类风湿的生物治疗

nullnull类风湿关节炎的生物治疗类风湿关节炎的生物治疗孔德军 哈尔滨医科大学第二临床医学院 风湿免疫科nullLandre-Beauvais，于1800年首次描述RA 1922年英国卫生部正式采纳类风湿关节炎的命名。 概念: 类风湿关节炎是一种病因不明以关节滑膜炎为特征的慢性全身性自身免疫性疾病。滑膜炎持久反复发作，可导致关节内软骨和骨破坏，关节功能障碍，甚至残废。血官炎病变累及全身各个器官 。 null【发病机制】 类风湿性关节炎是一种自身免疫性疾病， 但是自身免疫性疾 病,包括类风湿性关节 炎是如何起病的仍并不清楚。一般认为, 环境因素（如微生物感染）为触发因子。 但如何触发 疾病却仍是个谜。 推测: 抗原进入体内 → 被巨噬细胞吞噬→　　　　　 MHC-II +抗原→复合物→被Ｔ细胞受体识　 　　　 别→该Ｔ附助淋巴细胞被激活→分泌→ null 细胞因子 免疫球蛋白 免 → 生长因子→B细胞被激活→RF →疫 各种介质 其它抗体 复 合 　　　　 　　　　↘　　　　　　　　↓　　　　↙ 物 　　 关节出现炎症和破坏 null【临床现】 多数隐匿形式起病最多见、乏力、低热是常为首发症状，数月后渐出现多关节肿胀，疼痛，活动受限，发展为典型类风湿关节炎。 少数急性发病：在较短的时间内出现明显的、对称性的多关节肿胀、疼痛，活动明显受限，晨僵，伴有低热，肌痛，淋巴结肿大。 （一）关节表现 1.晨僵：指早上醒来时关节局部或全部活动不灵、发紧、僵硬的感觉 。缓解，而类风湿关节炎的晨僵1h以上。晨僵是炎症的一种非特异性表现，持续时间的长短与关节的炎症程度呈正比。 null 2.疼痛与压痛： 疼痛可表现为关节隐痛、胀痛、钝痛、锥 钻 痛、麻痛、刀割痛和剧痛，可间歇痛,也可持 续样疼痛。疼痛关节往往伴有压痛,是炎症的 客观指标。 3.肿胀： 关节肿胀是关节滑膜炎症的典型表现。早期是 由于各种炎性物质引起滑膜充血、水肿，关节 腔渗出，关节周围软组织水肿所致。中晚期是 由于滑膜增生，纤维组织增生,骨赘形成致。 null 少数患者关节肿胀时可有关节局部发热，关节表面皮肤温度常升高，多见于炎症明显的活动性病变关节。 4.关节畸形 类风湿关节炎可累及全身所有大小关节的滑膜、软骨、骨、肌腱、韧带、滑囊、肌膜及附近的肌肉。近端指间关节最常发病，呈梭状肿大；其次为掌指、趾、腕、膝、肘、踝、肩和髋关节等。病变关节最后变成僵硬而畸形，膝、肘、手指、腕部都固定在屈位。有钮扣畸形、天鹅颈，尺侧偏移、足下垂、足外翻畸形等改变。 nullnullRheumatoid arthritis often affects small and large joints on both sides of the body (symmetry), such as both hands, both wrists or elbows, or the balls of both feet. Less commonly affected are hips and the neck null nullnull null null The syndrome ordinarily emerges after years of seropositive, persistently active RA; however, vasculitis may occur when joints are inactive null诊断 1．晨僵至少1小时（≥6周）。 2．3个或3个以上关节肿（≥6周）。 3．腕、掌指关节或近端指间关节肿（≥6周）。 4．对称性关节肿（≥6周）。 5．皮下结节。 6．手X光片改变。 7．类风湿因子含量升高。 具备4条或4条以上标可确诊为RA 。其敏感性为 93%，特异性为90%。 在发病的第1年30%的患者会出关节侵蚀， 2年内70%的患者出现关节破坏， 4年内有近40% 的患者丧失劳动力。在发病的第1年30%的患者会出关节侵蚀， 2年内70%的患者出现关节破坏， 4年内有近40% 的患者丧失劳动力。null 类风湿关节炎现行的治疗 类风湿性关节炎至今尚无特效疗法,现行治疗的目的在于： ★减轻关节及其它组织的炎症，缓解症状； ★控制关节炎的发展，防止和减少关节破坏，保持功 能和防止畸形； ★促进已破坏的关节修复。 一 . 一般疗法 关节制动（急性期）、关节功能锻炼 （恢复期）、物理疗法等。 二. 药物治疗 ( 一)非甾体类抗炎药（NSAIDS） 其作用机理主要 抑制环氧化酶使前列腺素生成受抑制而起作用，以 达到消炎止痛缓解症状的效果。但不能阻止RA病 变的自然过程。 近 20年来在风湿病学界已达成共识，治疗 策略应该是：早期联合治疗，即在病程早期联合应用二种或二种以上改善病情抗风湿药（DMARD）。早期联合治疗确能改善病情控制病情进展。近 20年来在风湿病学界已达成共识，治疗 策略应该是：早期联合治疗，即在病程早期联合应用二种或二种以上改善病情抗风湿药（DMARD）。早期联合治疗确能改善病情控制病情进展。 null 改善病情抗风湿药（DMARD） 1. 氨甲蝶呤（MTX） 有免疫抑制与抗炎症作用，可降血沉，改善骨侵蚀，每周5～15mg肌注或口服，3个月为一疗程。副作用有厌食、恶心、呕吐、口腔炎、脱发、白细胞或血小板减少。 2．柳氮磺胺吡啶（SSZ）可使白介素-1、白介素-6及肿瘤坏死因子α显著减少。SSZ能减轻疼痛及关节局部炎症，晨僵得到改善，可使血沉和C反应蛋白下降。第一周，0.5g，每日二次；第二周，0.5g，每日三次；第三周，1.0g，每日2次，也有人用到1.0g，每日三次，用此量维持1-3年。 3．氯喹 有一定抗风湿作用，但显效甚慢，常6周至6个月才能达到最大疗效。可作为水杨酸制剂或递减皮质类固醇剂量时的辅助药物。每次口服250～500mg，每日2次。疗程中常有较多胃肠道反应如恶心、呕吐和食欲减退等。长期应用须注意视网膜的退行性变和视神经萎缩等。 甲氨蝶呤(methotrexate,MTX甲氨蝶呤(methotrexate,MTX别名氨甲喋呤、甲氨叶酸、氨克生(trexan)是核酸合成拮抗剂，是细胞周期特异性免疫 抑制剂，主要作用于细胞G1→S期的过渡期，MTX可以抑制淋巴C的增生和增强CD8+TC活性和初次与再次抗体反应及抑制IgG型及IgA型RF的产生，增加IL-1ra的 生和抑制IL-8的产生。 MTX除有免疫抑制作用外，还有较强的抗炎作用。MTX适应症MTX适应症主要用于以关节症状为主的自身免疫病，为RA、AS、ReA、PA、DM/PM、SLE、系统性血管炎等，多采用小剂量脉冲疗法，每周一次，口服、皮下注射或静注。一般剂量5~15mg/周，最大剂量25mg/周。 由于治疗RA起效快（最早1个月，一般2~3个月），疗效好，无远期致癌作用，可以与所有慢作用药合用，因此成为治疗RA首选药。 MTX的不良反应MTX的不良反应胃肠道反应发生率约15%，多于用药后几天~1个月出现，常见恶心、呕吐、腹泻，与剂量有关，减量或分次服可减轻，一般停药3~5天可消失。 MTX的不良反应MTX的不良反应 肝毒性：过去用大剂量MTX治疗银屑病时用药5年，平均总量2.2g，肝硬化发生率为25.6%，而目前小剂量脉冲疗法治疗RA引起肝损害少且轻，仅少数人转氨酶高，用药3个月后发生率为8%~38%，慢性肝病患者、饮酒及使用肝毒性药可加重肝损害。MTX的不良反应MTX的不良反应 血液系统：偶见Wbc↓,plat ↓或巨幼红C贫血，严重者可出现全血C减少，合并感染时危及生命。 肺病变极罕见：MTX可引起急性肺病，药物性间质性肺炎，高敏感者易出现肺感染。 其他如肾毒性、口腔炎、皮肤损害、生殖系统、神经系统均少见。不良反应不良反应1、胃肠道反应：腹泻、恶心、呕吐和胃肠炎。 2、血液系统： Wbc↓和贫血。 3、感染。 4、恶性肿瘤和淋巴疾患(1%),与安慰剂无明 显差异。 5、注射部位静脉炎和血栓(4%)。null 类风湿关节炎的生物治疗 应用生物制剂治疗类风湿关节炎，目前尚处于研究、探索阶段。由 于生物制剂具有药理作用环节的选择性高、毒副作用较小的优点有 较广阔的应用前景。 1细胞因 目前已用于类风湿关节炎治疗的生物制剂有: 抗TNF-α (类克infliximab, 益赛普 etanercept, 阿达木单抗 adalimumab); IL-1 (anakinra); IL-6抑制剂(tocilizumab); T细胞协同刺激阻断药(abatacept)。 null2. Cell therapy for autoimmune diseases （1） B cell targeting in autoimmune diseaseswith anti-CD20) （2） Haematopoietic stem cell transplantation （3） Targeting antigen presenting cells (APCs （4） regulatory T cells. （5）T helper (Th) cells with antibodies specific for CD4 3. Gene therapy of the rheumatic diseases细胞因子抑制剂细胞因子抑制剂 细胞因子是免疫功能关键的信号介质，细胞因子具有多效性，它们依据靶细胞和细胞因子的整体环境而发挥不同的作用。目前常用的细胞因子抑制剂有以下三大类。TNF-α抑制剂TNF-α抑制剂有关RA的发病机制研究最详尽的细胞因子就是TNF-α，它主要由单核细胞、巨噬细胞分泌 。 TNF-α是导致炎症反应和免疫病理损伤的重要促炎因子，介导了许多自身免疫病病程中的一系列炎症反应，在局部软骨/骨破坏和全身性反应中都起到了重要作用。 针对TNF-α的靶向生物制剂，通过阻断TNF-α的作用而达到治疗炎症反应的目的，不仅可减轻症状，而且能延缓骨质破坏，因此又称生物DMARDS。目前上市的TNF-α拮抗剂有三种目前上市的TNF-α拮抗剂有三种 null依那西普（Etanercept）是II型可溶性TNF-α受体(p75)与IgG1 Fc段嵌合形成的融合蛋白。Etanercept的不良反应轻, 主要是注射部位的局部反应和感染。 英夫利昔单抗（Infliximab）是一种嵌合的人源化小鼠抗人TNF-α抗体；其鼠抗人TNF抗体可变区部分与TNFα具有很高的亲和力,因此可以阻断TNFα与其受体的结合,使得TNFα无法发挥其生物活性。 阿达木（Adalimumab）单抗是完全人源化抗TNF-α的IgG1抗体。结构和功能上与天然人IgG1无法区别，与Infliximab相比免疫原性低,特异性高，疗效更强且作用更持 这三种生物制剂除在RA,JIA,PsA,AS和crohn病的治疗取得显著疗效外，还试用于B,D，成人still病，巨细胞动脉炎和WG，取得较好疗效。 因此，有人说生物制剂在风湿病领域里的应用是风湿病治疗进入新阶段的里程碑。TNF抑制剂在临床应用多年,特点是在多数患者中起效迅速,疗效明显,能延缓骨质侵蚀。适应证不断扩大,已被批准的适应证有RA、幼年型RA、克罗恩病、强直性脊柱炎和银屑病关节炎等。 但随着治疗时间延长,发现1/3的患者治疗失败,合并感染者增多,有严重感染甚至死亡的病例。淋巴瘤发病率也有所升高,但不能肯定淋巴瘤增多是疾病本身所致还是受药物影响。此外,治疗费用昂贵。 排除结核病 患有慢性阻塞性肺病的患者使用应严密监测. 乙肝活动 乙肝病毒的风湿病患者接受免疫抑制剂治疗可能导致乙肝活动、肝炎甚至肝功能失代偿。 下列情况需要接受筛查:1.  高危患者:来自乙肝高发地区、TNF抑制剂在临床应用多年,特点是在多数患者中起效迅速,疗效明显,能延缓骨质侵蚀。适应证不断扩大,已被批准的适应证有RA、幼年型RA、克罗恩病、强直性脊柱炎和银屑病关节炎等。 但随着治疗时间延长,发现1/3的患者治疗失败,合并感染者增多,有严重感染甚至死亡的病例。淋巴瘤发病率也有所升高,但不能肯定淋巴瘤增多是疾病本身所致还是受药物影响。此外,治疗费用昂贵。 排除结核病 患有慢性阻塞性肺病的患者使用应严密监测. 乙肝活动 乙肝病毒的风湿病患者接受免疫抑制剂治疗可能导致乙肝活动、肝炎甚至肝功能失代偿。 下列情况需要接受筛查:1.  高危患者:来自乙肝高发地区、高危性行为；静脉注射毒品、接受血液透析、有HBV接触史;2.  接受高危治疗:大剂量糖皮质激素、甲氨蝶呤、来氟米特等。         评估策略:测定HBsAg、抗HBc抗体、抗HBs抗体。如HBsAg+,抗病毒治疗,并推荐给肝病专家;如HBsAg-,抗HBc+、抗HBs±密切监测,个体化治疗;如HBsAg-,抗HBs-、抗HBs-建议接种疫苗。         风湿性疾病合并乙肝活动的治疗策略:如接受短期免疫抑制治疗,在开始治疗前1周开始拉米夫定100  mg/d治疗,直到停止免疫抑制剂治疗后继续服用3~6个月。如接受长期的免疫抑制剂治疗,在治疗前1周开始拉米夫定或阿德福韦10  mg/d治疗。不论是否接受预防性抗病毒治疗,须密切监测丙氨酸氨基转移酶、HBV  DNA水平。高危性行为；静脉注射毒品、接受血液透析、有HBV接触史;2.  接受高危治疗:大剂量糖皮质激素、甲氨蝶呤、来氟米特等。         评估策略:测定HBsAg、抗HBc抗体、抗HBs抗体。如HBsAg+,抗病毒治疗,并推荐给肝病专家;如HBsAg-,抗HBc+、抗HBs±密切监测,个体化治疗;如HBsAg-,抗HBs-、抗HBs-建议接种疫苗。         风湿性疾病合并乙肝活动的治疗策略:如接受短期免疫抑制治疗,在开始治疗前1周开始拉米夫定100  mg/d治疗,直到停止免疫抑制剂治疗后继续服用3~6个月。如接受长期的免疫抑制剂治疗,在治疗前1周开始拉米夫定或阿德福韦10  mg/d治疗。不论是否接受预防性抗病毒治疗,须密切监测丙氨酸氨基转移酶、HBV  DNA水平。null1、抗CD20单克隆抗体1、抗CD20单克隆抗体Rituximab是最早被批准用于治疗CD20+B细胞淋巴瘤的嵌合的抗CD20单克隆抗体。 CD20是存在于pre-B和成熟B细胞表面的标志物，在干细胞中不存在，已分化的浆细胞也不表达。Rituximab进行B细胞去除治疗的作用机制包括： （1）抗体依赖细胞介导细胞毒作用。自然杀伤细胞、巨噬细胞及单核细胞通过其Fcγ受体与表面CD20结合，引起CD20+B细胞裂解； （2）补体介导细胞毒作用。Rituximab与表面CD20结合，可诱导C1q结合，活化补体系统，膜攻击复合物引起CD20+B细胞裂解； （3）此外，rituximab还可促进CD20＋B细胞凋亡。 通过这些机制，rituximab可引起CD20+B细胞一过性去除，持续时间可长达6个月，随后在9-12个月左右，B细胞水平又慢慢恢复正常。 null2.抗CD20单克隆抗体治疗RA的作用机制     B细胞在RA免疫发病机制中的可能作用目前认为有几方面：（1）作为抗原呈递细胞，提供重要共刺激信号，刺激CD4+T 细胞克隆扩增和作用；（2）在RA滑膜中的B细胞也会分泌TNF-α等前炎症因子和趋化因子；（3）分泌类风湿因子（RF），而RF阳性患者关节炎进展更快，关节外表现多，预后更差。RF反过来又会刺激B细胞活化和对Th细胞的抗原呈递作用；（4）尽管T细胞在RA发病中非常重要， 但B细胞对T细胞的活化具有重要的调控作用。 用rituximab进行B细胞去除治疗RA获得较好疗效，深化了人们对RA的发病机制的认识，说明B细胞通过多重机制在RA发病中起关键作用。 null2006年美国食物与药品管理局（FDA）批准对于中－重度成人RA患者，如对1种或以上TNF-α生物制剂疗效不佳，可使用rituximab治疗。因此RA患者除常规DMARDs和TNF-α生物制剂治疗外，又多了一种有效的治疗手段。     Rituximab治疗RA的标准治疗（成人）是：间隔2周各予1000mg输注。第一次输注时数度为50mg/h，如无过敏反应或输液反应，输注速度可逐渐提升，最高可达400mg/h。在每次输注前予静脉输注糖皮质激素如甲基强的松龙100mg以减少减轻输液反应。输注rituximab应联用甲氨喋呤 。nullRituximab输注相关不良事件主要是输液反应。一般第一次输液时最容易出现，多在30~120min内出现，表现为发热、畏寒或寒战、恶心、头痛，有时有一过性低血压。在rituximab治疗淋巴瘤患者的研究中发现，第一次输注时有反应者可高达70％~80％，但多为轻－中反应，时间短暂，减慢输液速度或短暂停止输液反应可逐渐消失。在RA患者中，rituximab输液反应要较淋巴瘤患者少见。在DANCER研究中，rituximab 500mg和1000mg组急性输液反应分别为23％和32％，安慰剂为17％。不用激素者rituximab 500mg、1000mg组和安慰剂组急性输液反应分别为32％、37％和14％，同时使用激素时，三组急性输液反应则分别为19％、29％和19％，说明同时给予激素治疗可明显减少rituximab急性输液反 null 3、 总结     B细胞在RA发病中起重要作用。大量的临床研究证实采用抗CD20单克隆抗体rituximab选择性去除B细胞可以治疗RA，也进一步提高了我们对RA发病机制的认识。 Rituximab治疗RA临床上是安全而有效的。对于顽固性RA，经典DMARDs和/或TNF-α生物制剂治疗无效时，可使用rituximab治疗。 To date, rituximab has been used off-label in more than18 autoimmune diseases  Cell therapy for autoimmune diseases  Cell therapy for autoimmune diseases  nullFigure 4. Haematopoietic stem cell transplantation for autoimmunity. (A) Chronic autoimmune reaction disturbs the homoeostasis of peripheral immunocyte populations. (B) During immunoablation antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) efficiently eliminate resting long lived plasma cells, antigen presenting cells (APCs), or resting memory lymphocytes, and cyclophosphamide (Cy) targets the differentiation of memory B and T cells into effector immunocytes. (C) Purification of autologous stem cells prevents reinfusion with autoreactive immunocytes. Immune reconstitution with new naive B and T cells help to reset and maintain tolerance and normal immunocyte homoeostasis. ADOPTIVE TRANSFER OR IN VIVO GENERATION OF REGULATORY T CELLS ADOPTIVE TRANSFER OR IN VIVO GENERATION OF REGULATORY T CELLS Figure 5. Control of pathogenic autoimmune reactions with regulatory T cells. An alternative strategy involves the isolation of specific regulatory T cells or Tregs from the peripheral blood of patients with autoimmunity. After isolation, autoantigen specific regulatory T cells can be further expanded and reinfused in high numbers back into the patient. At the site of inflammation they exert their suppressive anti-inflammatory effects after specific activation from activated APCs. Here regulatory T cells potentially compete with inflammatory T cells for antigen and growth factors but they also most likely suppress local inflammation through secretion of suppressive cytokines (for example IL-10). Gene therapy of the rheumatic diseases: 1998 to 2008 Christopher H Evans1, Steven C Ghivizzani2 and Paul D Robbins3 1Center for Advanced Orthopaedic Studies, Harvard Medical School, BIDMC-RN115, 330 Brookline Avenue, Boston, MA 02215, USA 2Department of Orthopaedics and Rehabilitation, Florida University College of Medicine, 1600 SW Archer Road, MSB Room M2-210, FL 32610, USA 3Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, BST W1246, PA 15261, USA Arthritis Research & Therapy 2009, 11:209 MJH Coenen1 and PK Gregersen2 1Department of Human Genetics of the Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 2The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA Genes Immun. 2009 March ; 10(2): 101–111Introduction The first properly authorized gene transfer to a human in 1989, to a total of 368 by 1998. Despite the worst predictions of the skeptics, there had been no serious adverse events and the field looked forward, like the economy that was fuelling much speculation in the area, to continued rapid growth. Optimists predicted that the first genetic medicines would be on the market within a few years. Rheumatoid arthritis (RA) had become an early target for gene therapy capturing the optimism of the early 1990s and beginning clinical trials in 1996. The first International Meeting on the Gene Therapy of Arthritis and Related Disorders (GTARD) was held at the National Institutes of Health (NIH) (Bethesda, MD, USA) in 1998 [1] and attracted over 200 participants.. Introduction The first properly authorized gene transfer to a human in 1989, to a total of 368 by 1998. Despite the worst predictions of the skeptics, there had been no serious adverse events and the field looked forward, like the economy that was fuelling much speculation in the area, to continued rapid growth. Optimists predicted that the first genetic medicines would be on the market within a few years. Rheumatoid arthritis (RA) had become an early target for gene therapy capturing the optimism of the early 1990s and beginning clinical trials in 1996. The first International Meeting on the Gene Therapy of Arthritis and Related Disorders (GTARD) was held at the National Institutes of Health (NIH) (Bethesda, MD, USA) in 1998 [1] and attracted over 200 participants.. Matters then changed abruptly. The 1999 death of Jesse Gelsinger [2] reopened safety concerns. Jesse Gelsinger, had a fatal systemic inflammatory response to adenoviral vector gene transfer (a ornithine transcarbamylase鸟氨酸氨甲酰基转移酶deficient following adenoviral gene transfer ). This, in turn, made it more difficult to obtain funding from traditional sources, such as the NIH, as well as the biotechnology industry, which was also dealing with a rapidly slowing economy. Many rheumatic diseases, though serious, are not considered to be life threatening,a factor that further reduced enthusiasm for gene therapy research in this area under these circumstances Matters then changed abruptly. The 1999 death of Jesse Gelsinger [2] reopened safety concerns. Jesse Gelsinger, had a fatal systemic inflammatory response to adenoviral vector gene transfer (a ornithine transcarbamylase鸟氨酸氨甲酰基转移酶deficient following adenoviral gene transfer ). This, in turn, made it more difficult to obtain funding from traditional sources, such as the NIH, as well as the biotechnology industry, which was also dealing with a rapidly slowing economy. Many rheumatic diseases, though serious, are not considered to be life threatening,a factor that further reduced enthusiasm for gene therapy research in this area under these circumstances Although the first flush of enthusiasm is over, the past decade(98-2008) has seen steady progress in developing genetic therapies for several conditions, and the number of clinical trials worldwide is approaching 1,500. The first commercial gene therapeutic, Gendicin for cancer of the head and neck, has been launched in China [3], Wilson JM: Gendicine: the first commercial gene therapy product. Hum Gene Ther 2005, 16:1014-1015.and gene therapy for familial lipoprotein lipase deficiency is available as an orphan drug in Europe and the US. Cures have been reported for X-linked severe combined immunodeficiency disease (SCID) [4],adenosine deaminase-SCID [5],重症联合免疫缺陷（SCID）患者缺乏正常的人体免疫功能，只要稍被细菌或者病毒感染，就会发病死亡。这个病的机理是细胞的一个常染色体上编码腺苷酸脱氨酶（简称ADA）的基因（ada）发生了突变。可以通过基因工程的方法治疗。Although the first flush of enthusiasm is over, the past decade(98-2008) has seen steady progress in developing genetic therapies for several conditions, and the number of clinical trials worldwide is approaching 1,500. The first commercial gene therapeutic, Gendicin for cancer of the head and neck, has been launched in China [3], Wilson JM: Gendicine: the first commercial gene therapy product. Hum Gene Ther 2005, 16:1014-1015.and gene therapy for familial lipoprotein lipase deficiency is available as an orphan drug in Europe and the US. Cures have been reported for X-linked severe combined immunodeficiency disease (SCID) [4],adenosine deaminase-SCID [5],重症联合免疫缺陷（SCID）患者缺乏正常的人体免疫功能，只要稍被细菌或者病毒感染，就会发病死亡。这个病的机理是细胞的一个常染色体上编码腺苷酸脱氨酶（简称ADA）的基因（ada）发生了突变。可以通过基因工程的方法治疗。and X-linked chronic granulomatous disease [6] . Striking success in treating Leber’s congenital amaurosis has recently been reported by two independent groups [7,8].先天性黑蒙症,又称遗传性先天性视网膜病,是发生最早、最严重的遗传性视网膜病变, 出生时或出生后一年内双眼锥杆细胞功能完全丧失。到目前为止已发现有9种不同的突变基因可以造成雷伯氏先天性黑蒙。根据不同的基因突变，此病可分为不同的亚型。达大学和宾夕法尼亚大学进行的一期临床试验是先天性黑蒙二型是由于视网膜色素上皮细胞内RPE65基因突变引起视循环通路受阻致使网膜视细胞不能生成对视觉形成至关重要的视紫红紫而造成的。在此病例，就是把RPE65基因通过腺相关病毒载体转入到视网膜色素上皮细胞。 There has also been steady growth of research into developing gene therapies for the rheumatic diseases. and X-linked chronic granulomatous disease [6] . Striking success in treating Leber’s congenital amaurosis has recently been reported by two independent groups [7,8].先天性黑蒙症,又称遗传性先天性视网膜病,是发生最早、最严重的遗传性视网膜病变, 出生时或出生后一年内双眼锥杆细胞功能完全丧失。到目前为止已发现有9种不同的突变基因可以造成雷伯氏先天性黑蒙。根据不同的基因突变，此病可分为不同的亚型。达大学和宾夕法尼亚大学进行的一期临床试验是先天性黑蒙二型是由于视网膜色素上皮细胞内RPE65基因突变引起视循环通路受阻致使网膜视细胞不能生成对视觉形成至关重要的视紫红紫而造成的。在此病例，就是把RPE65基因通过腺相关病毒载体转入到视网膜色素上皮细胞。 There has also been steady growth of research into developing gene therapies for the rheumatic diseases. Progress can be gauged, to some degree, by reading the summaries of the biennial GTARD meetings [1,9,10]. These, too, have reached their 10th anniversary and GTARD-5 was recently held in Seattle. As discussed below, there have been a number of clinical trials in the area of arthritis gene therapy, one of which has entered phase II, and some other areas are in an advanced preclinical stage of development.Progress can be gauged, to some degree, by reading the summaries of the biennial GTARD meetings [1,9,10]. These, too, have reached their 10th anniversary and GTARD-5 was recently held in Seattle. As discussed below, there have been a number of clinical trials in the area of arthritis gene therapy, one of which has entered phase II, and some other areas are in an advanced preclinical stage of development.nullEnglish language publications on arthritis gene therapy in the refereed literature. The data are based on a PubMed search using ‘arthritis gene therapy’ as the search term. The first paper on arthritis gene therapy was published in 1992 [27]. The first efficacy data for animal models of rheumatoid arthritis (RA) appeared in 1996 [103,104], and the first efficacy data for animal models of osteoarthritis (OA) followed a year later [79]. The first human trial for RA began in 1996 [29]. Seven clinical trials for RA and OA have been initiated, one of them reaching phase II(Table 1). The first evidence of possible clinical responses to gene transfer was published this year [31]. Reprinted with permission [105Gene transfer vectors Gene transfer vectors can be broadly categorized into two groups: viral and non-viral vectors. Plasmid DNA The most common non-viral vector used in arthritis studies is plasmid DNA. Plasmid DNA can be delivered by liposomes, gene gun, or direct injection of the plasmid. The use of plasmid DNA tends to be less toxic and less immunogenic than the use of viral vectors and is also easy and relatively inexpensive to produce. However, plasmid DNA often leads to low transfection efficiency and short-term expression of the transgene, lasting only 1–2 weeks [21–23]. These limitations make it unlikely that local delivery of plasmid DNA in the joint will be successful . Gene transfer vectors Gene transfer vectors can be broadly categorized into two groups: viral and non-viral vectors. Plasmid DNA The most common non-viral vector used in arthritis studies is plasmid DNA. Plasmid DNA can be delivered by liposomes, gene gun, or direct injection of the plasmid. The use of plasmid DNA tends to be less toxic and less immunogenic than the use of viral vectors and is also easy and relatively inexpensive to produce. However, plasmid DNA often leads to low transfection efficiency and short-term expression of the transgene, lasting only 1–2 weeks [21–23]. These limitations make it unlikely that local delivery of plasmid DNA in the joint will be successful . The most success with the use of plasmid DNA in gene transfer for arthritis has been garnered through delivery of transgenes to skeletal muscle. Electrotransfer of soluble TNF-a receptor I variants to the tibial-cranial muscle at the onset of collagen-induced arthritis (CIA) led to a decrease in the clinical and histological signs of disease for up to 5 weeks [24]. Viral vectors Viral vectors are by far the most widely used vectors for delivering transgenes in arthritic animal models [39]. There are several different viral vectors that have been examined for use in gene transf