雷珠单抗治疗新生血管性老年性黄斑变性的药物基因学研究进展
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摘要
老年性黄斑变性是我国老年人致盲的重要眼病之一,雷珠单抗作为一线用药用于新生血管性老年性黄斑变性的临床治疗。然而患者对雷珠单抗的治疗应答具有个体差异,有约10%患者治疗无效。抗血管内皮生长因子(VEGF)药物疗效受多因素影响,其中药物基因多态性可能是导致治疗失败的重要因素。本文综述雷珠单抗药物基因学的相关研究,期待能为老年性黄斑变性的个体化诊疗提供依据。
Age-related macular degeneration is one of eye diseases that may cause blindness in the elderly in China. Ranibizumab is recommended as the first-line treatment for neovascular age-related macular degeneration. However,there are individual differences in the clinical efficacy,and almost ten percent of the patients are sufferring from ineffectiveness. Anti-vascular endothelial growth factor( VEGF) drug effects are affected by multiple factors,and drug gene polymorphism may be an important factor leading to treatment failure. This paper reviews the researches of ranibizumab pharmacogenomics,expecting to provide evidences to support the individualized treatment of age-related macular degeneration.
Age-related macular degeneration is one of eye diseases that may cause blindness in the elderly in China. Ranibizumab is recommended as the first-line treatment for neovascular age-related macular degeneration. However,there are individual differences in the clinical efficacy,and almost ten percent of the patients are sufferring from ineffectiveness. Anti-vascular endothelial growth factor( VEGF) drug effects are affected by multiple factors,and drug gene polymorphism may be an important factor leading to treatment failure. This paper reviews the researches of ranibizumab pharmacogenomics,expecting to provide evidences to support the individualized treatment of age-related macular degeneration.
引文
[1]中华医学会眼科学分会眼底病学组.中国老年性黄斑变性临床诊断治疗路径[J].中华眼底病杂志,2013,29(4):343-355.
[2]邹海东,张皙,许迅等.上海市静安区曹家渡街道年龄相关性黄斑变性的患病率调查[J].中华眼科杂志,2005,41(1):15-19.
[3]BROWN D M,KAISER P K,MICHELS M,et al.Ranibizumab versus verteporfin for neovascular age-related macular degeneration[J].New Engl J Med,2006,355(14):1432-1444.
[4]ROSENFELD P J,SHAPIRO H,TUOMI L,et al.Characteristics of patients losing vision after 2 years of monthly dosing in the phaseⅢranibizumab clinical trials[J].Ophthalmology,2011,118(3):523-530.
[5]TAYLOR H R,PEZZULLO M L,KEEFFE J E.The economic impact and cost of visual impairment in Australia[J].Br J Ophthalmol,2006,90(3):272-275.
[6]REIN D B,ZHANG P,WIRTH K E,et al.The economic burden of major adult visual disorders in the United States[J].Arch Ophthalmol,2006,124(12):1754-1760.
[7]DAY S,ACQUAH K,LEE P P,et al.Medicare costs for neovascular age-related macular degeneration,1994-2007[J].Am JOphthalmol,2011,152(6):1014-1020.
[8]KAISER P K,BROWN D M,ZHANG K,et al.Ranibizumab for predominantly classic neovascular age-related macular degeneration:subgroup analysis of first-year ANCHOR results[J].Am JOphthalmol,2007,144(6):850-857.
[9]YING G S,HUANG J,MAGUIRE M G,et al.Baseline predictors of visual acuity response to ranibizumab and bevacizumab in the Comparison of AMD Treatment Trial(CATT)[J].Invest Ophthalmol Vis Sci,2012,53(14):3681.
[10]LEVY J,SHNECK M,ROSEN S,et al.Intravitreal bevacizumab(avastin)for subfoveal neovascular age-related macular degeneration[J].Int Ophthalmol,2009,29(5):349-357.
[11]FINGER R P,WICKREMASINGHE S S,BAIRD P N,et al.Predictors of anti-VEGF treatment response in neovascular agerelated macular degeneration[J].Surv Ophthalmol,2014,59(1):1-18.
[12]KLEIN R.Race/ethnicity and age-related macular degeneration[J].Am J Ophthalmol,2011,152(2):153-154.
[13]LEVEZIEL N,TILLEUL J,PUCHE N,et al.Genetic factors associated with age-related macular degeneration[J].Ophthalmologica,2010,226(3):87-102.
[14]CHEN H,YU K D,XU G Z.Association between variant Y402Hin age-related macular degeneration(AMD)susceptibility gene CFH and treatment response of AMD:a meta-analysis[J].PLoSOne,2012,7(8):e42464.2012-08-14[2018-05-22].https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042464.
[15]DIKMETAS O,KADAYIFCILAR S,ELDEM B.The effect of CFHpolymorphisms on the response to the treatment of age-related macular degeneration(AMD)with intravitreal ranibizumab[J].Mol Vis,2013,19(5):2571-2578.
[16]VELOSO C E,ALMEIDA L N,NEHEMY M B.CFH Y402H polymorphism and response to intravitreal ranibizumab in Brazilian patients with neovascular age-related macular degeneration[J].Rev Col Bras Cir,2014,41(6):386-392.
[17]YUAN D,YUAN D,LIU X,et al.Genetic association with response to intravitreal ranibizumab for neovascular age-related macular degeneration in the Han Chinese population[J].Ophthalmologica,2013,230(4):227-232.
[18]FRANCIS P J.The influence of genetics on response to treatment with ranibizumab(lucentis)for age-related macular degeneration:the lucentis genotype study(an american ophthalmological society thesis)[J/OL].Trans Am Ophthalmol Soc,2011,109:115-156.2011-12-01[2018-05-22].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259677/.
[19]HERMANN M M,VAN A F,MUETHER P S,et al.Polymorphisms in vascular endothelial growth factor receptor 2 are associated with better response rates to ranibizumab treatment in age-related macular degeneration[J].Ophthalmology,2014,121(4):905.
[20]HAGSTROM S A,YING G S,MAGUIRE M G,et al.VEGFR2gene polymorphisms and response to anti-vegf therapy in age-related macular degeneration[J].Ophthalmology,2015,122(8):1563-1568.
[21]LAZZERI S,FIGUS M,ORLANDI P,et al.VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration[J].Pharmacogenomics,2013,14(6):623-630.
[22]PARK U C,SHIN J Y,KIM S J,et al.Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration[J].Retina,2014,34(2):288-297.
[23]DZENITA S,MUETHER P S,JOHN C,et al.Cumulative effect of risk alleles in cfh,arms2,and vegfa,on the response to ranibizumab treatment in age-related macular degeneration[J].Ophthalmology,2012,119(11):2304-2311.
[24]MIYAKE M,YAMASHIRO K,AKAGIKURASHIGE Y,et al.Vascular endothelial growth factor gene and the response to antivascular endothelial growth factor treatment for choroidal neovascularization in high myopia[J].Ophthalmology,2014,121(1):225.
[25]CHANG W,DONG H N,MIN S,et al.Pharmacogenetic association with early response to intravitreal ranibizumab for age-related macular degeneration in a Korean population[J].Mol Vis,2013,19(3):702-709.
[26]HAGSTROM S A,YING G,PAUER G J,et al.VEGF-A and VEGFR-2 gene polymorphisms and response to Anti-VEGF therapy in the comparison of AMD treatments trials(CATT)[J].JAMAOphthalmol,2014,132(5):521-527.
[27]ABEDI F,WICKREMASINGHE S,RICHARDSON A J,et al.Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration[J].Ophthalmology,2013,120(8):1641-1648.
[28]TIAN J,QIN X,FANG K,et al.Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population[J].Pharmacogenomics,2012,13(7):779-787.
[29]PARK U C,SHIN J Y,KIM S J,et al.Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration.[J].Retina,2014,34(2):288-297.
[30]HAGSTROM S A,YING G,PAUER G J,et al.Pharmacogenetics for genes associated with age-related macular degeneration(AMD)in the comparison of AMD treatments trials(CATT)[J].Ophthalmology,2013,120(3):593-599.
[31]AMOUYEL P,FEINGOLD J,LAGARDE J P.The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration.[J].Am J Ophthalmol,1998,125(3):353-359.
[32]BOJANOWSKI C M,SHEN D,CHEW E Y,et al.An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation[J].Am J Ophthalmol,2007,143(4):594.
[33]ADAMS M K M,SIMPSON J A,RICHARDSON A J,et al.Apolipoprotein E gene associations in age-related macular degeneration the melbourne collaborative cohort study[J].Am J Epidemiol,2012,175(6):511.
[34]WICKREMASINGHE S S,XIE J,LIM J,et al.Variants in the APOE gene are associated with improved outcome after anti-VEGFtreatment for neovascular AMD[J].Invest Ophthalmol Vis Sci,2011,52(7):4072-4079.
[35]BAKBAK B,OZTURK B T,ZAMANI A G,et al.Association of apolipoprotein e polymorphism with intravitreal ranibizumab treatment outcomes in age-related macular degeneration[J].Curr Eye Res,2016,41(6):862-866.
[36]LORéS-MOTTA L,VAN A F,MUETHER P S,et al.A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration[J].Pharmacogenet Genomics,2016,26(1):20-27.
[37]GEERLINGS M J,JONG E K D,HOLLANDER A I D.The complement system in age-related macular degeneration:A review of rare genetic variants and implications for personalized treatment[J/OL].Mol Immunol,2016,84:65-76.2017-04-01[2018-05-22].https://www.sciencedirect.com/science/article/pii/S0161589016302553?via%3Dihub.
[38]FRANCIS P J.The influence of genetics on response to treatment with ranibizumab(lucentis)for age-related macular degeneration:the lucentis genotype study(An American ophthalmological society thesis)[J/OL].Trans Am Ophthalmol Soc,2011,109:115-156.2011-12-01[2018-05-22].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259677/.
[2]邹海东,张皙,许迅等.上海市静安区曹家渡街道年龄相关性黄斑变性的患病率调查[J].中华眼科杂志,2005,41(1):15-19.
[3]BROWN D M,KAISER P K,MICHELS M,et al.Ranibizumab versus verteporfin for neovascular age-related macular degeneration[J].New Engl J Med,2006,355(14):1432-1444.
[4]ROSENFELD P J,SHAPIRO H,TUOMI L,et al.Characteristics of patients losing vision after 2 years of monthly dosing in the phaseⅢranibizumab clinical trials[J].Ophthalmology,2011,118(3):523-530.
[5]TAYLOR H R,PEZZULLO M L,KEEFFE J E.The economic impact and cost of visual impairment in Australia[J].Br J Ophthalmol,2006,90(3):272-275.
[6]REIN D B,ZHANG P,WIRTH K E,et al.The economic burden of major adult visual disorders in the United States[J].Arch Ophthalmol,2006,124(12):1754-1760.
[7]DAY S,ACQUAH K,LEE P P,et al.Medicare costs for neovascular age-related macular degeneration,1994-2007[J].Am JOphthalmol,2011,152(6):1014-1020.
[8]KAISER P K,BROWN D M,ZHANG K,et al.Ranibizumab for predominantly classic neovascular age-related macular degeneration:subgroup analysis of first-year ANCHOR results[J].Am JOphthalmol,2007,144(6):850-857.
[9]YING G S,HUANG J,MAGUIRE M G,et al.Baseline predictors of visual acuity response to ranibizumab and bevacizumab in the Comparison of AMD Treatment Trial(CATT)[J].Invest Ophthalmol Vis Sci,2012,53(14):3681.
[10]LEVY J,SHNECK M,ROSEN S,et al.Intravitreal bevacizumab(avastin)for subfoveal neovascular age-related macular degeneration[J].Int Ophthalmol,2009,29(5):349-357.
[11]FINGER R P,WICKREMASINGHE S S,BAIRD P N,et al.Predictors of anti-VEGF treatment response in neovascular agerelated macular degeneration[J].Surv Ophthalmol,2014,59(1):1-18.
[12]KLEIN R.Race/ethnicity and age-related macular degeneration[J].Am J Ophthalmol,2011,152(2):153-154.
[13]LEVEZIEL N,TILLEUL J,PUCHE N,et al.Genetic factors associated with age-related macular degeneration[J].Ophthalmologica,2010,226(3):87-102.
[14]CHEN H,YU K D,XU G Z.Association between variant Y402Hin age-related macular degeneration(AMD)susceptibility gene CFH and treatment response of AMD:a meta-analysis[J].PLoSOne,2012,7(8):e42464.2012-08-14[2018-05-22].https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042464.
[15]DIKMETAS O,KADAYIFCILAR S,ELDEM B.The effect of CFHpolymorphisms on the response to the treatment of age-related macular degeneration(AMD)with intravitreal ranibizumab[J].Mol Vis,2013,19(5):2571-2578.
[16]VELOSO C E,ALMEIDA L N,NEHEMY M B.CFH Y402H polymorphism and response to intravitreal ranibizumab in Brazilian patients with neovascular age-related macular degeneration[J].Rev Col Bras Cir,2014,41(6):386-392.
[17]YUAN D,YUAN D,LIU X,et al.Genetic association with response to intravitreal ranibizumab for neovascular age-related macular degeneration in the Han Chinese population[J].Ophthalmologica,2013,230(4):227-232.
[18]FRANCIS P J.The influence of genetics on response to treatment with ranibizumab(lucentis)for age-related macular degeneration:the lucentis genotype study(an american ophthalmological society thesis)[J/OL].Trans Am Ophthalmol Soc,2011,109:115-156.2011-12-01[2018-05-22].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259677/.
[19]HERMANN M M,VAN A F,MUETHER P S,et al.Polymorphisms in vascular endothelial growth factor receptor 2 are associated with better response rates to ranibizumab treatment in age-related macular degeneration[J].Ophthalmology,2014,121(4):905.
[20]HAGSTROM S A,YING G S,MAGUIRE M G,et al.VEGFR2gene polymorphisms and response to anti-vegf therapy in age-related macular degeneration[J].Ophthalmology,2015,122(8):1563-1568.
[21]LAZZERI S,FIGUS M,ORLANDI P,et al.VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration[J].Pharmacogenomics,2013,14(6):623-630.
[22]PARK U C,SHIN J Y,KIM S J,et al.Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration[J].Retina,2014,34(2):288-297.
[23]DZENITA S,MUETHER P S,JOHN C,et al.Cumulative effect of risk alleles in cfh,arms2,and vegfa,on the response to ranibizumab treatment in age-related macular degeneration[J].Ophthalmology,2012,119(11):2304-2311.
[24]MIYAKE M,YAMASHIRO K,AKAGIKURASHIGE Y,et al.Vascular endothelial growth factor gene and the response to antivascular endothelial growth factor treatment for choroidal neovascularization in high myopia[J].Ophthalmology,2014,121(1):225.
[25]CHANG W,DONG H N,MIN S,et al.Pharmacogenetic association with early response to intravitreal ranibizumab for age-related macular degeneration in a Korean population[J].Mol Vis,2013,19(3):702-709.
[26]HAGSTROM S A,YING G,PAUER G J,et al.VEGF-A and VEGFR-2 gene polymorphisms and response to Anti-VEGF therapy in the comparison of AMD treatments trials(CATT)[J].JAMAOphthalmol,2014,132(5):521-527.
[27]ABEDI F,WICKREMASINGHE S,RICHARDSON A J,et al.Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration[J].Ophthalmology,2013,120(8):1641-1648.
[28]TIAN J,QIN X,FANG K,et al.Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population[J].Pharmacogenomics,2012,13(7):779-787.
[29]PARK U C,SHIN J Y,KIM S J,et al.Genetic factors associated with response to intravitreal ranibizumab in Korean patients with neovascular age-related macular degeneration.[J].Retina,2014,34(2):288-297.
[30]HAGSTROM S A,YING G,PAUER G J,et al.Pharmacogenetics for genes associated with age-related macular degeneration(AMD)in the comparison of AMD treatments trials(CATT)[J].Ophthalmology,2013,120(3):593-599.
[31]AMOUYEL P,FEINGOLD J,LAGARDE J P.The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration.[J].Am J Ophthalmol,1998,125(3):353-359.
[32]BOJANOWSKI C M,SHEN D,CHEW E Y,et al.An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation[J].Am J Ophthalmol,2007,143(4):594.
[33]ADAMS M K M,SIMPSON J A,RICHARDSON A J,et al.Apolipoprotein E gene associations in age-related macular degeneration the melbourne collaborative cohort study[J].Am J Epidemiol,2012,175(6):511.
[34]WICKREMASINGHE S S,XIE J,LIM J,et al.Variants in the APOE gene are associated with improved outcome after anti-VEGFtreatment for neovascular AMD[J].Invest Ophthalmol Vis Sci,2011,52(7):4072-4079.
[35]BAKBAK B,OZTURK B T,ZAMANI A G,et al.Association of apolipoprotein e polymorphism with intravitreal ranibizumab treatment outcomes in age-related macular degeneration[J].Curr Eye Res,2016,41(6):862-866.
[36]LORéS-MOTTA L,VAN A F,MUETHER P S,et al.A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration[J].Pharmacogenet Genomics,2016,26(1):20-27.
[37]GEERLINGS M J,JONG E K D,HOLLANDER A I D.The complement system in age-related macular degeneration:A review of rare genetic variants and implications for personalized treatment[J/OL].Mol Immunol,2016,84:65-76.2017-04-01[2018-05-22].https://www.sciencedirect.com/science/article/pii/S0161589016302553?via%3Dihub.
[38]FRANCIS P J.The influence of genetics on response to treatment with ranibizumab(lucentis)for age-related macular degeneration:the lucentis genotype study(An American ophthalmological society thesis)[J/OL].Trans Am Ophthalmol Soc,2011,109:115-156.2011-12-01[2018-05-22].https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259677/.