中华眼底病杂志

中华眼底病杂志

萎缩型老年性黄斑变性的治疗研究进展

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萎缩型老年性黄斑变性(AMD)早期可不表现出明显的视觉功能丧失,因而不易被重视;进展至晚期,患者多因黄斑区视网膜地图样萎缩影响夜视力及中心视力而就医。目前用于临床或已进入临床试验治疗萎缩型AMD的药物包括改善脉络膜灌注、减少有害物质蓄积、防止氧化应激损伤、抑制炎症反应的药物以及神经保护剂、脂类代谢药物等。干细胞移植治疗萎缩型AMD是目前最有前景的治疗手段。理论上讲,采用人类干细胞分化来源的视网膜光感受器细胞及RPE细胞替代治疗萎缩型AMD是可行的;但如何提高种子细胞的定向诱导分化效率以及如何保证安全有效的RPE细胞移植及移植后的存活等问题仍亟待解决。目前已有多项研究发现多个基因位点的突变与萎缩型AMD有关,因此基因治疗在疾病的发生发展中也起着重要作用。

Atrophic age-related macular degeneration (AMD) does not show obvious loss of visual function in the early stage, so it is not easy to be taken seriously. In the advanced stage, most of the patients suffered from macular area retinal map atrophy, which affected night vision and central vision. Drugs currently used in clinical or clinical trials to treat atrophic AMD include drugs for improving choroidal perfusion, reducing the accumulation of harmful substances, preventing oxidative stress injury, inhibiting inflammatory reactions, as well as neuroprotectants and lipid metabolism drugs. Stem cell transplantation for atrophic AMD is currently the most promising treatment. In theory, it is feasible to replace atrophic AMD with retinal photoreceptor cells and RPE cells derived from human stem cell differentiation. However, there are still many problems to be solved, such as how to improve the efficiency of directional differentiation of seed cells and how to ensure the safe and effective RPE cell transplantation and survival after transplantation. At present, several studies have found that multiple locus mutations are associated with atrophic AMD, so gene therapy also plays an important role in the development of the disease.

关键词: 黄斑变性/治疗; 地图样萎缩; 综述

Key words: Macular degeneration/therapy; Geographic atrophy; Review

引用本文: 薛瑢, 万光明. 萎缩型老年性黄斑变性的治疗研究进展. 中华眼底病杂志, 2019, 35(1): 94-98. doi: 10.3760/cma.j.issn.1005-1015.2019.01.023 复制

1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis[J]. Lancet Glob Health, 2014, 2(2): 106-116. DOI: 10.1016/S2214-109X(13)70145-1.
2. Patel HR, Hariprasad SM, Eichenbaum D. Geographic atrophy: clinical impact and emerging treatments[J]. Ophthalmic Surg Lasers Imaging Retina, 2015, 46(1): 8-13. DOI: 10.3928/23258160-20150101-01.
3. Chew EY, Clemons TE, Agron E, et al. Long-term effects of vitamins C and E, beta-carotene, and zinc on age-related macular degeneration: AREDS report no.35[J]. Ophthalmology, 2013, 120(8): 1604-1611. DOI: 10.1016/j.ophtha.2013.01.021.
4. Hanus J, Zhang H, Wang Z, et al. Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells[J/OL]. Cell Death Dis, 2013, 4: 965[2013-12-18]. http://dx.doi.org/10.1038/cddis.2013.478. DOI: 10.1038/cddis.2013.478.
5. Datta S, Cano M, Ebrahimi K, et al. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD[J]. Prog Retin Eye Res, 2017, 60: 201-218. DOI: 10.1016/j.preteyeres.2017.03.002.
6. Miller JW. Age-related macular degeneration revisited--piecing the puzzle: the LXIX Edward Jackson memorial lecture[J]. Am J Ophthalmol, 2013, 155(1): 1-35. DOI: 10.1016/j.ajo.2012.10.018.
7. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration[J]. Science, 2005, 308(5720): 385-389. DOI: 10.1126/science.1109557.
8. Jakobsdottir J, Conley YP, Weeks DE, et al. Susceptibility genes for age-related maculopathy on chromosome 10q26[J]. Am J Hum Genet, 2005, 77(3): 389-407. DOI: 10.1086/444437.
9. Spencer KL, Olson LM, Anderson BM, et al. C3 R102G polymorphism increases risk of age-related macular degeneration[J]. Hum Mol Genet, 2008, 17(12): 1821-1824. DOI: 10.1093/hmg/ddn075.
10. Augustin AJ, Diehm C, Grieger F, et al. Alprostadil infusion in patients with dry age related macular degeneration: a randomized controlled clinical trial[J]. Expert Opin Investig Drugs, 2013, 22(7): 803-812. DOI: 10.1517/13543784.2013.794782.
11. Grunwald JE, Metelitsina TI, Dupont JC, et al. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity[J]. Invest Ophthalmol Vis Sci, 2005, 46(3): 1033-1038. DOI: 10.1167/iovs.04-1050.
12. Pemp B, Garhofer G, Lasta M, et al. The effects of moxaverine on ocular blood flow in patients with age-related macular degeneration or primary open angle glaucoma and in healthy control subjects[J]. Acta Ophthalmol, 2012, 90(2): 139-145. DOI: 10.1111/j.1755-3768.2010.01878.x.
13. Schmidl D, Pemp B, Lasta M, et al. Effects of orally administered moxaverine on ocular blood flow in healthy subjects[J]. Graefe’s Arch Clin Exp Ophthalmol, 2013, 251(2): 515-520. DOI: 10.1007/s00417-012-2207-1.
14. Harris A, Kagemann L, Ehrlich R, et al. The effect of sildenafil on ocular blood flow[J]. Br J Ophthalmol, 2008, 92(4): 469-473. DOI: 10.1136/bjo.2007.131789.
15. Metelitsina TI, Grunwald JE, DuPont JC, et al. Effect of Viagra on the foveolar choroidal circulation of AMD patients[J]. Exp Eye Res, 2005, 81(2): 159-164. DOI: 10.1016/j.exer.2005.01.017.
16. Radu RA, Han Y, Bui TV, et al. Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases[J]. Invest Ophthalmol Vis Sci, 2005, 46(12): 4393-4401. DOI: 10.1167/iovs.05-0820.
17. Mata NL, Lichter JB, Vogel R, et al. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration[J]. Retina, 2013, 33(3): 498-507. DOI: 10.1097/IAE.0b013e318265801d.
18. Dugel PU, Novack RL, Csaky KG, et al. Phase Ⅱ, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration[J]. Retina, 2015, 35(6): 1173-1183. DOI: 10.1097/IAE.0000000000000606.
19. Ding JD, Johnson LV, Herrmann R, et al. Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration[J]. Proc Natl Acad Sci USA, 2011, 108(28): 279-287. DOI: 10.1073/pnas.1100901108.
20. Pfizer. Efficacy, safety and tolerability study of RN6G in subjects with geographic atrophy secondary to age-related macular degeneration. In: ClinicalTrials.gov [cited 2017-01-06].
21. GlaxoSmithKline. Clinical study to investigate safety and efficacy of GSK933776 in adult patients with geographic atrophy secondary to agerelated macular degeneration. In: ClinicalTrials.gov [cited 2017-01-06].
22. Rhee KD, Nusinowitz S, Chao K, et al. CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Muller glial cells[J]. Proc Natl Acad Sci USA, 2013, 110(47): 4520-4529. DOI: 10.1073/pnas.1303604110.
23. Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration[J]. Proc Natl Acad Sci USA, 2011, 108(15): 6241-6245. DOI: 10.1073/pnas.1018987108.
24. Lai RK, Chun T, Hasson D, et al. Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat[J]. Vis Neurosci, 2002, 19(2): 175-185. DOI: 10.1017/S0952523802191152.
25. Allergan. A safety and efficacy study of brimonidine intravitreal implant in geographic atrophy secondary to age-related macular degeneration (BEACON). In: ClinicalTrials.gov [cited 2017-01-06].
26. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial[J]. JAMA, 2013, 309(19): 2005-2015. DOI: 10.1001/jama.2013.4997.
27. Maccarone R, Di Marco S, Bisti S. Saffron supplement maintains morphology and function after exposure to damaging light in mammalian retina[J]. Invest Ophthalmol Vis Sci, 2008, 49(3): 1254-1261. DOI: 10.1167/iovs.07-0438.
28. Zhu W, Wu Y, Meng YF, et al. Effect of curcumin on aging retinal pigment epithelial cells[J]. Drug Des Devel Ther, 2015, 9: 5337-5344. DOI: 10.2147/DDDT.S84979.
29. Collier RJ, Wang Y, Smith SS, et al. Complement deposition and microglial activation in the outer retina in light-induced retinopathy: inhibition by a 5-HT1A agonist[J]. Invest Ophthalmol Vis Sci, 2011, 52(11): 8108-8116. DOI: 10.1167/iovs.10-6418.
30. Jaffe GJ, Schmitz-Valckenberg S, Boyer D, et al. Randomized trial to evaluate tandospirone in geographic atrophy secondary to age-related macular degeneration: the GATE Study[J]. Am J Ophthalmol, 2015, 160(6): 1226-1234. DOI: 10.1016/j.ajo.2015.08.024.
31. Borrelli E, Diadori A, Zalaffi A, et al. Effects of major ozonated autohemotherapy in the treatment of dry age related macular degeneration: a randomized controlled clinical study[J]. Int J Ophthalmol, 2012, 5(6): 708-713. DOI: 10.3980/j.issn.2222-3959.2012.06.11.
32. Danis RP, Lavine JA, Domalpally A. Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects[J]. Clin Ophthalmol, 2015, 9: 2159-2174. DOI: 10.2147/OPTH.S92359.
33. Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in the formation of drusen in the aging eye[J]. Am J Ophthalmol, 2002, 134(3): 411-431. DOI: 10.1016/S0002-9394(02)01624-0.
34. Thomas TC, Rollins SA, Rother RP, et al. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv[J]. Mol Immunol, 1996, 33(17-18): 1389-1401. DOI: 10.1016/S0161-5890(96)00078-8.
35. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study[J]. Ophthalmology, 2014, 121(3): 693-701. DOI: 10.1016/j.ophtha.2013.09.044.
36. Potentia Pharmaceuticals Inc. Safety of intravitreal POT-4 therapy for patients with neovascular age-related macular degeneration (AMD) (ASaP). In: ClinicalTrials.gov [cited 2017-01-06].
37. Le KN, Gibiansky L, van Lookeren Campagne M, et al. Population pharmacokinetics and pharmacodynamics of lampalizumab administered intravitreally to patients with geographic atrophy[J]. CPT Pharmacometrics Syst Pharmacol, 2015, 4(10): 595-604. DOI: 10.1002/psp4.12031.
38. Landa G, Butovsky O, Shoshani J, et al. Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related macular degeneration[J]. Curr Eye Res, 2008, 33(11): 1011-1013. DOI: 10.1080/02713680802484637.
39. Glybina IV, Kennedy A, Ashton P, et al. Intravitreous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats[J]. Invest Ophthalmol Vis Sci, 2010, 51(8): 4243-4252. DOI: 10.1167/iovs.09-4492.
40. Alimera Sciences. Fluocinolone acetonide intravitreal inserts in geographic atrophy. In: ClinicalTrials.gov [cited 2017-01-06].
41. Wong WT, Dresner S, Forooghian F, et al. Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase Ⅰ/Ⅱ clinical trial[J]. Invest Ophthalmol Vis Sci, 2013, 54(4): 2941-2950. DOI: 10.1167/iovs.13-11650.
42. Barbosa DT, Mendes TS, Cintron-Colon HR, et al. Age-related macular degeneration and protective effect of HMG Co-A reductase inhibitors (statins): results from the National Health and Nutrition Examination Survey 2005-2008[J]. Eye (Lond), 2014, 28(4): 472-480. DOI: 10.1038/eye.2014.8.
43. Gehlbach P, Li T, Hatef E. Statins for age-related macular degeneration[J/OL]. Cochrane Database Syst Rev, 2012(3): CD006927[2012-03-14]. https://doi.org/10.1002/14651858.CD006927.pub3. DOI: 10.1002/14651858.CD006927.pub3.
44. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report[J]. Lancet, 2012, 379(9817): 713-720. DOI: 10.1016/S0140-6736(12)60028-2.
45. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies[J]. Lancet, 2015, 385(9967): 509-516. DOI: 10.1016/S0140-6736(14)61376-3.
46. Reardon S, Cyranoski D. Japan stem-cell trial stirs envy[J]. Nature, 2014, 513(7518): 287-288. DOI: 10.1038/513287a.
47. Jones MK, Lu B, Girman S, et al. Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases[J]. Prog Retin Eye Res, 2017, 58: 1-27. DOI: 10.1016/j.preteyeres.2017.01.004.
48. Cashman SM, Gracias J, Adhi M, et al. Adenovirus-mediated delivery of factor H attenuates complement C3 induced pathology in the murine retina: a potential gene therapy for age-related macular degeneration[J]. J Gene Med, 2015, 17(10-12): 229-243. DOI: 10.1002/jgm.2865.
49. Grassmann F, Fleckenstein M, Chew EY, et al. Clinical and genetic factors associated with progression of geographic atrophy lesions in age-related macular degeneration[J/OL]. PLoS One, 2015, 10(5): 0126636[2015-05-11]. http://dx.plos.org/10.1371/journal.pone.0126636. DOI: 10.1371/journal.pone.0126636.
50. Montes T, Tortajada A, Morgan BP, et al. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B[J]. Proc Natl Acad Sci USA, 2009, 106(11): 4366-4371. DOI: 10.1073/pnas.0812584106.
51. Boyer D, Freund KB, Regillo C, et al. Long-term (60-month) results for the implantable miniature telescope: efficacy and safety outcomes stratified by age in patients with end-stage age-related macular degeneration[J]. Clin Ophthalmol, 2015, 9: 1099-1107. DOI: 10.2147/OPTH.S86208.
52. 江伟, 唐由之, 梁丽娜, 等. 二至明目汤治疗非渗出性年龄相关性黄斑变性临床分析[J]. 中国中医眼科杂志, 2013, 23(3): 201-203.Jiang W, Tang YZ, Liang LN, et al. Clinical analysis on effect of Erzhi Mingmu Decoction for nonexudative age-related macular degeneration[J]. Journal of Traditional Chinese Ophthalmology, 2013, 23(3): 201-203.
53. 钟情. 杞黄颗粒治疗肝肾阴虚型AMD(干性)的疗效及对血清C5b-9水平的影响[D]. 广州中医药大学, 2015.Zhong Q. Clinical efficacy and complement 5b-9 complex levels of Qinghuang Granule on patients with yin deficiency of liver and kindney of age-related macular degeneration with fry type[D]. Guangzhou University of Chinese Medicine, 2015.
54. 夏勇, 刘睿, 孙竞劲, 等. 深刺眶区穴位为主治疗年龄相关性黄斑变性的临床研究[J]. 上海针灸杂志, 2014, 33(5): 421-423. DOI: 10.13460/j.issn.1005-0957.2014.05.0421.Xia Y, Liu R, Sun JJ, et al. Clinical study of deep needling at orbital points as main treatment for age-related macular degeneration[J]. Shanghai J Acu-mox, 2014, 33(5): 421-423. DOI: 10.13460/j.issn.1005-0957.2014.05.0421.
55. 江丹, 刘新泉, 张殷建, 等. 耳穴贴敷联合怡开片治疗干性黄斑变性的临床研究[J]. 世界中西医结合杂志, 2015(10): 1409-1411. DOI: 10.13935/j.cnki.sjzx.151024.Jiang D, Liu XQ, Zhang YJ, et al. Clinical study on auricular point applicator combined with pancreatick-ininogenase enteric-coated tablets ain treating macular degeneration[J]. World Journal of Integrated Traditional and Western Medicine, 2015(10): 1409-1411. DOI: 10.13935/j.cnki.sjzx.151024.
56. 栾相佳, 张隽. 中西医结合治疗肝肾不足型非渗出性年龄相关性黄斑变性的疗效观察[J]. 黑龙江医学, 2014(7): 785-786. DOI: 10.3969/j.issn.1004-5775.2014.07.018.Luan XJ, Zhang J. Clinical observation of combined Chinese and western medicine in the treatment of non-exudative age-related macular degeneration of liver and kidney deficiency[J]. Heilongjiang Medical Journal, 2014(7): 785-786. DOI: 10.3969/j.issn.1004-5775.2014.07.018.