药学学报

Treatment	Drug	Limitation
Glycemic control	-	Side effects including headaches and weight gain. Metabolic memory
Laser photocoagulation	-	Laser scar
Anti-VEGF therapy	Ranibizumab, bevacizumab, aflibercept	Corneal scars. Resistance to treatment after repeated injections
Corticosteroid therapy	Dexamethasone, triamcinolone, fluocinolone	Side effects: secondary ocular hypertension and cataracts
PKC inhibitors	Ruboxistaurin	Only be effective in conjunction with laser photocoagulation

Treatment	Drug	Limitation
Glycemic control	-	Side effects including headaches and weight gain. Metabolic memory
Laser photocoagulation	-	Laser scar
Anti-VEGF therapy	Ranibizumab, bevacizumab, aflibercept	Corneal scars. Resistance to treatment after repeated injections
Corticosteroid therapy	Dexamethasone, triamcinolone, fluocinolone	Side effects: secondary ocular hypertension and cataracts
PKC inhibitors	Ruboxistaurin	Only be effective in conjunction with laser photocoagulation

Classification	Agent	Disease	Target	ROA	Sponsor	Phase	Trail No.	BCVA (letters)
Antibody therapy	Lucentis	NPDR	VEGFA	IVT	Wonkwang University Hospital	4	NCT02834663	+8.76
Conbercept	PDR, TRD	PlGF/VEGF	IVT	Ruijin Hospital	4	NCT02816710	+9.2
Bevacizumab	PDR, TRD	VEGFA	IVT	Iran University of Medical Sciences	1	NCT00548197	+15
THR-317	DR, DME	PlGF	IVT	Thrombogenics	2	NCT03071068	\
Brolucizumab/RTH258	DME	VEGFA	IVT	Alcon Research	3	NCT02434328	+0.7
Faricimab (RO6867461)	DR	Ang-2/VEGFA	IVT	Hoffmann-La Roche	2	NCT02699450	+1.4/3.6
REGN910 (nesvacumab)	DME	Ang-2	IVT	Regeneron Pharmaceuticals	2	NCT02712008	-0.3/2
Small molecule drugs	Doxycycline monohydrate	DR	16S ribosomal RNA	Oral	Thomas Gardner	2	NCT00917553	\
BI 1467335	DR	VAP-1	IVT	Boehringer Ingelheim	2	NCT04424290	\
AKB-9778	NPDR	Tie2	SC	Aerpio Pharmaceuticals	2	NCT03197870	\
Emixustat hydrochloride	PDR	RPE65	Oral	Kubota Vision Inc	2	NCT02753400	\
Aminoguanidine	DR	AGEs	Oral	University of Minnesota	1	NCT02099981	+14.5/20
Fenofibrate	Diabetes, DR	PPARα	Oral	Jaeb Center for Health Research	4	NCT04661358	\
Spironolactone	DN, DR	Zinc ion	Oral	Peter Rossing	2/3	NCT02040441	\
Cholestyramine	Diabetes, DR, DN	Bile acids	Oral	University of Chile	4	NCT02249897	\
THR-149	DM, DR, DME	Plasma kallikrein	IVT	ThromboGenics	1/2	NCT04527107	+6.5
MS-553	DME, DR	PKC	Oral	MingSight Pharmaceuticals, Inc.	1	NCT04187443	\
APX3330	DME, DR	APE1	Oral	Ocuphire Pharma, Inc.	2	NCT04692688	\
α-Lipoic acid	NPDR	NF-κB	Oral	Ludwig-Maximilians	3	NCT01208948	\
Ubiquinone	NPDR	CoQ10	Oral	University of Guadalajara	2	NCT02062034	\
ASP8232	DME	VAP-1	IVT	Astellas Pharma Europe B.V	2	NCT02302079	\
Minocycline	DME	Microglial	Oral	National Eye Institute	1/2	NCT01120899	+9.3
SLV348	DME	PPARα	Oral	Abbott Products	2	NCT00683176	\
Bevasiranib	AMD, DR	VEGF	IVT	OPKO Health, Inc.	3	NCT00499590	\
Gene therapy	AGN 211745	DME	VEGFR	IVT	Allergan	2	NCT00395057	\
PF-04523655	DME, DR	RTP801	IVT	Quark Pharmaceuticals	2	NCT01445899	+2.7
Pegaptanib	PDR	VEGF165	IVT	Eyetech/Pfizer	3	NCT01189461	+2.21
ADVM-022	DME, DR	VEGF	IVT	Adverum Biotechnologies, Inc.	2	NCT04418427	+6.8
RGX-314	DR, w-AMD	VEGF	SCS	REGENXBIO	2	NCT03999801	\
rAAV.sFlt-1	MD	sFLT-1	SR	Adverum Biotechnologies	1/2	NCT01494805	+6.0
AAVCAGsCD59	d-AMD	Soluble CD59	IVT	Hemera Biosciences	1	NCT03144999	\
RetinoStat	AMD	Endostatin- angiostatin	SR	Oxford BioMedica	1	NCT01301443	+1.8
AdGVPEDF.11D	MD	PEDF	IVT	GenVec	1	NCT00109499	\
ARC1905	AMD	C5	IVT	Ophthotech Corporation	1	NCT00950638	\
EYE001 anti-VEGF aptamer	MD	VEGF	IVT	Eyetech Pharmaceuticals	2/3	NCT00021736	\

Classification	Agent	Disease	Target	ROA	Sponsor	Phase	Trail No.	BCVA (letters)
Antibody therapy	Lucentis	NPDR	VEGFA	IVT	Wonkwang University Hospital	4	NCT02834663	+8.76
Conbercept	PDR, TRD	PlGF/VEGF	IVT	Ruijin Hospital	4	NCT02816710	+9.2
Bevacizumab	PDR, TRD	VEGFA	IVT	Iran University of Medical Sciences	1	NCT00548197	+15
THR-317	DR, DME	PlGF	IVT	Thrombogenics	2	NCT03071068	\
Brolucizumab/RTH258	DME	VEGFA	IVT	Alcon Research	3	NCT02434328	+0.7
Faricimab (RO6867461)	DR	Ang-2/VEGFA	IVT	Hoffmann-La Roche	2	NCT02699450	+1.4/3.6
REGN910 (nesvacumab)	DME	Ang-2	IVT	Regeneron Pharmaceuticals	2	NCT02712008	-0.3/2
Small molecule drugs	Doxycycline monohydrate	DR	16S ribosomal RNA	Oral	Thomas Gardner	2	NCT00917553	\
BI 1467335	DR	VAP-1	IVT	Boehringer Ingelheim	2	NCT04424290	\
AKB-9778	NPDR	Tie2	SC	Aerpio Pharmaceuticals	2	NCT03197870	\
Emixustat hydrochloride	PDR	RPE65	Oral	Kubota Vision Inc	2	NCT02753400	\
Aminoguanidine	DR	AGEs	Oral	University of Minnesota	1	NCT02099981	+14.5/20
Fenofibrate	Diabetes, DR	PPARα	Oral	Jaeb Center for Health Research	4	NCT04661358	\
Spironolactone	DN, DR	Zinc ion	Oral	Peter Rossing	2/3	NCT02040441	\
Cholestyramine	Diabetes, DR, DN	Bile acids	Oral	University of Chile	4	NCT02249897	\
THR-149	DM, DR, DME	Plasma kallikrein	IVT	ThromboGenics	1/2	NCT04527107	+6.5
MS-553	DME, DR	PKC	Oral	MingSight Pharmaceuticals, Inc.	1	NCT04187443	\
APX3330	DME, DR	APE1	Oral	Ocuphire Pharma, Inc.	2	NCT04692688	\
α-Lipoic acid	NPDR	NF-κB	Oral	Ludwig-Maximilians	3	NCT01208948	\
Ubiquinone	NPDR	CoQ10	Oral	University of Guadalajara	2	NCT02062034	\
ASP8232	DME	VAP-1	IVT	Astellas Pharma Europe B.V	2	NCT02302079	\
Minocycline	DME	Microglial	Oral	National Eye Institute	1/2	NCT01120899	+9.3
SLV348	DME	PPARα	Oral	Abbott Products	2	NCT00683176	\
Bevasiranib	AMD, DR	VEGF	IVT	OPKO Health, Inc.	3	NCT00499590	\
Gene therapy	AGN 211745	DME	VEGFR	IVT	Allergan	2	NCT00395057	\
PF-04523655	DME, DR	RTP801	IVT	Quark Pharmaceuticals	2	NCT01445899	+2.7
Pegaptanib	PDR	VEGF165	IVT	Eyetech/Pfizer	3	NCT01189461	+2.21
ADVM-022	DME, DR	VEGF	IVT	Adverum Biotechnologies, Inc.	2	NCT04418427	+6.8
RGX-314	DR, w-AMD	VEGF	SCS	REGENXBIO	2	NCT03999801	\
rAAV.sFlt-1	MD	sFLT-1	SR	Adverum Biotechnologies	1/2	NCT01494805	+6.0
AAVCAGsCD59	d-AMD	Soluble CD59	IVT	Hemera Biosciences	1	NCT03144999	\
RetinoStat	AMD	Endostatin- angiostatin	SR	Oxford BioMedica	1	NCT01301443	+1.8
AdGVPEDF.11D	MD	PEDF	IVT	GenVec	1	NCT00109499	\
ARC1905	AMD	C5	IVT	Ophthotech Corporation	1	NCT00950638	\
EYE001 anti-VEGF aptamer	MD	VEGF	IVT	Eyetech Pharmaceuticals	2/3	NCT00021736	\

糖尿病视网膜病变治疗的现状与前景

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孔维文 ¹^,² , 任进 ¹^,²^,^*

药学学报 | 综述 2022,57(2): 287-295

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药学学报 | 综述 2022, 57(2): 287-295

糖尿病视网膜病变治疗的现状与前景

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孔维文¹^,², 任进¹^,²^,^*

作者信息

1.中国科学院上海药物研究所, 上海 201203

2.中国科学院大学, 北京 100049

通讯作者:

*任进, Tel/Fax: 86-21-58382922, E-mail: jren@cdser.simm.ac.cn

Current status and prospects for treatment of diabetic retinopathy

Wei-wen KONG¹^,², Jin REN¹^,²^,^*

Affiliations

1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

2. University of Chinese Academy of Sciences, Beijing 100049, China

出版时间: 2022-02-12 doi: 10.16438/j.0513-4870.2021-0519

文章导航

摘要

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糖尿病视网膜病变（diabetic retinopathy，DR）作为常见的糖尿病并发症之一，是导致失明的主要原因。由于目前临床上已有的治疗手段存在一定的局限性，亟待研发新靶标和新治疗药物。本文举例、总结了近年来DR治疗药物的临床试验进展，认为基因治疗可能是未来DR新兴治疗手段的潜在发展方向。眼部因其体积小、相对独立且具有免疫赦免特权、可局部给药等特点使基因治疗在DR治疗中可有效地发挥其优势，并且基因治疗所具有的长期治疗效果也提高了DR患者的依从性，这些都提示了基因治疗是DR治疗未来发展的方向。

关键词

糖尿病视网膜病变 / 病理机制 / 治疗局限性 / 临床试验 / 基因治疗

Abstract

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Diabetic retinopathy (DR), one of the common complications of diabetes, is the main cause of blindness. Due to the limitations of the existing clinical treatment methods, it is urgent to develop new targets or/and new therapeutic drugs. This review summarizes the clinical trials of anti-DR drugs in recent years, and we note that gene therapy is a potential direction for DR treatment development. Due to the characteristics of ocular structure, including small size, a relatively independent organ, immune privilege and the opportunity for local administration, gene therapy could well be advantageous in the treatment of DR. Furthermore, the long-term therapeutic effects of gene therapy also improve compliance by DR patients. All these indicate that gene therapy is likely a future direction for development of DR therapies.

Key words

diabetic retinopathy / pathological mechanism / treatment limitation / clinical trial / gene therapy

引用本文

孔维文, 任进. 糖尿病视网膜病变治疗的现状与前景. 药学学报, 2022 , 57 (2) : 287 -295 . DOI: 10.16438/j.0513-4870.2021-0519

Wei-wen KONG, Jin REN. Current status and prospects for treatment of diabetic retinopathy[J]. Acta Pharmaceutica Sinica, 2022 , 57 (2) : 287 -295 . DOI: 10.16438/j.0513-4870.2021-0519

正文

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糖尿病视网膜病变(diabetic retinopathy, DR) 发生在近1/3的糖尿病患者中^[1]。约有90%的1型糖尿病患者、55%未进行胰岛素干预的2型糖尿病患者患有DR, 这也是劳动年龄人群中主要的失明原因^[2]。DR根据病理特征可分为非增殖性DR (non-proliferative DR, NPDR) 和增殖性DR (proliferative DR, PDR)。广义上讲, 两种类型的DR均可影响视神经或周围视网膜^[3]。NPDR表现为微动脉瘤、出血、硬性渗出和微血管异常, 许多患有严重NPDR的患者将发展为以微血管增生和玻璃体出血为特征的PDR^[4]。PDR还以黄斑变性、黄斑水肿和局部缺血为主要临床表现。糖尿病性视网膜黄斑水肿(diabetic retinal macular edema, DME) 是由DR引起的严重眼病, 它可以在DR的任何阶段发生, 并且是DR患者失明的主要原因之一^[5]。血-视网膜屏障(blood-retinal barrier, BRB) 功能障碍也属于DR的常见病理特征, 主要表现为血管通透性增加^[6]。视网膜周细胞存在于血管组织周围, 是BRB的主要成分^[7], 在血管稳定中起重要作用, 这种细胞的丢失是导致BRB功能障碍的主要病理原因之一^[8]。

已有多项研究报道了DR的发病机制, 其中较为清楚的发病机制是高血糖诱发的氧化应激^[9]、炎症^[10]和线粒体功能障碍等。除了降糖药物外, 临床上DR常见的针对性治疗策略主要包括以激光光凝疗法为主的物理治疗和以血管内皮生长因子(vascular endothelial growth factor, VEGF) 抗体为主的药物治疗, 但是这些治疗方法均存在局限性。因此, 新靶标的发现和新治疗药物的开发亟待解决。目前, 处于临床研究中的DR治疗新型药物主要分为小分子、抗体和基因治疗药物。这些药物有的已经进入或完成了临床试验, 如蛋白激酶C (protein kinase C, PKC) 抑制剂AR-13503处于临床Ⅰ期^[11], 血管保护剂calcium dobesilate^[12]、前列腺素受体激动剂latanoprost^[13]和抗VEGF抗体药物aflibercept^[14]已经完成了临床试验。其中, 许多DR基因疗法的临床前及临床试验所显示的令人信服的结果提示基因治疗药物在DR治疗药物开发方面的潜力。基因治疗是当今药物开发中的热门话题, 尽管目前尚无针对DR的有效基因疗法批准进入临床使用, 但基因治疗的优势和眼部的特点等决定了基因治疗会是未来DR新兴疗法的关键研究方向。

1 DR病理机制、治疗现状及局限性

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1.1 病理机制

DR的发病机制非常复杂(图 1), 血糖升高会引起多种信号通路紊乱, 从而导致眼内发生多种生理生化的改变, 最终诱发视网膜微血管损伤和生理功能异常^[15-17]。

1.1.1 代谢信号通路异常

研究表明, 由高血糖引起的多种代谢信号传导途径失调可引发DR。如PKC的激活是高血糖引起的常见代谢异常之一, 高血糖会增加视网膜血管组织中的二酰基甘油(diacylglycerol, DAG) 水平, 这可能会触发DAG-PKC途径的激活^[18]。PKC的异常激活可通过上调丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)、转化生长因子-β (transforming growth factor-β, TGFβ)、VEGF和其他细胞因子来增加视网膜血管通透性并促进微血管增殖。同时, PKC还可以激活烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate, NADPH) 氧化酶, 从而加速血管内皮细胞和神经节细胞的氧化应激^[19]。

1.1.2 氧化应激和线粒体损伤

在DR患者中, 氧化应激主要由代谢信号通路异常引起。长时间暴露于高血糖环境下所致的糖基化终产物(advanced glycation end product, AGE) 可与视网膜细胞中高表达的AGEs受体(receptor for AGEs, RAGE) 结合, 激活下游的氧化应激反应^{[16, 20]}。此外, 高血糖促进的活性氧(reactive oxygen species, ROS) 异常积累也会导致氧化应激, 而氧化应激激活的下游反应最终会导致DR的发生^[21]。

研究表明, 由高血糖引起的线粒体功能障碍可导致DR^[22]。但是, 具体机制尚不清楚。更为可靠的假设是, ROS上调和氧化应激使线粒体的氧化呼吸链功能异常, 从而导致线粒体功能障碍。线粒体功能障碍导致细胞生理异常并促进细胞凋亡, 视网膜细胞的损伤和凋亡触发视网膜神经血管功能障碍, 进一步导致DR^[23]。

1.1.3 代谢性炎症

代谢性炎症是由营养物和代谢过剩所触发的炎症。在高血糖引起的氧化应激或血脂积累的影响下, 糖尿病患者眼内会产生大量炎症因子, 如白细胞介素6 (interleukin-6, IL-6)、白细胞介素2 (interleukin-2, IL-2) 和肿瘤坏死因子α (tumor necrosis factor α, TNFα) 等^[24]。炎症因子募集白细胞并介导白细胞与视网膜血管内皮细胞之间的相互作用, 导致视网膜血管内皮功能障碍。此外, 高血糖会破坏视网膜的神经感觉功能, 加速神经元凋亡, 从而加剧DR进程。更重要的是, 炎症因子可以促进VEGF的表达, 从而促进视网膜血管的渗漏和异常增生^[25]。因此, 炎症在DR的发病机制中起着至关重要的作用。

1.1.4 VEGF

实验数据表明, DR患者视网膜中VEGF的表达上调。在高血糖环境中, 视网膜胶质细胞会分泌大量VEGF^[26]。通过细胞外液的运输, VEGF将作用于视网膜血管内皮细胞, 并影响内皮细胞的结构和功能^[27]。VEGF还会影响血管内皮细胞的紧密连接, 这一过程是通过磷酸化细胞紧密连接蛋白, 如连环蛋白(catenin)^[28]、闭合蛋白(occludin)^[29]、连接蛋白(claudin5)^[30]、胞质紧密黏连蛋白(zonula occludens1)^[31]和接合素(connexin43)^[32]等实现的视网膜血管内皮细胞紧密连接受损, 从而导致血管渗漏。另外, VEGF还可以促进视网膜血管生成, 进一步影响DR进程。

1.2 治疗手段与局限性

糖尿病视网膜病变的临床治疗手段多种多样, 以激光光凝治疗和玻璃体注射抗体药物为主。尽管这些方法有一定效果, 但它们不能完全治愈DR, 同时也存在局限性(表 1)。

糖尿病控制与并发症试验(clinical data from diabetes control and complications trial, DCCT)、英国糖尿病前瞻性研究(UK diabetes prospective study, UKPDS) 和Accord Healthcare的临床数据表明, 通过注射胰岛素控制血糖是DR治疗的常见方法之一^[33]。但是, 血糖控制不能逆转DR的发展, 胰岛素治疗的不良反应也不能忽略。长期注射胰岛素可引发患者头痛、体重增加、耐药性产生等不良反应, 影响后续治疗。激光光凝疗法被广泛认为是DR的主要临床治疗方法, 对预防DR引起的视力丧失有缓解作用, 但是激光光凝疗法引起的激光疤痕会损害视网膜色素上皮并降低视力^[34]。

在过去的十年中, 抗VEGF治疗已成为一种更有效、更普遍的治疗方法^[35]。靶向VEGF信号通路的药物已经取得了进展, 包括ranibizumab、bevacizumab和aflibercept, 它们都是VEGF的抗体片段^[36]。Pegaptanib是与两个分支的20 kD聚乙二醇(PEG) 链共价连接的28-mer RNA适体, 具有抗血管生成活性。Pegaptanib可以结合并阻断VEGF的活性, 特别是165个氨基酸的同工型分子VEGF165^[35]。即使抗VEGF疗法非常有效, 但不良反应仍然不可忽略。由于抗体药物半衰期较短, 需要频繁地眼内给药, 这大大增加了患者的治疗痛苦。此外患者在多次注射后极易产生耐药性, 影响后续的治疗。

此外, DR的临床治疗还包括糖皮质激素、PKC抑制剂等。如今, 有多种糖皮质激素治疗药物, 如玻璃体注射的dexamethasone、triamcinolone、fluocinolone等, 这种治疗的不良反应包括继发性高眼压和白内障^[37]。研究表明, ruboxistaurin作为PKC抑制剂可以缓解糖尿病动物模型中的BRB功能障碍。但是, 已有研究证明该方法仅与激光光凝结合才有效^{[38, 39]}。

2 临床试验

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如今, 与DR治疗有关的多种药物已经进入临床试验阶段, 本节总结并举例说明了这些年来已完成或正在进行的临床试验的创新药物(表 2)。

2.1 抗体疗法

VEGF在DR患者眼内表达量上调, 是DR的主要治疗靶点, 抗VEGF抗体疗法也成为DR临床治疗的首选方法^[40]。由于这种疗法具有不可忽略的限制性, 因此, 在现有的抗体药物基础上, 为了提高治疗效果, 针对多靶点的抗体药物及联合疗法已成为未来研究的内容之一。

2.1.1 Faricimab

血管生成素-2 (angiopoietin-2, Ang-2) 是促进血管异常生成的蛋白, 在DR视网膜血管增生中发挥重要作用, 现在已被用作DR治疗的靶点^[41]。抗Ang-2和抗VEGF双抗疗法是临床DR的有效治疗方法, 可以稳定视网膜血管的形态和功能。Faricimab是一种用于糖尿病视网膜血管异常的抗Ang-2/抗VEGF抗体药物。该药已完成临床Ⅰ期和Ⅱ期试验, 其安全性和有效性得到了确认^{[42, 43]}。

在Ⅱ期临床试验中, faricimab、ranibizumab分别按照1.5、0.3 mg的剂量, 每月一次眼内注射给予未接受抗VEGF疗法的DR患者。通过36周的观察, 研究人员发现, 注射faricimab组患者的预后效果优于仅给予ranibizumab组。并且该药表现出良好的安全性, 现在已进入Ⅲ期临床试验^[44]。在Ⅲ期试验中, 患者将被随机分配为每16周给予faricimab或每8周给予对照药物aflibercept两组, 这项试验预计将于2022年或2023年结束。

2.1.2 Conbercept

Conbercept是一种新型重组融合抗体药物, 由VEGF受体(vascular endothelial growth factor receptor, VEGFR) 1的胞外域2、VEGFR2的胞外域3/4及人IgG的Fc段组成^[14]。这种抗体药物不仅可以阻断VEGF的多个亚型, 如VEGFA、VEGFB、VEGFC, 也可以阻断具有促进血管增生功能且被认为是DR治疗潜在靶点的胎盘生长因子(placental growth factor, PlGF)^[45]。研究表明, 在使用conbercept 3个月后, 患者视网膜的黄斑区的厚度达到最低, 并且注射过程中没有明显的并发症。研究人员认为, 除现有的抗VEGF治疗药物外, conbercept的现有临床试验结果可以证明其作为DR治疗药物的潜力^{[46, 47]}。

2.2 小分子药物

除了抗体药物外, 小分子抗炎类药物, 如糖皮质激素等也被用于DR的临床治疗。随着人们对DR发病机制和潜在分子靶点的认识不断深入, 已有多种相应的小分子药物进入临床研究。此外, 小分子药物和抗体药物的联合治疗也是DR药物开发的重点。

2.2.1 Fasudil

RHO激酶(Rho kinase, ROCK) 信号通路参与多种生理过程, 包括细胞增殖、细胞骨架调节、细胞间紧密连接等。研究表明, ROCK抑制剂可以缓解视神经损伤动物模型的眼部损伤^{[48, 49]}。Fasudil是ROCK的抑制剂。为了比较玻璃体内bevacizumab-fasudil联合给药、bevacizumab或fasudil单独给药的治疗效果, 研究者开展了试验。结果显示, 在联合给药组中, 54.5%患者的最佳矫正视力(best corrected visual acuity, BCVA) 提升多于15个字母, 而单独给药组仅10%的患者达到相同的治疗效果。因此, 玻璃体内注射ROCK抑制剂fasudil可能会增强和延长抗VEGF药物的治疗效果^[50]。

2.2.2 THR-149

血浆激肽释放酶(kallikrein) 是一种丝氨酸蛋白酶, 在炎症过程中起重要作用, 并参与DR的发展^[51]。THR-149是血浆kallikrein抑制剂, 研究者已对该药物进行临床研究。在临床试验中, THR-149体现了良好的安全性, 并且改善了患者的视力。在一次注射THR-149后, 患者的BCVA平均增加了6.4个字母。目前, 这种药物已成功结束了Ⅰ期临床试验, 正在进行Ⅱ期临床试验^[31]。

2.2.3 维生素D

据报道, 维生素D对由糖尿病引起的血管疾病具有保护作用^[52]。乳腺退化蛋白39 (breast regression protein 39, BRP-39/YKL-40) 是一种血管异常的生物标志物, 它可加剧糖尿病及其并发症^[53], 单核趋化蛋白-1 (monocyte chemoattractant protein-1, MCP-1) 被认为影响血管渗透性^[54]。为了研究维生素D对糖尿病患者血清中YKL-40和MCP-1的抑制作用, 研究人员进行了临床试验。糖尿病患者每日口服施用维生素D, 12周后, 检测了服用100 mg维生素D或安慰剂患者YKL-40、MCP-1、胰岛素、IL-6、TNF-α、25-(OH)-维生素D和糖化血红蛋白(glycated hemoglobin, HbA1c) 的血清水平。结果表明, 与安慰剂组相比, 维生素D干预患者血清中YKL-40和MCP-1的水平显著降低、胰岛素抵抗指数(homeostatic model assessment of insulin resistance, HOMA-IR) 降低^[55]。因此, 维生素D可以通过抑制血清中YKL-40和MCP-1的含量来缓解糖尿病的血管并发症。

2.3 基因治疗药物

除上述两种药物外, 基因治疗也进入了研究者的视野。DR基因治疗主要分为两个方面: 抑制视网膜血管的异常增殖和保护视网膜血管免受损伤^[56]。根据这两种分类, 研究人员已经启动了针对不同靶基因的临床研究, 其中VEGF仍是临床试验中占比最大的基因治疗靶点。在临床试验中, 腺相关病毒(adeno-associated virus, AAV) 载体占比最大。DR基因治疗药物也以视网膜下腔注射和玻璃体内注射为主要给药途径。

2.3.1 Bevasiranib

Bevasiranib是一种靶向VEGF基因的小干扰RNA (small interfering RNA, siRNA) 药物。据报道, bevasiranib可用于治疗年龄相关性黄斑变性(age-related macular degeneration, AMD)。在DR患者的视网膜中, VEGF含量显著增加, 该药物也可用作由糖尿病引起的眼科疾病的潜在药物^[57]。虽然在治疗以血管内容物渗出为病理特征的湿性AMD (wet age-related macular degeneration, w-AMD) 方面, bevasiranib作为ranibizumab的辅助药物显示出良好的药理活性, 但在安全方面, 该药物相比于ranibizumab没有明显的优势。因此, 该药物在临床Ⅲ期被终止。

2.3.2 PF-04523655

DNA损伤诱导转录子4 (DNA-damage-inducible transcript 4, DDIT4/RTP801) 是由缺氧诱导因子1 (hypoxia inducible factor 1, HIF-1) 响应基因表达的关键蛋白, 其在DR动物模型中上调, 是DR的潜在治疗靶点^{[58, 59]}。PF-04523655是靶向RTP801基因的siRNA药物, 主要针对高血糖引起的黄斑水肿。它剂量依赖性地抑制RTP801在大鼠视网膜中的表达, 并将临床分级为3或4级的严重DR发生率降低约60%。在临床试验的阶段, 与对照药物ranibizumab组相比, PF-04523655和ranibizumab联合用药组患者的BCVA改善了2.7个字母^{[60, 61]}。

2.3.3 RGX-314

RGX-314是由Regenxbio公司开发的基因治疗药物。它使用腺相关病毒AAV8携带编码VEGF单抗的基因片段, 旨在中和VEGF的活性, 改变新生血管泄漏和视网膜积液的形成。该药物的适应症包括w-AMD、DR和其他慢性视网膜疾病等^{[56, 62]}。在单次治疗严重AMD患者2个月后, RGX-314显示出持久的抗VEGF效应。73%接受RGX-314的患者在9个月后仍然不需要抗VEGF抗体药物注射, 这显示出良好的疗效。因此, 该药物可以作为DR治疗的潜在药物。

2.3.4 ADVM-022

ADVM-022是一种使用腺相关病毒作为载体的基因治疗药物, 该药物在临床前实验中表现了良好的DR治疗效果^[63]。这种疗法可以在眼内持续提供抗VEGF抗体aflibercept^[63]。和市售的VEGF抗体药物(商品名Eylea) 不同的是, Eylea需要定期眼内注射, 而ADVM-022有可能成为“一生一次”的眼内注射疗法, 这预计将显著降低全球数百万w-AMD和DME患者的治疗负担。在临床试验中, 与对照药物aflibercept相比, ADVM-022显示出良好的治疗效果, 高剂量组的患者不再需要抗VEGF治疗, 并且BCVA得到改善。

3 DR治疗前景—基因治疗

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现有的治疗手段均由于多种限制因素不再满足于DR患者的临床治疗。随着DNA重组技术的发展, 基因治疗已成为研究人员的关注重点。基因治疗药物可以在体内不断释放用于校正异常表达基因的外源基因或非编码序列, 无需频繁干预, 这减少了患者的治疗痛苦, 大大提高了患者的依从性^[64]。眼球体积小、相对独立等特征减少了外源物质引发的免疫反应, 使基因治疗成为更理想的DR治疗手段^[65]。前文提到的临床试验, 如RGX-314和ADVM-022都表现出良好的治疗效果和安全性^[66]。因此, 基因治疗已成为DR治疗手段有潜力的研究方向^[67]。

DR是一种由多因素导致的复杂代谢性疾病, 单一靶点的治疗方式效果可能并不显著, 因此研究者也已经发现了多个新的DR治疗潜在靶点, 如可溶性环氧化物水解酶2 (epoxide hydrolase 2, EPHX2)^[68]、NADPH氧化酶(NADPH oxidase, NOX)^[69]、去整合素-金属蛋白酶17 (A disintegrin and metalloproteinases 17, ADAM17)^[70]等, 这为DR的基因治疗提供了广阔的空间。

除了基因治疗靶点的选择, 载体的选择也十分重要。基因治疗载体分为病毒载体和非病毒载体。病毒载体主要包括腺病毒(adenovirus, Ad) 载体、AAV载体和慢病毒(lentivirus, LV) 载体等, 其中AAV载体在DR及其他眼部疾病的研究中占比最大。病毒载体由于良好的递送效果和较完善的纯化方法, 在临床前及临床试验中被广泛使用。但由于潜在的致基因突变毒性, 越来越多研究人员开展了非病毒载体的研究。相比于病毒载体, 非病毒载体具有更大的基因片段装载量及更好的安全性, 但非病毒载体的递送及转染能力有限, 因此对于非病毒载体的递送效率及给药方式仍需进一步优化^[71-73]。

4 总结与展望

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DR是具有复杂发病机制的糖尿病并发症之一, 其发生与许多信号通路有关。如今, 除基本的血糖控制药物外, 临床上还有许多新兴的治疗方法。治疗DR的抗体药物, 如ranibizumab、aflibercept等已经被纳入临床治疗手段^[36]。但是注射药物引起的疼痛和不良反应使新疗法的开发更加迫切。

现有DR药物的临床试验中, 抗体药物所占比例较大, 仅次于小分子药物, 而基因治疗药物所占比例较小。小分子药物以口服降糖药和小分子激素类药物为主, 抗体药物主要包括抗VEGF家族和VEGFR抗体。尽管这两种类型的药物仍是临床治疗的主流, 但是由于其治疗效果和给药方法的局限性, 它们并不是最理想的治疗方法。相对较少的眼部注射和长期有效性是解决此问题的最佳方式。罗氏最近宣布的雷珠单抗新药物递送系统在临床试验中发挥了良好作用。该药物输送系统需要植入到患者的玻璃体中, 通过在玻璃体内不断释放兰尼单抗来达到治疗效果, 从而减轻了患者多次注射的负担。尽管如此, 但是每年两次的补液可能仍会引起不良反应, 因此, 这种给药方法仍需要改进。

DR基因治疗很大程度上减轻了患者的治疗痛苦, 并且可以从转录水平直接抑制或激活靶基因的表达, 从而达到长期治疗效果。因此, 使用基因治疗手段治疗DR及黄斑变性是未来研究的重要方向。尽管已有部分DR基因治疗药物在临床研究中取得了良好的结果, 但大部分仍处于临床前试验阶段^[74]。体内基因表达的不可控性问题则是基因治疗中亟需解决的难题, 除此之外, 载体的选择和如今创伤性的给药方式也是DR基因治疗中的瓶颈。但随着科学技术的发展, 这些问题将被逐个攻破, 基因治疗将会成为DR的主要治疗手段之一。

作者贡献: 孔维文撰写; 任进指导修改。

利益冲突: 所有作者声明不存在利益冲突。

基金

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国家重大新药创制科技重大专项(2018ZX09201017-004)

参考文献

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2022年第57卷第2期

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doi: 10.16438/j.0513-4870.2021-0519

接收时间：2021-04-08
首发时间：2025-12-22
出版时间：2022-02-12

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收稿日期：2021-04-08
修回日期：2021-06-21

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国家重大新药创制科技重大专项(2018ZX09201017-004)

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1.中国科学院上海药物研究所, 上海 201203

2.中国科学院大学, 北京 100049

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*任进, Tel/Fax: 86-21-58382922, E-mail: jren@cdser.simm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Treatment	Drug	Limitation
Glycemic control	-	Side effects including headaches and weight gain. Metabolic memory
Laser photocoagulation	-	Laser scar
Anti-VEGF therapy	Ranibizumab, bevacizumab, aflibercept	Corneal scars. Resistance to treatment after repeated injections
Corticosteroid therapy	Dexamethasone, triamcinolone, fluocinolone	Side effects: secondary ocular hypertension and cataracts
PKC inhibitors	Ruboxistaurin	Only be effective in conjunction with laser photocoagulation

Treatment

Drug

Limitation

Glycemic control

Side effects including headaches and weight gain. Metabolic memory

Laser photocoagulation

Laser scar

Anti-VEGF therapy

Ranibizumab, bevacizumab, aflibercept

Corneal scars. Resistance to treatment after repeated injections

Corticosteroid therapy

Dexamethasone, triamcinolone, fluocinolone

Side effects: secondary ocular hypertension and cataracts

PKC inhibitors

Ruboxistaurin

Only be effective in conjunction with laser photocoagulation

Classification	Agent	Disease	Target	ROA	Sponsor	Phase	Trail No.	BCVA (letters)
Antibody therapy	Lucentis	NPDR	VEGFA	IVT	Wonkwang University Hospital	4	NCT02834663	+8.76
Conbercept	PDR, TRD	PlGF/VEGF	IVT	Ruijin Hospital	4	NCT02816710	+9.2
Bevacizumab	PDR, TRD	VEGFA	IVT	Iran University of Medical Sciences	1	NCT00548197	+15
THR-317	DR, DME	PlGF	IVT	Thrombogenics	2	NCT03071068	\
Brolucizumab/RTH258	DME	VEGFA	IVT	Alcon Research	3	NCT02434328	+0.7
Faricimab (RO6867461)	DR	Ang-2/VEGFA	IVT	Hoffmann-La Roche	2	NCT02699450	+1.4/3.6
REGN910 (nesvacumab)	DME	Ang-2	IVT	Regeneron Pharmaceuticals	2	NCT02712008	-0.3/2
Small molecule drugs	Doxycycline monohydrate	DR	16S ribosomal RNA	Oral	Thomas Gardner	2	NCT00917553	\
BI 1467335	DR	VAP-1	IVT	Boehringer Ingelheim	2	NCT04424290	\
AKB-9778	NPDR	Tie2	SC	Aerpio Pharmaceuticals	2	NCT03197870	\
Emixustat hydrochloride	PDR	RPE65	Oral	Kubota Vision Inc	2	NCT02753400	\
Aminoguanidine	DR	AGEs	Oral	University of Minnesota	1	NCT02099981	+14.5/20
Fenofibrate	Diabetes, DR	PPARα	Oral	Jaeb Center for Health Research	4	NCT04661358	\
Spironolactone	DN, DR	Zinc ion	Oral	Peter Rossing	2/3	NCT02040441	\
Cholestyramine	Diabetes, DR, DN	Bile acids	Oral	University of Chile	4	NCT02249897	\
THR-149	DM, DR, DME	Plasma kallikrein	IVT	ThromboGenics	1/2	NCT04527107	+6.5
MS-553	DME, DR	PKC	Oral	MingSight Pharmaceuticals, Inc.	1	NCT04187443	\
APX3330	DME, DR	APE1	Oral	Ocuphire Pharma, Inc.	2	NCT04692688	\
α-Lipoic acid	NPDR	NF-κB	Oral	Ludwig-Maximilians	3	NCT01208948	\
Ubiquinone	NPDR	CoQ10	Oral	University of Guadalajara	2	NCT02062034	\
ASP8232	DME	VAP-1	IVT	Astellas Pharma Europe B.V	2	NCT02302079	\
Minocycline	DME	Microglial	Oral	National Eye Institute	1/2	NCT01120899	+9.3
SLV348	DME	PPARα	Oral	Abbott Products	2	NCT00683176	\
Bevasiranib	AMD, DR	VEGF	IVT	OPKO Health, Inc.	3	NCT00499590	\
Gene therapy	AGN 211745	DME	VEGFR	IVT	Allergan	2	NCT00395057	\
PF-04523655	DME, DR	RTP801	IVT	Quark Pharmaceuticals	2	NCT01445899	+2.7
Pegaptanib	PDR	VEGF165	IVT	Eyetech/Pfizer	3	NCT01189461	+2.21
ADVM-022	DME, DR	VEGF	IVT	Adverum Biotechnologies, Inc.	2	NCT04418427	+6.8
RGX-314	DR, w-AMD	VEGF	SCS	REGENXBIO	2	NCT03999801	\
rAAV.sFlt-1	MD	sFLT-1	SR	Adverum Biotechnologies	1/2	NCT01494805	+6.0
AAVCAGsCD59	d-AMD	Soluble CD59	IVT	Hemera Biosciences	1	NCT03144999	\
RetinoStat	AMD	Endostatin- angiostatin	SR	Oxford BioMedica	1	NCT01301443	+1.8
AdGVPEDF.11D	MD	PEDF	IVT	GenVec	1	NCT00109499	\
ARC1905	AMD	C5	IVT	Ophthotech Corporation	1	NCT00950638	\
EYE001 anti-VEGF aptamer	MD	VEGF	IVT	Eyetech Pharmaceuticals	2/3	NCT00021736	\

Classification

Agent

Disease

Target

ROA

Sponsor

Phase

Trail No.

BCVA (letters)

Antibody therapy

Lucentis

NPDR

VEGFA

IVT

Wonkwang University Hospital

NCT02834663

+8.76

Conbercept

PDR, TRD

PlGF/VEGF

IVT

Ruijin Hospital

NCT02816710

+9.2

Bevacizumab

PDR, TRD

VEGFA

IVT

Iran University of Medical Sciences

NCT00548197

+15

THR-317

DR, DME

PlGF

IVT

Thrombogenics

NCT03071068

Brolucizumab/RTH258

DME

VEGFA

IVT

Alcon Research

NCT02434328

+0.7

Faricimab (RO6867461)

Ang-2/VEGFA

IVT

Hoffmann-La Roche

NCT02699450

+1.4/3.6

REGN910 (nesvacumab)

DME

Ang-2

IVT

Regeneron Pharmaceuticals

NCT02712008

-0.3/2

Small molecule drugs

Doxycycline monohydrate

16S ribosomal RNA

Oral

Thomas Gardner

NCT00917553

BI 1467335

VAP-1

IVT

Boehringer Ingelheim

NCT04424290

AKB-9778

NPDR

Tie2

Aerpio Pharmaceuticals

NCT03197870

Emixustat hydrochloride

PDR

RPE65

Oral

Kubota Vision Inc

NCT02753400

Aminoguanidine

AGEs

Oral

University of Minnesota

NCT02099981

+14.5/20

Fenofibrate

Diabetes, DR

PPARα

Oral

Jaeb Center for Health Research

NCT04661358

Spironolactone

DN, DR

Zinc ion

Oral

Peter Rossing

2/3

NCT02040441

Cholestyramine

Diabetes, DR, DN

Bile acids

Oral

University of Chile

NCT02249897

THR-149

DM, DR, DME

Plasma kallikrein

IVT

ThromboGenics

1/2

NCT04527107

+6.5

MS-553

DME, DR

PKC

Oral

MingSight Pharmaceuticals, Inc.

NCT04187443

APX3330

DME, DR

APE1

Oral

Ocuphire Pharma, Inc.

NCT04692688

α-Lipoic acid

NPDR

NF-κB

Oral

Ludwig-Maximilians

NCT01208948

Ubiquinone

NPDR

CoQ10

Oral

University of Guadalajara

NCT02062034

ASP8232

DME

VAP-1

IVT

Astellas Pharma Europe B.V

NCT02302079

Minocycline

DME

Microglial

Oral

National Eye Institute

1/2

NCT01120899

+9.3

SLV348

DME

PPARα

Oral

Abbott Products

NCT00683176

Bevasiranib

AMD, DR

VEGF

IVT

OPKO Health, Inc.

NCT00499590

Gene therapy

AGN 211745

DME

VEGFR

IVT

Allergan

NCT00395057

PF-04523655

DME, DR

RTP801

IVT

Quark Pharmaceuticals

NCT01445899

+2.7

Pegaptanib

PDR

VEGF165

IVT

Eyetech/Pfizer

NCT01189461

+2.21

ADVM-022

DME, DR

VEGF

IVT

Adverum Biotechnologies, Inc.

NCT04418427

+6.8

RGX-314

DR, w-AMD

VEGF

SCS

REGENXBIO

NCT03999801

rAAV.sFlt-1

sFLT-1

Adverum Biotechnologies

1/2

NCT01494805

+6.0

AAVCAGsCD59

d-AMD

Soluble CD59

IVT

Hemera Biosciences

NCT03144999

RetinoStat

AMD

Endostatin- angiostatin

Oxford BioMedica

NCT01301443

+1.8

AdGVPEDF.11D

PEDF

IVT

GenVec

NCT00109499

ARC1905

AMD

IVT

Ophthotech Corporation

NCT00950638

EYE001 anti-VEGF aptamer

VEGF

IVT

Eyetech Pharmaceuticals

2/3

NCT00021736