administration. In practice, when treatment with a VEGF inhibitor is considered for AMD, it is more prudent to choose ranibizumab, despite its currently unacceptable price.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/economia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/economia , Degeneração Macular/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Análise Custo-Benefício , Humanos , Injeções Intravítreas , Degeneração Macular/metabolismo , Uso Off-Label , Ensaios Clínicos Controlados Aleatórios como Assunto , Ranibizumab , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
PURPOSE: To determine the effects of chromosome 1 genotype and cigarette smoking on levels of complement activation and inflammation in the human macula. METHODS: Donor macular tissue was stratified into three groups by diplotype at the AMD-associated CFH-to-F13B locus: homozygous "risk" (n = 9, 56-78 years), homozygous neutral (n = 2, 64-79 years), and homozygous "protective" (n = 6, 61-78 years) diplotype. Importantly, all donors were homozygous nonrisk at the ARMS2/HTRA1 locus, so that purely chromosome 1-directed pathways were examined. Immunohistochemistry was performed by using 14 antibodies, mostly against markers of complement and inflammation, followed by confocal microscopy and immunofluorescence quantification (all masked to donor status). RESULTS: Donors homozygous risk at CFH-to-F13B exhibited significantly higher levels of terminal complement complex (TCC) in macular Bruch's membrane (BM; P = 0.03), choriocapillaris (CC; P = 0.04), and choriocapillaris intercapillary septa (CC IS; P = 0.03), compared to homozygous protected donors. Smoking was associated with increased TCC in BM (P = 0.05), CC IS (P = 0.03), and choroidal stroma (CS; P = 0.01), and with substantially elevated C-reactive protein (CRP) levels in RPE (P = 0.04), BM (P = 0.01), CC (P = 0.05), and CS (P = 0.05). Smoking was associated with higher levels of oxidative stress in macular RPE (P = 0.04) and CS (P = 0.01). CONCLUSIONS: Genetic risk at the CFH-to-F13B locus was associated with higher levels of complement activation at the human macular RPE-choroid interface, as was cigarette smoking. Levels of CRP were substantially elevated in risk donors with smoking history. Examination of human macular tissue from donors with "pure" diplotypes allows assessment of AMD-associated pathways driven solely by CFH-to-F13B. These findings have important implications for identifying chromosome 1-directed pathways and therapeutic targets.
Assuntos
Lâmina Basilar da Corioide/metabolismo , Cromossomos Humanos Par 1/genética , Ativação do Complemento/genética , Fator H do Complemento/genética , Complexo de Ataque à Membrana do Sistema Complemento/genética , DNA/genética , Degeneração Macular/genética , Idoso , Fator H do Complemento/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Genótipo , Homozigoto , Humanos , Imuno-Histoquímica , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Doadores de TecidosRESUMO
PURPOSE: The chemokine Ccl2, or monocyte chemoattractant protein-1 (MCP-1), has previously been identified as playing a potential role in many ocular diseases; however, its role in mice is less clear. We sought to correlate changes in retinal pigment epithelium (RPE) and retinal morphology with changes in function in aging Ccl2(-/-) mice. METHODS: Ccl2(-/-) mice on a C57BL6J background were genotyped for Crb1(rd8/rd8) and were free of this mutation. Ccl2(-/-) mice and wild-type (WT) C57BL6J mice were investigated for changes in the retinal fundus and histology as a function of age. The function of the rod and cone pathways, and the rate of dark adaptation, was assessed using the electroretinogram (ERG) up to 15 months of age. RESULTS: Fifteen-month-old Ccl2(-/-) mice had fundus lesions, more subretinal microglia/macrophages, and an increase in RPE cell size, indicative of RPE cell loss, when compared with WT mice. Within the retina, gross morphology was normal but there was an increase in Müller cell gliosis and microglial activation. These morphological changes in the Ccl2(-/-) RPE/retina did not correlate with a change in either rod or cone ERG pathway function, or with the rate of dark adaptation. CONCLUSIONS: These data show that Ccl2 is important for preserving RPE and glial morphology with age, yet retinal function and gross morphology are maintained. Altered signaling in this chemokine pathway may, however, increase RPE and retinal vulnerability to disease.
Assuntos
Envelhecimento/fisiologia , Degeneração Macular/fisiopatologia , Retina/fisiopatologia , Animais , Células Cultivadas , Quimiocinas/metabolismo , Adaptação à Escuridão , Modelos Animais de Doenças , Eletrorretinografia , Imuno-Histoquímica , Degeneração Macular/genética , Degeneração Macular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Retina/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/fisiopatologiaRESUMO
PURPOSE: To investigate the developmental stages and genetic etiology of the optical gap phenotype in recessive Stargardt disease (STGD1). METHODS: Single and longitudinal data points from 15 patients, including four sibling pairs, exhibiting an optical gap phenotype on spectral-domain optical coherence tomography (SD-OCT) with confirmed disease-causing ABCA4 alleles were retrospectively analyzed. Fundus images with corresponding SD-OCT scans were collected with a confocal scanning laser ophthalmoscope. Structural phenotypes were assigned to three developmental stages according to SD-OCT. The ABCA4 gene was screened in all patients. RESULTS: At least two disease-causing ABCA4 variants where identified in each patient; all except one (91%) were compound heterozygous for the p.G1961E mutation. All patients exhibited structural findings on SD-OCT that grouped into three progressive developmental stages over several years. Stage 1 was characterized by mild disruptions of the ellipsoid zone (EZ) band over the fovea. Stage 2 was a progressive expansion of the EZ band loss resulting in an empty lesion devoid of photoreceptors. Stage 3 observed a structural collapse of the inner retinal layers into the optical gap space leading to involvement and atrophy of the RPE thereafter. CONCLUSIONS: The optical gap phenotype in STGD1 can be structurally divided into three progressive stages spanning several years. This particular phenotype also appears to be highly associated with the p.G1961E mutation of ABCA4. Taken together, it appears that a focal loss of photoreceptors sequentially precedes RPE dysfunction in the early development of ABCA4-associated optical gap lesions.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , DNA/genética , Mutação , Retina/patologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Seguimentos , Humanos , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Fenótipo , Retina/metabolismo , Retina/fisiopatologia , Estudos Retrospectivos , Doença de Stargardt , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: To examine the use of anti-vascular endothelial growth factor (VEGF) therapy in clinical practice among patients with neovascular age-related macular degeneration (AMD). DESIGN: Retrospective cohort study. METHODS: Among 459 237 Medicare beneficiaries, we identified anti-VEGF treatment using claims for intravitreal injections of anti-VEGF medications with a supporting diagnosis of neovascular AMD. We used the cumulative incidence function to calculate the frequency of anti-VEGF treatments and treatment visits for neovascular AMD per treated eye in the first and second year after the initial anti-VEGF injection. We calculated the mean number of treatments and treatment visits per eye using the mean frequency function. Rates of discontinuation were estimated using Kaplan-Meier methods. RESULTS: The mean number of injections was 4.3 in the first year, with 58% of patients receiving 1-4 injections, 20% receiving 5-6 injections, and 22% receiving 7 or more injections. Among patients who received 7 or more injections during the first year, 31% received a comparable number during the second year, and 12% received no injections. Of patients who received 1-4 injections during the first year, 70% received no injections and 24% received 1-4 injections during the second year. Rates of anti-VEGF discontinuation were 57% within 12 months and 71% within 24 months. CONCLUSIONS: The frequency of anti-VEGF injections for neovascular AMD was lower than that recommended by large-scale clinical trials, and rates of discontinuation were high. National practice patterns in anti-VEGF therapy for patients with neovascular AMD do not reflect optimal treatment strategies suggested by recent clinical trial evidence.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Degeneração Macular/tratamento farmacológico , Medicare/economia , Neovascularização Retiniana/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Bevacizumab , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Degeneração Macular/diagnóstico , Degeneração Macular/metabolismo , Masculino , Ranibizumab , Neovascularização Retiniana/diagnóstico , Neovascularização Retiniana/metabolismo , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: We characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease. METHODS: Full clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken. RESULTS: The mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype. CONCLUSIONS: The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , DNA/genética , Angiofluoresceinografia/métodos , Degeneração Macular/congênito , Mutação , Epitélio Pigmentado da Retina/patologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Eletrorretinografia , Feminino , Seguimentos , Fundo de Olho , Genótipo , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Doença de Stargardt , Adulto JovemRESUMO
PURPOSE: To use novel OCT parameters in assessing the differential pharmacodynamic effects of bevacizumab (Avastin; Genentech, South San Francisco, CA), pegaptanib (Macugen; OSI Pharmaceuticals, New York, NY), and verteporfin photodynamic therapy (PDT; Novartis, Basel, Switzerland) in a recently completed phase III/IV clinical trial. METHODS: Data from 122 patients participating in the Avastin (Bevacizumab) for Choroidal Neovascularization (ABC) trial, were evaluated. OCT scans were analyzed with custom software. Changes in the volume of the neurosensory retina, amount of subretinal fluid (SRF), pigment epithelium detachment (PED), and subretinal tissue (SRT), were calculated over the 54-week trial period. RESULTS: Reductions in retinal edema were more than twice as great from bevacizumab as from pegaptanib (-0.82 mm³ vs. -0.31 mm³), whereas SRF reduction was more than three times greater (-0.54 mm³ vs. -0.15 mm³. Both bevacizumab and pegaptanib led to rapid reductions in SRT; however, in those receiving pegaptanib, these improvements were not maintained (at week 54, -0.22 mm³ vs. +0.18 mm³). Acute increases in SRF were seen 1 week after PDT (+0.36 mm³) and, across all treatment groups, PED volume tended to remain unchanged or to regress only slowly. CONCLUSIONS: In clinical trials, quantitative OCT subanalysis increases the amount of clinically useful information that can be obtained from OCT images. In the emerging era of neovascular AMD therapeutics, the capacity of OCT to provide such detailed pharmacodynamic information in a noninvasive manner is likely to attain increased importance. In future comparative studies, evaluation of SRT may highlight differential effects on vascular proliferation, whereas measurement of PED volume may be useful for the estimation of retinal and subretinal pigment epithelium (RPE) therapeutic penetration. (ClinicalTrials.gov number, ISRCTN83325075.).
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Aptâmeros de Nucleotídeos/farmacocinética , Neovascularização de Coroide/prevenção & controle , Degeneração Macular/patologia , Tomografia de Coerência Óptica/métodos , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , Bevacizumab , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Fator A de Crescimento do Endotélio VascularRESUMO
Ischemia and hypoxia have been implicated in the pathophysiology of age related macular degeneration (AMD). This has mostly been based on studies on choroidal perfusion, which is not the only contributor to retinal hypoxia found in AMD eyes. Other features of AMD may also interfere with retinal oxygen metabolism including confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion. Each of these features contributes to retinal hypoxia: the drusen and retinal elevation by increasing the distance between the choriocapillaris and retina; vitreoretinal adhesion by reducing diffusion and convection of oxygen towards and vascular endothelial growth factor (VEGF) away from hypoxic retinal areas. Hypoxia-inducible-factor is known to exist in subretinal neovascularization and hypoxia is the main stimulus for the production of VEGF. Each feature may not by itself create enough hypoxia and VEGF accumulation to stimulate wet AMD, but they may combine to do so. Choroidal ischemia in AMD has been demonstrated by many researchers, using different technologies. Choroidal ischemia obviously decreases oxygen delivery to the outer retina. Confluent drusen, thickening of Bruch's membrane and any detachment of retina or retinal pigment epithelium, increases the distance between the choriocapillaris and the retina and thereby reduces the oxygen flux from the choroid to the outer retina according to Fick's law of diffusion. Retinal elevation and choroidal ischemia may combine forces to reduce choroidal oxygen delivery to the outer retina, produce retinal hypoxia. Hypoxia leads to production of VEGF leading to neovascularization and tissue edema. A vicious cycle may develop, where VEGF production increases effusion, retinal detachment and edema, further increasing hypoxia and VEGF production. Adhesion of the viscous posterior vitreous cortex to the retina maintains a barrier to diffusion and convection currents in the vitreous cavity according to the laws of Fick's, Stokes-Einstein and Hagen-Poiseuille. If the vitreous is detached from the surface of the retina, the low viscosity fluid transports oxygen and nutrients towards an ischemic area of the retina, and cytokines away from the retina, at a faster rate than through attached vitreous gel. Vitreoretinal adhesion can exacerbate retinal hypoxia and accumulation of cytokines, such as VEGF. Vitreoretinal traction can also cause hypoxia by retinal elevation. Conceivably, the basic features of AMD, drusen, choroidal ischemia, and vitreoretinal adhesion are independently determined by genetics and environment and may combine in variable proportions. If the resulting hypoxia and consequent VEGF accumulation crosses a threshold, this will trigger effusion and neovascularization.
Assuntos
Neovascularização de Coroide/metabolismo , Degeneração Macular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Lâmina Basilar da Corioide/metabolismo , Neovascularização de Coroide/etiologia , Humanos , Fluxometria por Laser-Doppler/métodos , Degeneração Macular/complicações , Degeneração Macular/patologia , Drusas do Disco Óptico/complicações , Drusas do Disco Óptico/economia , Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Corpo Vítreo/metabolismoRESUMO
Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing proteins and the ataxia network. To begin to understand the biological relevance of these protein interactions within the ataxia network, we used OMIM to identify diseases associated with the expanded ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary ataxia. We found that patients with ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with ataxia is macular degeneration (MD). The ataxia network is significantly (P= 7.37 × 10(-5)) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7(266Q/+) mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of ataxia, MD, and diseases comorbid with ataxia.
Assuntos
Canais de Cálcio/genética , Degeneração Macular/genética , Prontuários Médicos , Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares/genética , Animais , Ataxina-7 , Canais de Cálcio/metabolismo , Comorbidade , Imunofluorescência , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Hibridização In Situ , Degeneração Macular/metabolismo , Medicare , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Retina/anormalidades , Retina/metabolismo , Ataxias Espinocerebelares/metabolismo , Expansão das Repetições de Trinucleotídeos , Estados UnidosRESUMO
Age-related macular degeneration (ARMD) is the most common cause for visual impairment in the elderly in western countries. Recently several anti-vascular endothelial growth factor (VEGF) drugs like pegaptanib sodium (Macugen), ranibizumab (Lucentis) and bevacizumab (Avastin) are available for use in the management of wet ARMD. A major limitation of these drugs is that they require multiple intravitreal injections, every 4 to 6 weeks interval for a period of 2 years. Moreover, most of these drugs are too expensive for the general masses to afford in developing nations. Avastin, though used "off-label", offers a comparable result at affordable cost, however, long term results are awaited. The drug industry should review the entire pricing policy of these drugs in developing countries like India, and develop affordable alternative compounds. The article reviews the economic burden and affordability issues of these Anti-VEGF drugs in ARMD.