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https://www.readbyqxmd.com/read/28816076/current-drug-and-molecular-therapies-for-the-treatment-of-atrophic-age-related-macular-degeneration-phase-i-to-phase-iii-clinical-development
#1
Huiling Li, Sumana R Chintalapudi, Monica M Jablonski
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly. Atrophic AMD, including early, intermediate and geographic atrophy (GA), accounts for ~90% of all cases. It is a multifactorial degeneration characterized by chronic inflammation, oxidative stress and aging components. Although no FDA-approved treatment yet exists for the late stage of atrophic AMD, multiple pathological mechanisms are partially known and several promising therapies are in various stages of development...
August 17, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28814744/monocyte-infiltration-and-proliferation-reestablish-myeloid-cell-homeostasis-in-the-mouse-retina-following-retinal-pigment-epithelial-cell-injury
#2
Wenxin Ma, Yikui Zhang, Chun Gao, Robert N Fariss, Johnny Tam, Wai T Wong
Age-related macular degeneration (AMD), a leading contributor of vision loss, currently lacks comprehensive treatment. While AMD histopathology involves retinal pigment epithelium (RPE) injury associated with immune cell infiltration, the nature of immune cell responses to RPE injury remains undefined. We induced RPE injury pharmacologically and genetically in transgenic mouse models in which microglia and systemic monocytes were separately tagged, enabling a spatial and temporal dissection of the relative contributions of microglia vs...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813576/joint-analysis-of-nuclear-and-mitochondrial-variants-in-age-related-macular-degeneration-identifies-novel-loci-trpm1-and-abhd2-rlbp1
#3
Patrice J Persad, Iris M Heid, Daniel E Weeks, Paul N Baird, Eiko K de Jong, Jonathan L Haines, Margaret A Pericak-Vance, William K Scott
Purpose: Presently, 52 independent nuclear single nucleotide polymorphisms (nSNPs) have been associated with age-related macular degeneration (AMD) but their effects do not explain all its variance. Genetic interactions between the nuclear and mitochondrial (mt) genome may unearth additional genetic loci previously unassociated with AMD risk. Methods: Joint effects of nSNPs and selected mtSNPs were analyzed by two degree of freedom (2df) joint tests of association in the International AMD Genomics Consortium (IAMDGC) dataset (17,832 controls and 16,144 advanced AMD cases of European ancestry)...
August 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28775256/a-genome-wide-association-study-identified-a-novel-genetic-loci-ston1-gtf2a1l-lhcgr-fshr-for-bilaterality-of-neovascular-age-related-macular-degeneration
#4
Kyoko Kawashima-Kumagai, Kenji Yamashiro, Munemitsu Yoshikawa, Masahiro Miyake, Gemmy Cheung Chui Ming, Qiao Fan, Jia Yu Koh, Masaaki Saito, Masako Sugahara-Kuroda, Maho Oishi, Yumiko Akagi-Kurashige, Isao Nakata, Hideo Nakanishi, Norimoto Gotoh, Akio Oishi, Hiroshi Tamura, Sotaro Ooto, Akitaka Tsujikawa, Yasuo Kurimoto, Tetsuju Sekiryu, Fumihiko Matsuda, Chiea-Chuen Khor, Ching-Yu Cheng, Tien Yin Wong, Nagahisa Yoshimura
Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian. The discovery stage compared 581,252 single nucleotide polymorphisms (SNPs) between 803 unilateral and 321 bilateral Japanese cases but no SNP showed genome-wide significance, while SNPs at six regions showed P-value < 1...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28767736/cigarette-smoke-induced-autophagy-impairment-regulates-amd-pathogenesis-mechanisms-in-arpe-19-cells
#5
Viren Kumar Govindaraju, Manish Bodas, Neeraj Vij
Age related macular degeneration (AMD) is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS) initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE) cells...
2017: PloS One
https://www.readbyqxmd.com/read/28750115/association-of-c-reactive-protein-genetic-polymorphisms-with-late-age-related-macular-degeneration
#6
Valentina Cipriani, Ruth E Hogg, Reecha Sofat, Anthony T Moore, Andrew R Webster, John R W Yates, Astrid E Fletcher
Importance: C-reactive protein (CRP) is a circulating inflammatory marker associated with late age-related macular degeneration (AMD). It remains uncertain whether the association between CRP concentrations and AMD is causal. Objective: To assess whether CRP (OMIM 123260) single-nucleotide polymorphisms that influence circulating CRP concentrations are associated with late AMD. Design, Setting, and Participants: Participants in 2 UK, hospital-based, case-control studies (Cambridge AMD study and Moorfields Eye Hospital AMD study) and 1 pan-European, cross-sectional, population-based study (the European Eye [EUREYE] Study) were recruited between November 6, 2000, and April 30, 2007...
July 27, 2017: JAMA Ophthalmology
https://www.readbyqxmd.com/read/28735646/hyperhomocysteinemia-and-age-related-macular-degeneration-role-of-inflammatory-mediators-and-pyroptosis-a-proposal
#7
Mahavir Singh, Suresh C Tyagi
Age-related macular degeneration (AMD) and pyroptosis cause irreversible vascular changes in the eyes leading to central vision loss in patients. It is the most common eye disease affecting millions of people aged 50years or older, and is slowly becoming a major health problem worldwide. The disease mainly affects macula lutea, an oval-shaped pigmented area surrounding fovea near the center of retina, a region responsible for visual acuity. It is fairly a complex disease as genetics of patients, environmental triggers as well as risk factors such as age, family history of CVDs, diabetes, gender, obesity, race, hyperopia, iris color, smoking, diabetes, exposure to sun light and pyroptosis have all been clubbed together as probable causes of macular degeneration...
August 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28703135/genome-wide-association-study-of-neovascular-age-related-macular-degeneration-in-the-thai-population
#8
Paisan Ruamviboonsuk, Mongkol Tadarati, Panisa Singhanetr, Sukanya Wattanapokayakit, Punna Kunhapan, Thanyapat Wanitchanon, Nuanjun Wichukchinda, Taisei Mushiroda, Masato Akiyama, Yukihide Momozawa, Michiaki Kubo, Surakameth Mahasirimongkol
We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10(-17)), HTRA1 rs11200638 (P=5.47 × 10(-17)) and complement factor H gene (CFH) rs800292 (P=2.53 × 10(-8)) with neovascular AMD, all loci passing the genome-wide significance level (P<5...
July 13, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28698208/plasma-lipoprotein-sub-fraction-concentrations-are-associated-with-lipid-metabolism-and-age-related-macular-degeneration
#9
Chui Ming Gemmy Cheung, Alfred Gan, Qiao Fan, Miao Ling Chee, Rajendra S Apte, Chiea Chuen Khor, Ian Yeo, Ranjana Mathur, Ching-Yu Cheng, Tien Yin Wong, E Shyong Tai
Disturbance in lipid metabolism has been suggested as a major pathogenic factor for age-related macular degeneration (AMD). Conventional lipid measures have been inconsistently associated with AMD. Other factors which can alter lipid metabolism include lipoprotein phenotype and genetic mutations. We performed a case-control study to examine the association between lipoprotein profile and neovascular AMD (nAMD), and whether the cholesterylester transfer protein CETP D442G mutation modulates these associations...
July 11, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28637922/targeting-factor-d-of-the-alternative-complement-pathway-reduces-geographic-atrophy-progression-secondary-to-age-related-macular-degeneration
#10
Brian L Yaspan, David F Williams, Frank G Holz, Carl D Regillo, Zhengrong Li, Amy Dressen, Menno van Lookeren Campagne, Kha N Le, Robert R Graham, Tatiana Beres, Tushar R Bhangale, Lee A Honigberg, Ashley Smith, Erin C Henry, Carole Ho, Erich C Strauss
Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly (n = 42) and every other month (n = 41) versus sham control (n = 40) in patients with geographic atrophy secondary to AMD...
June 21, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28637435/association-between-polymorphism-rs11200638-in-the-htra1-gene-and-the-response-to-anti-vegf-treatment-of-exudative-amd-a-meta-analysis
#11
Ya-Li Zhou, Chun-Li Chen, Yi-Xiao Wang, Yao Tong, Xiao-Ling Fang, Lin Li, Zhao-Yang Wang
BACKGROUND: Anti-angiogenesis treatments are the most commonly used treatments for the vision loss caused by exudative age-related macular degeneration (AMD), in which the anti-vascular endothelial growth factor (VEGF) drugs with ranibizumab and bevacizumab are current standard treatments. However, the outcome of anti-VEGF therapeutics is not uniform in all patients. METHODS: We performed a literature-based meta-analysis including, five published studies relevant to HTRA1 and response to anti-VEGF treatment (bevacizumab or ranibizumab)...
June 21, 2017: BMC Ophthalmology
https://www.readbyqxmd.com/read/28621538/discovery-of-highly-potent-and-selective-small-molecule-reversible-factor-d-inhibitors-demonstrating-alternative-complement-pathway-inhibition-in-vivo
#12
Edwige Lorthiois, Karen Anderson, Anna Vulpetti, Olivier Rogel, Frederic Cumin, Nils Ostermann, Stefan Steinbacher, Aengus Mac Sweeney, Omar Delgado, Sha-Mei Liao, Stefan Randl, Simon Rüdisser, Solene Dussauge, Kamal Fettis, Laurence Kieffer, Andrea de Erkenez, Louis Yang, Constanze Hartwieg, Upendra A Argikar, Laura R La Bonte, Ronald Newton, Viral Kansara, Stefanie Flohr, Ulrich Hommel, Bruce Jaffee, Jürgen Maibaum
The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties...
July 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28605809/retinal-macrophages-synthesize-c3-and-activate-complement-in-amd-and-in-models-of-focal-retinal-degeneration
#13
Riccardo Natoli, Nilisha Fernando, Haihan Jiao, Tanja Racic, Michele Madigan, Nigel L Barnett, Joshua A Chu-Tan, Krisztina Valter, Jan Provis, Matt Rutar
Purpose: Complement system dysregulation is strongly linked to the progression of age-related macular degeneration (AMD). Deposition of complement including C3 within the lesions in atrophic AMD is thought to contribute to lesion growth, although the contribution of local cellular sources remains unclear. We investigated the role of retinal microglia and macrophages in complement activation within atrophic lesions, in AMD and in models of focal retinal degeneration. Methods: Human AMD donor retinas were labeled for C3 expression via in situ hybridization...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28602950/on-phagocytes-and-macular-degeneration
#14
REVIEW
Xavier Guillonneau, Chiara M Eandi, Michel Paques, José-Alain Sahel, Przemyslaw Sapieha, Florian Sennlaub
Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid...
June 7, 2017: Progress in Retinal and Eye Research
https://www.readbyqxmd.com/read/28583181/bringing-the-age-related-macular-degeneration-high-risk-allele-age-related-maculopathy-susceptibility-2-into-focus-with-stem-cell-technology
#15
REVIEW
Shuo Sun, ZhiQing Li, Patrick Glencer, BinCui Cai, XiaoMin Zhang, Jin Yang, XiaoRong Li
Age-related macular degeneration (AMD) is a major cause of blindness in older adults in developed countries. It is a multifactorial disease triggered by both environmental and genetic factors. High-temperature requirement A serine peptidase 1 (HTRA1) and age-related maculopathy susceptibility 2 (ARMS2) are two genes that are strongly associated with AMD. Because ARMS2 is an evolutionarily recent primate-specific gene and because the ARMS2/HTRA1 genes are positioned at a locus on chromosome 10q26 in a region with strong linkage disequilibrium, it is difficult to distinguish the functions of the individual genes...
June 6, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28558370/genetic-polymorphisms-and-the-phenotypic-characterization-of-individuals-with-early-age-related-macular-degeneration
#16
Michael Oeverhaus, Verena Meyer Zu Westrup, Martha Dietzel, Hans-Werner Hense, Daniel Pauleikhoff
PURPOSE: While the importance of risk polymorphisms for the pathogenesis of age-related macular degeneration (AMD) is well established, their impact on morphological and functional phenotypes is largely unclear. We aimed to characterize individual phenotypes in patients who were either homozygous for a risk allele in the CFH gene, ARMS2 gene, or both as compared to non-carriers. METHODS: Patients with early AMD (n = 85) were assessed during a follow-up examination of a prospective study (MARS) with multimodal diagnostics including SD-OCT and microperimetry...
2017: Ophthalmologica. Journal International D'ophtalmologie
https://www.readbyqxmd.com/read/28557901/improving-the-age-related-macular-degeneration-construct-a-new-classification-system
#17
Richard F Spaide
Previous models of disease in age-related macular degeneration (AMD) were incomplete in that they did not encompass subretinal drusenoid deposits (pseudodrusen), subtypes of neovascularization, and polypoidal choroidal vasculopathy. In addition, Type 3 neovascularization starts in the retina and may not necessarily involve the choroid. As such, the term choroidal neovascularization is not appropriate for these eyes. The new aspects in the AMD construct are to include specific lipoprotein extracellular accumulations, namely drusen and subretinal drusenoid deposits, as early AMD...
May 26, 2017: Retina
https://www.readbyqxmd.com/read/28553324/the-complexities-underlying-age-related-macular-degeneration-could-amyloid-beta-play-an-important-role
#18
REVIEW
Savannah A Lynn, Eloise Keeling, Rosie Munday, Gagandeep Gabha, Helen Griffiths, Andrew J Lotery, J Arjuna Ratnayaka
Age-related macular degeneration (AMD) causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals...
April 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28522341/systemic-and-ocular-fluid-compounds-as-potential-biomarkers-in-age-related-macular-degeneration
#19
REVIEW
Eveline Kersten, Constantin C Paun, Rosa L Schellevis, Carel B Hoyng, Cécile Delcourt, Imre Lengyel, Tunde Peto, Marius Ueffing, Caroline C W Klaver, Sascha Dammeier, Anneke I den Hollander, Eiko K de Jong
Biomarkers can help unravel mechanisms of disease and identify new targets for therapy. They can also be useful in clinical practice for monitoring disease progression, evaluation of treatment efficacy and risk assessment in multifactorial diseases, such as age-related macular degeneration (AMD). AMD is a highly prevalent progressive retinal disorder for which multiple genetic and environmental risk factors have been described, but the exact etiology is not yet fully understood. Many compounds have been evaluated for their association with AMD...
May 15, 2017: Survey of Ophthalmology
https://www.readbyqxmd.com/read/28482029/from-compliment-to-insult-genetics-of-the-complement-system-in-physiology-and-disease-in-the-human-retina
#20
Robert F Mullins, Alasdair N Warwick, Elliott H Sohn, Andrew J Lotery
Age-related macular degeneration (AMD) is a major cause of visual impairment that affects the central retina. Genome wide association studies and candidate gene screens have identified members of the complement pathway as contributing to the risk of AMD. In this review, we discuss the complement system, its importance in retinal development and normal physiology, how its dysregulation may contribute to disease, and how it might be targeted to prevent damage to the aging choriocapillaris in AMD.
May 8, 2017: Human Molecular Genetics
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