Review of Genetics in Age Related Macular Degeneration

Montezuma, Sandra R.; Sobrin, Lucia; Seddon, Johanna M.

doi:10.1080/08820530701745140

Cited by 95 publications

(58 citation statements)

References 154 publications

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“…The prevalence of AMD increases dramatically with age, and both photo-oxidation and inflammation have been implicated in the pathogenic mechanism for AMD (Hejtmancik et al, 2006), in addition the risk associated with cigarette smoking is thought to imply a role for oxidative stress in AMD. Variants in the gene for complement factor H (CFH) and the genes PLEKHA1/LOC387715/HTRA1, Factor B (BF) and complement component 2 (C2) have been implicated as major risk or protective factors for the development of AMD (Montezuma et al, 2007).…”

Section: Mitochondrial Ros Systems and Maculopathymentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

162

141

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Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O 2 -) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (OONO -). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr)

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Section: Mitochondrial Ros Systems and Maculopathymentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

162

141

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“…Because the AP functions in an "always on" mode, a host of negative regulators keeps this pathway's activity in check. Beyond its role in peripheral diseases, several lines of genetic and pathophysiologic evidence implicate overactivation of AP in AMD (Hageman et al, 2001;Johnson et al, 2001;Anderson et al, 2002Anderson et al, , 2010Edwards et al, 2005;Montezuma et al, 2007;Yates et al, 2007;Francis et al, 2009;Loyet et al, 2012;Ebrahimi et al, 2013;Fritsche et al, 2013). Preclinical and clinical evidence explicitly implicate fD in AMD.…”

Section: Introductionmentioning

confidence: 99%

Complement Inhibition in Cynomolgus Monkeys by Anti–Factor D Antigen-Binding Fragment for the Treatment of an Advanced Form of Dry Age-Related Macular Degeneration

Loyet¹,

Good²,

Davancaze³

et al. 2014

J Pharmacol Exp Ther

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Anti-factor D (AFD; FCFD4514S, lampalizumab) is a humanized IgG Fab fragment directed against factor D (fD), a rate-limiting serine protease in the alternative complement pathway (AP). Evaluation of AFD as a potential intravitreal (IVT) therapeutic for dry age-related macular degeneration patients with geographic atrophy (GA) is ongoing. However, it is unclear whether IVT administration of AFD can affect systemic AP activation and potentially compromise host-immune responses. We characterized the pharmacologic properties of AFD and assessed the effects of AFD administered IVT (2 or 20 mg) or intravenous (0.2, 2, or 20 mg) on systemic complement activity in cynomolgus monkeys. For the IVT groups, serum AP activity was reduced for the 20 mg dose group between 2 and 6 hours postinjection. For the intravenous groups, AFD inhibited systemic AP activity for periods of time ranging from 5 minutes (0.2 mg group) to 3 hours (20 mg group). Interestingly, the concentrations of total serum fD increased up to 10-fold relative to predose levels following administration of AFD. Furthermore, AFD was found to inhibit systemic AP activity only when the molar concentration of AFD exceeded that of fD. This occurred in cynomolgus monkeys at serum AFD levels $2 mg/ml, a concentration 8-fold greater than the maximum serum concentration observed following a single 10 mg IVT dose in a clinical investigation in patients with GA. Based on these findings, the low levels of serum AFD resulting from IVT administration of a clinically relevant dose are not expected to appreciably affect systemic AP activity.

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“…No form of prevention is available for the nonexudative (dry) form of AMD, apart from dietary intervention. With regard to the exudative (wet) form of AMD, intraocular injection of the monoclonal antibody Lucentis (Genentech Inc), targeting VEGF, is being used in a growing number of cases; however, severe endophthalmitis, resulting in blindness, has been reported to occur in up to 2% of treated patients (25). Proliferative diabetic retinopathy is treatable by scatter and focal laser surgery, but the procedure itself induces significant retinal damage and can involve in excess of 1,000 laser burns to the retinas of diseased patients (26).…”

Section: Discussionmentioning

confidence: 99%

An experimental platform for systemic drug delivery to the retina

Campbell

Nguyen

Kiang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders-major causes of world blindness-are potentially treatable by using lowmolecular weight neuroprotective, antiapoptotic, or antineovascular drugs. These agents are, however, not in current systemic use owing to, among other factors, their inability to passively diffuse across the microvasculature of the retina because of the presence of the inner blood-retina barrier (iBRB). Moreover, preclinical assessment of the efficacies of new formulations in the treatment of such conditions is similarly compromised. We describe here an experimental process for RNAi-mediated, size-selective, transient, and reversible modulation of the iBRB in mice to molecules up to 800 Da by suppression of transcripts encoding claudin-5, a protein component of the tight junctions of the inner retinal vasculature. MRI produced no evidence indicative of brain or retinal edema, and the process resulted in minimal disturbance of global transcriptional patterns analyzed in neuronal tissue. We show that visual function can be improved in IMPDH1 ؊/؊ mice, a model of autosomal recessive retinitis pigmentosa, and that the rate of photoreceptor cell death can be reduced in a model of light-induced retinal degeneration by systemic drug delivery after reversible barrier opening. These findings provide a platform for high-throughput drug screening in models of retinal degeneration, and they ultimately could result in the development of a novel ''humanized'' approach to therapy for conditions with little or no current forms of treatment.blood-retina barrier ͉ retinitis pigmentosa ͉ RNAi ͉ tight junctions ͉ claudin-5

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Review of Genetics in Age Related Macular Degeneration

Cited by 95 publications

References 154 publications

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Complement Inhibition in Cynomolgus Monkeys by Anti–Factor D Antigen-Binding Fragment for the Treatment of an Advanced Form of Dry Age-Related Macular Degeneration

An experimental platform for systemic drug delivery to the retina

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