视网膜色素变性遗传学研究概况及基因治疗展望

视网膜色素变性遗传学研究概况及基因治疗展望汪东生李建军张铁民承德医学院附属医院眼科（０６７０００）视网膜色素变性（ｒｅｔｉｎｉｔｉｓｐｉｇｍｅｎｔｏｓａＲＰ）是一种发病机制尚未完全查明的遗传性疾病，它的临床表现以夜盲、进行性视野缩窄、眼底特征性改变和...     

视网膜色素变性的遗传学及治疗学研究进展

视网膜色素变性(retinitis pigmentosa，RP)是一组常见的、具有高度遗传异质性的可致盲性眼病，近年来随着分子遗传学及生物化学的介入，RP的遗传学研究取得了很大进展，为其治疗提供了新的方向，本就其遗传学及治疗学研究现状进行综述。     

视网膜色素变性的分子生物学及基因治疗研究进展

视网膜色素变性（retinitis pigmentosa,RP)是导致视觉损害最常见的遗传性眼病，历来是众医学家的研究焦点，本文对晚近RP的分子生物学和基因治疗前景进行了综述。     

视网膜色素变性分子遗传学研究现状

视网膜色素变性是由于视网膜感光细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的最常见的遗传性眼底病,具有大的临床和遗传异质性。其遗传方式可为常染色体显性、常染色体隐性、Ｘ染色体连锁遗传和散发型。目前已发现ＲＰ相关基因１４种,其中常染色体显性遗传４种,常染色体隐性遗传８种（包括视紫质）,Ｘ染色体连锁遗传２种,本文着重阐述了已知ＲＰ相关基因的研究现状。     

视网膜色素变性基因治疗的相关研究进展

视网膜色素变性(RP)是以视杆和视锥感光细胞退化及视网膜色素上皮细胞变性为特征的遗传性视网膜疾病。RP发病年龄和病情进展与基因和遗传方式有关,受环境影响。基因治疗通过载体转移治疗性基因,对靶细胞进行遗传修饰,纠正或替代致病RP基因。本文介绍RP基因治疗相关基因载体研究进展,并就5个常见基因型(RHO、PDE6B、MERTK、RLBP1、RPGR)对RP基因治疗疗效及安全性研究进展予以综述。     

视网膜色素变性的遗传学及治疗学研究进展

视网膜色素变性(retinitis pigmentosa,RP)是一组常见的、具有高度遗传异质性的可致盲性眼病,近年来随着分子遗传学及生物化学的介入,RP的遗传学研究取得了很大进展,为其治疗提供了新的方向,本文就其遗传学及治疗学研究现状进行综述。     

常染色体隐性遗传性视网膜色素变性的分子遗传学研究

目前发现视网膜色素变性 (ＲｅｔｉｎｉｔｉｓＰｉｇｍｅｎｔｏｓａ ,ＲＰ)与视紫红质基因的数十种突变有关 ,其中大部分为常染色体显性遗传型ＲＰ (ＡＤＲＰ)。由于常染色体隐性遗传型ＲＰ (ＡｕｔｏｓｏｍａｌＲｅｃｅｓｓｉｖｅＲＰ ,ＡＲＲＰ)家系相对较小且致病基因携带者     

药物治疗与基因治疗视网膜色素变性研究进展

视网膜色素变性（RP）是一组遗传性退行性视网膜疾病，主要影响视杆细胞和视网膜色素上皮细胞（RPE）。早期特征性临床表现为夜盲和周边视野的丧失，最终导致中心视力的丧失。RP全世界发病率为1／3500，它具有多种遗传方式，其中常染色体显性遗传（ADRP）占15％～20％，常染色体隐性遗传（ARRP）占20％～25％，X染色体连锁遗传（XLRP）占10％～15％，散发型占40％～45％。近来在药物治疗及基因治疗RP方面取得了一些进展，下面就对这两方面进行综述。     

家族性视网膜色素变性临床遗传学研究

对一家系６代视网膜色素变性患者及家族成员８０余人进行调查，结果表明患病人数２４例，患病率３０％。其中男性患者１５例，女性患者９例。而在本家族血统者６２人中，患病率３９％。家系中连续６代均有患者，男女发病机率均等，遗传学分析确定为常染色体显性遗传病。文中列举讨论了一些典型病例和特异现象，如并发恶性青光眼、先天性白内障、先天性视网膜血管异常等，值得进一步研究和探讨。     

原发性视网膜色素变性抗凋亡治疗研究进展

视网膜色素变性的病理学基础是色素上皮细胞和锥杆细胞的渐进性死亡。这些细胞的死亡是经过凋亡的形式完成的。bcl—2和睫状神经营养因子能抑制这种自然进程的的凋亡。本文从抗细胞凋亡的角度综述了视网膜色素变性的基因治疗。     

视网膜变性Pde6b基因突变小鼠治疗的研究进展

视网膜变性动物模型是研究人类遗传性视网膜变性疾病治疗的重要工具,目前常用于基础研究的视网膜变性动物模型包括系列视杆细胞变性小鼠(rd),如rd1小鼠、rd10小鼠和nmf137小鼠,这些模型鼠均为磷酸二酯酶β亚基(Pde6b,PDEβ)基因突变的小鼠模型,因其发病机制与人类具有某些同源性,因而已大量应用于视网膜变性疾病的基因诊断和治疗研究中.为了探索更为有效的治疗方法,就3种模型鼠的发病机制、药物治疗、神经营养治疗以及干细胞治疗方法、疗效等的研究进展进行综述.     

视网膜色素变性治疗的研究进展

视网膜色素变性(retinitis pigmentosa,RP)是由视网膜光感受器和视网膜色素上皮变性所引起的致盲性、遗传性眼病,目前尚无有效的治疗方法,相关治疗研究还处于探索阶段,如基因治疗、药物治疗、移植治疗、人工视网膜假体等。基因治疗RP是目前的研究热点,包括修复致病基因、核酸治疗、RNA干扰技术等。基因治疗、干细胞移植、人工视网膜假体治疗RP已经进入临床试验阶段,为治疗该病带来了新的希望。本文就RP治疗的研究进展做一综述。     

Recent advances in the molecular genetics of retinitis pigmentosa

In recent years a rapid development in gene cloning techniques has been seen which has, in part, been responsible for the elucidation of the molecular mechanisms involved in many hereditary diseases. Most noteworthy is the rapid detection of mutations in various genes Most noteworthy is the rapid detection of mutations in various genes associated with various retinal degenerations and disorders. There is an increasing need for ophthalmologists to keep abreast with these new developments to better understand disease processes and recognize new opportunities for the diagnosis and treatment of these conditions. In addition, more recent discoveries in molecular genetics have revealed previously unrecognized associations between different clinical entities that share common gene mutations (gene sharing), as well as distinctly different molecular alterations within the spectrum of what traditionally was believed to be the same disease (locus heterogeneity). These findings will most likely, in the future, invoke the need to redefine disease categories at the molecular level. This article reviews basic molecular genetics useful to ophthalmologists and examines in detail these concepts with regard to one representative hereditary retinal disease--retinitis pigmentosa.     

Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives

Retinitis Pigmentosa (RP) is a hereditary retinopathy that affects about 2.5 million people worldwide. It is characterized with progressive loss of rods and cones and causes severe visual dysfunction and eventual blindness in bilateral eyes. In addition to more than 3000 genetic mutations from about 70 genes, a wide genetic overlap with other types of retinal dystrophies has been reported with RP. This diversity of genetic pathophysiology makes treatment extremely challenging. Although therapeutic attempts have been made using various pharmacologic agents (neurotrophic factors, antioxidants, and anti-apoptotic agents), most are not targeted to the fundamental cause of RP, and their clinical efficacy has not been clearly proven. Current therapies for RP in ongoing or completed clinical trials include gene therapy, cell therapy, and retinal prostheses. Gene therapy, a strategy to correct the genetic defects using viral or non-viral vectors, has the potential to achieve definitive treatment by replacing or silencing a causative gene. Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP. It is about to be approved as the first ocular gene therapy biologic product. Despite current limitations such as limited target genes and indicated patients, modest efficacy, and the invasive administration method, development in gene editing technology and novel gene delivery carriers make gene therapy a promising therapeutic modality for RP and other hereditary retinal dystrophies in the future.     

常染色体显性视网膜色素变性家系基因定位的研究与视紫红质基因突变的检测分析

对一常染色体显性视网膜色素变性 (autosomaldominantretinitispigmentosa ,ADRP)大家系进行基因定位 ,并检测该家系12名患者的视紫红质基因是否存在突变。方法 :采用多个已知位点的遗传标记对该ADRP家系进行连锁分析 ,确定致病基因的大致染色体位置 ;在所定位的染色体区域将RHO基因作为侯选基因进行直接测序检测突变。结果 :连锁分析结果发现遗传标记D3S12 92 ,当θ =0 1时有最大Lod值 =2 732 85 2 ,因此考虑该家系致病基因位于D3S12 92附近。直接测序结果发现该家系中大部分患者在RHO基因的第 3外显子序列 ,第 182密码子的第 2个碱基发生G→A置换突变 ,导致甘氨酸 (Gly)变为天冬氨酸 (Asp) ,命名为Gly -182 -Asp突变 ,而在 2例患者中则未发现突变 ;同时 ,在该家系正常成员以及正常对照者中均未发现此突变。结论 :ADRP存在分子水平的遗传异质性 ,某些ADRP是由于RHO基因突变所致。但是由于本研究所涉及的ADRP家系中尚有2名患者未找到RHO基因突变 ,故不能将Gly -182 -Asp突变认为是该家系的致病原因。在D3S12 92与RHO基因之间可能存在新的基因 ,还需进一步研究证明。     

神经营养因子治疗视网膜色素变性的研究进展

神经营养因子是能够促进神经元存活、生长、分化及维持其功能的多效性肽类因子的总称,可被作为有效的神经保护剂用于治疗多种神经变性类疾病.视网膜色素变性(RP)是以光感受器-视网膜色素上皮复合体损害为主的高度遗传异质性视网膜变性疾病,神经营养因子作为不针对致病基因的RP治疗策略,其疗效已在多种视网膜变性的动物模型中得到证实.以病毒为载体的转基因治疗和细胞包囊技术为神经营养因子提供了有效的给药途径,可使疗效明显提高.对神经营养因子在视网膜中的表达及其调节、受体分布特点、作用通路、疗效及副作用等方面的深入研究为神经营养因子的临床应用奠定了基础.     

Nanoparticle applications in ocular gene therapy

The use of nanoparticles as carriers for the delivery of therapeutic materials to target tissues has became popular in recent years and has demonstrated great potentials for the treatments of a wide range of diseases. In this review, we summarize the advantages of nanotechnology as a common gene delivery strategy with emphasis on ocular therapy. Particular attention is paid to the CK30-PEG compacted DNA nanoparticles that have been successfully tested in the eye, lung, and brain. These particles resulted in higher transfection efficiency and longer duration of expression than other non-viral vectors without any toxicity or other side effects. They have been safely used clinically and are efficient for a broad range of gene therapy applications. The review also discusses mechanisms of nanoparticle uptake and internalization by cells, obstacles and limitations to the use of this technology, as well as novel methodologies to optimize nanoparticle driven gene expression.     

散发性视网膜色素变性视紫红质基因突变筛查

目的研究中国人散发性视网膜色素变性（sporadic retinitis pigmentosa，SRP）患者视紫红质（rhodopsin，RHO）基因突变频率及特征，揭示其在SRP发病机制中的潜在作用。方法运用聚合酶链反应一单链构象多态性（polymerase chain reaction—single—strand conformation polymorphism，PCR—SSCP）结合DNA测序技术，对80例SRP患者和80例健康对照者进行RHO基因5个外显子的突变筛查。结果SRP患者RHO基因5个外显子PCR扩增产物经SSCP分析后，发现其电泳带型与对照组一致，均包括2条单链带和1条双链带，且电泳迁移率相同，即在患者和对照组中均未检测到RHO基因突变。结论中国人SRP患者RHO基因外显子的突变率较低；PCR—SSCP分子遗传学方法快速、简单、灵敏，适用于大批量RP患者的基因变异筛查。（中国眼耳鼻喉科杂志，2008，8：351—353）