中华眼底病杂志

中华眼底病杂志

适配体及其在老年性黄斑变性治疗中的应用现状

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血管内皮生长因子(VEGF)、血小板源性生长因子(PDGF)和补体在老年性黄斑变性(AMD)的发病过程中发挥着重要作用。以VEGF165为靶分子获取的适配体哌加他尼钠已获美国食品与药品管理局批准用于渗出型AMD的治疗;而以PDGF-B、补体C5为靶分子获取的适配体E10030、ARC1905也已进入临床试验阶段,并均获得较好疗效。目前,针对AMD发病机制中多个作用靶点的联合治疗已成为AMD治疗的发展方向;多靶点拮抗的适配体目前已进入研发阶段,将可能成为AMD治疗的首选药物。

Vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and complements play key roles in the pathogenesis of age-related macular degeneration (AMD). Pegaptanib, the first therapeutic aptamer against VEGF165, has been approved by the Food and Drug Administration (FDA) of US for the treatment of exudative AMD. Another two aptamers E10030 and ARC1905, each target PDGF-B and complement C5 respectively, are undergoing clinical trials. Recent trends to treat AMD are combined therapies targeting multiple key molecules in the pathogenesis of AMD; aptamers against multiple targets may become the preferred drug for AMD.

关键词: 黄斑变性/治疗; 适体,核苷/治疗应用; 综述

Key words: Macular degeneration/therapy; Aptamers, nucleotide/therapeutic use; Review

引用本文: 卢建民, 孙晓晶, 马翔. 适配体及其在老年性黄斑变性治疗中的应用现状. 中华眼底病杂志, 2017, 33(4): 427-430. doi: 10.3760/cma.j.issn.1005-1015.2017.04.028 复制

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1. 白玉婧, 黎晓新. 新生血管性老年性黄斑变性药物治疗面临的挑战与未来的发展趋势[J]. 中华眼底病杂志, 2016, 32(1): 3-7. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.002.Bai YJ, Li XX. Progression and challenge of therapeutic strategies in neovascular age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2016, 32(1): 3-7. DOI: 10.3760/cma.j.issn.1005-1015.2016.01.002.
2. Hermann T, Patel DJ. Adaptive recognition by nucleic acid aptamers[J]. Science, 2000, 287(5454): 820-825. DOI: 10.1126/science.287.5454.820.
3. Kanwar JR, Shankaranarayanan JS, Gurudevan S, et al. Aptamer-based therapeutics of the past, present and future: from the perspective of eye-related diseases[J]. Drug Discov Today, 2014, 19(9): 1309-1321. DOI: 10.1016/j.drudis.2014.02.009.
4. Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase[J]. Science, 1990, 249(4968): 505-510. DOI: 10.1126/science.2200121.
5. Ellington AD, Szostak JW. In vitro selection of RNA molecules that bind specific ligands[J]. Nature, 1990, 346(6287): 818-822. DOI: 10.1038/346818a0.
6. Darmostuk M, Rimpelova S, Gbelcova H, et al. Current approaches in SELEX: an update to aptamer selection technology[J]. Biotechnol Adv, 2015, 33(6 Pt 2): 1141-1161. DOI: 10.1016/j.biotechadv.2015.02.008.
7. Sun H, Zu Y. A highlight of recent advances in aptamer technology and its application[J]. Molecules, 2015, 20(7): 11959-11980. DOI: 10.3390/molecules200711959.
8. Bruno JG. Predicting the uncertain future of aptamer-based diagnostics and therapeutics[J]. Molecules, 2015, 20(4): 6866-6887. DOI: 10.3390/molecules20046866.
9. Wang F, Rendahl KG, Manning WC, et al. AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat[J]. Invest Ophthalmol Vis Sci, 2003, 44(2): 781-790. DOI: 10.1167/iovs.02-0281.
10. Jellinek D, Green LS, Bell C, et al. Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth factor[J]. Biochemistry, 1994, 33(34): 10450-10456. DOI: 10.1021/bi00200a028.
11. Bell C, Lynam E, Landfair DJ, et al. Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro[J]. In Vitro Cell Dev Biol Anim, 1999, 35(9): 533-542. DOI: 10.1007/s11626-999-0064-y.
12. Drolet DW, Nelson J, Tucker CE, et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys[J]. Pharm Res, 2000, 17(12): 1503-1510. DOI: 10.1023/A: 1007657109012.
13. Eyetech Study Group. Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration[J]. Retina, 2002, 22(2): 143-152. DOI: 10.1097/00006982-200204000-00002.
14. Foy JW, Rittenhouse K, Modi M, et al. Local tolerance and systemic safety of pegaptanib sodium in the dog and rabbit[J]. J Ocul Pharmacol Ther, 2007, 23(5): 452-466. DOI: 10.1089/jop.2006.0149.
15. Eyetech Study Group. Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase Ⅱ study results[J]. Ophthalmology, 2003, 110(5): 979-986. DOI: 10.1016/S0161-6420(03)00085-X.
16. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration[J]. N Engl J Med, 2004, 351(27): 2805-2816. DOI: 10.1056/NEJMoa042760.
17. Siddiqui MA, Keating GM. Pegaptanib: in exudative age-related macular degeneration[J]. Drugs, 2005, 65(11): 1571-1579. DOI: 10.2165/00003495-200565110-00010.
18. CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration[J]. N Engl J Med, 2011, 364(20): 1897-1908. DOI: 10.1056/NEJMoa1102673.
19. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration[J]. N Engl J Med, 2006, 355(14): 1419-1431. DOI: 10.1056/NEJMoa054481.
20. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration[J]. Ophthalmology, 2012, 119(12): 2537-2548. DOI: 10.1016/j.ophtha.2012.09.006.
21. Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study[J]. Ophthalmology, 2014, 121(9): 1740-1747. DOI: 10.1016/j.ophtha.2014.03.026.
22. Farah SE. Treatment of neovascular age-related macular degeneration with pegaptanib and boosting with bevacizumab or ranibizumab as needed[J]. Ophthalmic Surg Lasers Imaging, 2008, 39(4): 294-298. DOI: 10.3928/15428877-20080701-05.
23. Hernández-Pastor LJ, Ortega A, García-Layana A, et al. Cost-effectiveness of ranibizumab compared with pegaptanib in neovascular age-related macular degeneration[J]. Graefe’s Arch Clin Exp Ophthalmol, 2010, 248(4): 467-476. DOI: 10.1007/s00417-009-1156-9.
24. Athanasakis K, Fragoulakis V, Tsiantou V, et al. Cost-effectiveness analysis of ranibizumab versus verteporfin photodynamic therapy, pegaptanib sodium, and best supportive care for the treatment of age-related macular degeneration in Greece[J]. Clin Ther, 2012, 34(2): 446-456. DOI: 10.1016/j.clinthera.2012.01.005.
25. Nishimura Y, Taguchi M, Nagai T, et al. Comparison of the effect between pegaptanib and ranibizumab on exudative age-related macular degeneration with small lesion size[J]. Clin Ophthalmol, 2012, 6: 365-368. DOI: 10.2147/OPTH.S30310.
26. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele[J]. Nature, 1996, 380(6573): 435-439. DOI: 10.1038/380435a0.
27. Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury[J]. Am J Pathol, 2007, 171(1): 53-67. DOI: 10.2353/ajpath.2007.061237.
28. Saint-Geniez M, Kurihara T, Sekiyama E, et al. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris[J]. Proc Natl Acad Sci USA, 2009, 106(44): 18751-18756. DOI: 10.1073/pnas.0905010106.
29. Friberg TR, Tolentino M, LEVEL Study Group, et al. Pegaptanib sodium as maintenance therapy in neovascular age-related macular degeneration: the LEVEL study [J]. Br J Ophthalmol, 2010, 94(12): 1611-1617. DOI: 10.1136/bjo.2009.174946.
30. Ishibashi T, LEVEL-J Study Group. Maintenance therapy with pegaptanib sodium for neovascular age-related macular degeneration: an exploratory study in Japanese patients (LEVEL-J study)[J]. Jpn J Ophthalmol, 2013, 57(5): 417-423. DOI: 10.1007/s10384-013-0255-7.
31. Inoue M, Kadonosono K, Arakawa A, et al. Long-term outcome of intravitreal pegaptanib sodium as maintenance therapy in Japanese patients with neovascular age-related macular degeneration[J]. Jpn J Ophthalmol, 2015, 59(3): 173-178. DOI: 10.1007/s10384-015-0374-4.
32. Lindahl P, Johansson BR, Levéen P, et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice[J]. Science, 1997, 277(5323): 242-245. DOI: 10.1126/science.277.5323.242.
33. Dong A, Seidel C, Snell D, et al. Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A[J]. Angiogenesis, 2014, 17(3): 553-562. DOI: 10.1007/s10456-013-9402-5.
34. Green LS, Jellinek D, Jenison R, et al. Inhibitory DNA ligands to platelet-derived growth factor B-chain[J]. Biochemistry, 1996, 35(45): 14413-14424. DOI: 10.1021/bi961544+.
35. Jaffe GJ, Eliott D, Wells JA, et al. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration[J]. Ophthalmology, 2016, 123(1): 78-85. DOI: 10.1016/j.ophtha.2015.09.004.
36. Jaffe GJ, Ciulla TA, Ciardella AP, et al. Dual Antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase Ⅱb, multicenter, randomized controlled trial[J]. Ophthalmology, 2017, 124(2): 224-234. DOI: 10.1016/j.ophtha.2016.10.010.
37. Mullins RF, Schoo DP, Sohn EH, et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning[J]. Am J Pathol, 2014, 184(11): 3142-3153. DOI: 10.1016/j.ajpath.2014.07.017.
38. Reynolds R, Hartnett ME, Atkinson JP, et al. Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes[J]. Invest Ophthalmol Vis Sci, 2009, 50(12): 5818-5827. DOI: 10.1167/iovs.09-3928.
39. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization[J]. Proc Natl Acad Sci USA, 2006, 103(7): 2328-2333. DOI: 10.1073/pnas.0408835103.
40. Cortright DN, Meade R, Waters SM, et al. C5a, but not C3a, increases VEGF secretion in ARPE-19 human retinal pigment epithelial cells[J]. Curr Eye Res, 2009, 34(1): 57-61. DOI: 10.1080/02713680802546658.
41. Coughlin B, Schnabolk G, Joseph K, et al. Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells[J]. Sci Rep, 2016, 6: 23794. DOI: 10.1038/srep23794.
42. Brandstetter C, Holz FG, Krohne TU. Complement component C5a primes retinal pigment epithelial cells for inflammasome activation by lipofuscin-mediated photooxidative damage[J]. J Biol Chem, 2015, 290(52): 31189-3198. DOI: 10.1074/jbc.M115.671180.
43. Bora PS, Sohn JH, Cruz JM, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization[J]. J Immunol, 2005, 174(1): 491-497. DOI: 10.4049/jimmunol.174.1.491.
44. Biesecker G, Dihel L, Enney K, et al. Derivation of RNA aptamer inhibitors of human complement C5[J]. Immunopharmacology, 1999, 42(1-3): 219-230. DOI: 10.1016/S0162-3109 (99)00020-X.
45. Drolet DW, Green LS, Gold L, et al. Fit for the eye: aptamers in ocular disorders[J]. Nucleic Acid Ther, 2016, 26(3): 127-146. DOI: 10.1089/nat.2015.0573.