RNAI技术治愈乙肝的可能性

kaorusai

去年8月份有则报道： 美国公司宣称可治愈癌症

其中有几句关键性的句子

1、ALN-VSP疗法实际上是一种RNAi干扰基因治疗技术，它通过将沉默与肿瘤组织血管生成相关的生长因子的蛋白合成，来抑制肿瘤区血管的生成，达到将癌细胞饿死的效果。这种创新的基因治疗方法是由美国奥尼兰姆（Ａｌｎｙｌａｍ）生物技术公司开发。药物包在脂肪薄层里，便可达到主要被肝脏吸收的效果。这允许医生从血管注射药物，而不是通过一点上的注射，这可改善药物的效果，确保整个肝脏都能接收到均等的剂量。

2、RNAi疗法可能在今后两年内日臻完善，包括加利福尼亚希望之城医疗中心的分子遗传学家约翰·罗西在内的专家们如此表示。奥尼兰姆计划再对36名其他的病人展开新药测试，增加药物用量，但早期的结果相当好，也表明了它可能成为第一批投放市场的RNAi疗法治疗药。“我认为RNAi对所有的病都有效，”罗西说，“但即使它只对肝癌有效，那也已经非常棒了。”对于那些饱受化疗和辐射巨大副作用、却不能治愈肝癌的患者来说，这绝对是灵丹妙药。

http://home.51.com/jxljh51/diary/item/10050550.html

我记得早在几年前就有几个科学家成功利用RNAI技术杀死乙肝病毒，只是难度就在怎么样把药物输送到肝脏，根据第1条这问题不是已经解决了吗？....
36个其他病人都是肝藏方面的疾病吗？？真想知道
既然研究到这个程度了，为什么不能开始研究乙肝药物呢？美国人好像对乙肝不是很重视...
我仍认为RNAI是根治乙肝的手段，但不知道要等多少年....



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回复 kaorusai 的帖子

实际进展比较快的.
RNA治疗药物国际产业进展
http://www.hbvhbv.com/forum/forum-viewthread-tid-1057506-fromuid-521998.html

抗体2005

现在 有种方法是介入治疗 就是把药直接打入肝脏

StephenW

RNA干扰                                                                                                                                        维基百科，自由的百科全书
                                                                                                                                                                                                                                                                                                                                                                                                                               
RNAi示意图


RNA干扰（RNA interference，缩写为RNAi）是指一种分子生物学上由双链RNA诱发的基因沉默现象，其机制是通过阻碍特定基因的翻译或转录来抑制基因表达。当细胞中导入与内源性mRNA编码区同源的双链RNA时，该mRNA发生降解而导致基因表达沉默[1] 。与其它基因沉默现象不同的是，在植物和線蟲中，RNAi具有传递性，可在细胞之间传播，此現象被稱作系統性RNA干擾(systemic RNAi)[2][3]。在秀丽隐杆线虫上实验时还可使子一代产生基因突变，甚到於可用喂食細菌給線蟲的方式讓線蟲得以產生RNA干擾現象。RNAi现象在生物中普遍存在。
RNAi与转录后基因沉默(post-transcriptional gene silencing and transgene silencing)在分子層次上被证实是同一种现象[來源請求]。

目录 [隐藏] 1 发现 2 机制 2.1 siRNA 2.2 microRNA 2.3 RNA干扰的作用 3 应用 4 参考文献

[编辑] 发现
在转基因的矮牵牛花中所观察到的RNA干扰现象[4]


RNA干扰现象是1990年由约根森（Jorgensen）研究小组在研究查尔酮合成酶对花青素合成速度的影响时，为得到颜色更深的矮牵牛花而过量表达查尔酮合成酶，结果意外得到了白色和白紫杂色的矮牵牛花，并且过量表达查尔酮合成酶的矮牵牛花中查尔酮合成酶的浓度比正常矮牵牛花中的浓度低50倍。约根森推测外源转入的编码查尔酮合成酶的基因同时抑制了花中内源查尔酮合成酶基因的表达[5]。
1992年，罗马诺（Romano）和Macino也在粗糙链孢霉中发现了外源导入基因可以抑制具有同源序列的内源基因的表达[6]。1995年，Guo和Kemphues在线虫中也发现了RNA干扰现象[7]。
1998年，安德鲁·法厄（Andrew Z. Fire）等在秀丽隐杆线虫（C.elegans）中进行反义RNA抑制实验时发现，作为对照加入的双链RNA相比正义或反义RNA显示出了更强的抑制效果[1]。从与靶mRNA的分子量比考虑，加入的双链RNA的抑制效果要强于理论上1:1配对时的抑制效果，因此推测在双链RNA引导的抑制过程中存在某种扩增效应并且有某种酶活性参与其中。并且将这种现象命名为RNA干扰。
2006年，安德鲁·法厄与克雷格·梅洛（Craig C. Mello）由于在RNAi机制研究中的贡献获得诺贝尔生理及医学奖。
[编辑] 机制[编辑] siRNA
RNA干扰现象的机理[8]


RNA干扰作用是通过一类较稳定的中间介质实现的。对植物的研究证明，双链RNA复合体先降解成为35nt左右的小RNA分子，然后他们通过序列互补与mRNA结合，从而导致mRNA降解[9][10]。对果蝇的研究证明，长度为21～23nt的小RNA分子是引起RNA干扰现象的直接原因[11][12]。这种小RNA分子被称之为小干扰RNA（small interfering RNA，siRNA）。
在RNA干扰中一个非常重要的酶是RNaseIII核酶家族的Dicer。它可与双链RNA结合，并将其剪切成21～23nt及3'端突出的小分子RNA片断，即siRNA。随后siRNA与若干个蛋白组成的，RNA引起的称之为RNA誘導沉默複合體（RNA-induced silencing complex，RISC）结合，解旋成单链，并由该复合体主导RNAi效应[13]。RISC被活化后，活化型RISC受已成单链的siRNA引导（guide strand），序列特异性地结合在标靶mRNA上并切断标靶mRNA，引发靶mRNA的特异性分解。
迄今为止已鉴定出包括Dicer在内的若干个与RNAi有关的蛋白因子[來源請求]。在果蝇（Drosophila melanogaster）RISC中，已知存在着称为Argonaute2(AGO2)的因子，AGO2蛋白的表达受到抑制时，RNAi效应缺失，也就是说AGO2是果蝇RNAi机制的必须因子[來源請求]。研究表明Argonaute家族蛋白具有RNA切割酶活性（slicer activity），RNAi机制正是由Argonaute家族蛋白的RNA切割酶活性主导[來源請求]。另外，几个RNA解旋酶（RNA helicase）也被鉴定为参与RNAi机制的因子[來源請求]。在秀丽隐杆线虫（C. elegans）的RNAi中必须的因子有EGO1[來源請求]，这是一种RdRP(RNA-dependent RNA Polymerase)，植物中也存在该蛋白同系物。RNAi中RdRP是将标靶mRNA作为模板，以导入的dsRNA（或siRNA）作为引物合成RNA，在细胞内针对于标靶mRNA合成新siRNA的酶。这一反应在一些生物的RNAi中为必须，但RdRP活性在人和果蝇的RNAi中是非必须的，这说明在不同物种之间RNAi机制的基本框架虽然相同，但存在着微妙差异[來源請求]。
[编辑] microRNAmicroRNA(miRNA) gene，RNA-code gene轉錄成具有5端帽跟Poli A tail的且具有70 nucleartide長的hairpin的primary miRNA，被兩種Class 2 RNases III Drosha與Pasha切除，形成Small hairpin RNA (shRNA)的precurorsor miRNA，經由exportin 5核膜蛋白通到轉移到細胞質中，被活化的Class 3 RNases III Dicer花費兩個ATP切割，形成miR-X:miR-X* duplex，其中的function RNA稱為guide strand or siRNA，另一條為anti-guide or passage strand則降解掉。guide strand則被Dicer攜帶，花費一個ATP與argonaute具有二價鎂離子的packet結合另與TRBP形成Rna induced silencing complex(RISC)，most animal miRNA為partical homology而造成Translational repression稱為Bypass mechanism；most plant miRNA為(nearly) perfect homology而造成 mRNA cleavage稱為Cleavage mechanism。
siRNA在核內downregulation (RNA induced transcription silencing(RITC)) or upregulation DNA/histone methylation，此種機制可遺傳。
PS：siRNA又可分為endogenous與exogenous， exogenous可經由病毒感染或實驗技術轉入， 用已調降或關閉特定基因。
在真核生物当中，还存在另外一种小分子RNA（microRNA）也能引起RNA干扰现象。microRNA大多20-22nt长，前体具有类似发夹性的茎环结构。microRNA产生于该茎环结构的双链区。其特点与siRNA基本上相同[14]。
[编辑] RNA干扰的作用2001年，Tuschl等将siRNA导入到哺乳动物细胞中并由此解决了在哺乳细胞内导入长的双链RNA时引发的干扰素效应，由此拓展了RNAi在基因治疗上应用前景[來源請求]。RNAi机制普遍存在于动植物，尤其是低等生物中[15]。因此被认为是进化上相对保守的基因表达调控机制[來源請求]。一种假说为[15]，RNAi机制是作为在RNA水平上抵御病毒入侵的防御机制而存在的。在病毒自身基因组所包含的，或在病毒复制过程中产生的双链RNA可以被Dicer识别，从而引起病毒RNA降解。但是许多病毒为抵抗宿主的RNA干扰机制，会产生抑制宿主RNA干扰的蛋白，以保护病毒基因在宿主体内的顺利复制。已经发现的可以抑制宿主RNA干扰的病毒蛋白有potyviruses编码的HC-PRO蛋白、马铃薯X病毒编码的Cmv2b蛋白、兽棚病毒编码的B2蛋白等[16]。
RNA干扰也是抑制破坏基因结构的一种DNA片段转錄子活性的重要方式。转錄子通常以逆转錄的方式在基因组中扩增。在逆转錄过程中产生的双链RNA分子可以被Dicer识别，从而被降解[15]。
目前发现[來源請求]，RNAi机制中的相关一些因子如内源性双链RNA及蛋白因子可以在多种层次上对基因表达进行调控，其范围已经超越了PTGS（post transcriptional gene silencing），如RNAi机制同样参与了转录水平上的基因表达调控过程中。
[编辑] 应用RNAi在基因沉默方面的具有高效性和简单性，所以是基因功能研究的重要工具。大多数药物属于標靶基因（或疾病基因）的抑制剂，因此RNAi 模拟了药物的作用，这功能丢失（LOF)的研究方法比传统的功能获得（GOF)方法更具优势。因此, RNAi 在今天的制药产业中是药物靶标确认的一个重要工具。同时，那些在靶标实验中证明有效的siRNA/shRNA本身还可以被进一步开发成为RNAi药物。
在药物標靶发现和确认方面，RNAi技术已获得了广泛的应用。生物技术公司或制药公司通常利用建立好的RNAi文库来引入细胞，然后通过观察细胞的表型变化来发现具有功能的基因。如可通过RNAi文库介导的肿瘤细胞生长来发现能抑制肿瘤的基因[來源請求]。一旦所发现的基因属于可用药的靶标（如表达的蛋白在细胞膜上或被分泌出细胞外），就可以针对此靶标进行大规模的药物筛选。此外，被发现的靶标还可用RNAi技术在细胞水平或动物体内进一步确认[來源請求]。
在疾病治疗方面，双链小分子RNA或siRNA已被用于临床测试用于几种疾病治疗，如老年视黄斑退化、肌肉萎縮性側索硬化症、类风湿性关节炎、肥胖症等。在抗病毒治疗方面，帕金森病等神经系统疾病已经开始初步采用RNA干扰疗法。肿瘤治疗方面也已经取得了一些成果[17]。

StephenW

kaorusai 发表于 2011-9-6 19:22
去年8月份有则报道： 美国公司宣称可治愈癌症

其中有几句关键性的句子

请看看这个:

大鹏鸟发表于 2011-8-10 11:07|:
讨论的这么热闹，有几个是专业人士？
siRNA只是针对mRNA，假如用来治疗乙肝的话，对CCCDNA并没有效果。而且各种递送方法的问题还多着呢，一是毒性问题，二是靶向性问题，你怎么让siRNA准确地靶向肝细胞呢？三是siRNA的脱靶效应。假如使用病毒载体也存在这几个问题，甚至慢病毒载体还存在致癌性的问题。
前途漫漫啊

苹苹苹

不知道能不能用于治疗乙肝

kaorusai

20.Tacere与Pfizer达成里程碑合作并签署许可协议--2010年2月4日，Tacere宣布与Pfizer签署协议，继续已在2007年12月授予的许可协议，以进一步开发和商品化Tacere的丙型肝炎病毒（HCV）化合物.这一化合物中包括三种独立的RNAi分子，同时针对丙型肝炎病毒三个不同的位点。在临床前动物研究中表明，单次静脉注射肝细胞渗透率较高，足以根除病毒。经过多年“鸡尾酒药物”的研究，，Tacere很高兴看到他们的付出终于有了回报。

链接地址:http://www.tacerebio.com/pdf_fil ... press%20release.pdf

能治疗丙肝应该就能治疗乙肝...

StephenW

回复 kaorusai 的帖子

                                                                         

                        这是另一种RNAi技术。没有提及，它可以用于治疗乙型肝炎，但它是与葛兰素史克合作，在治疗4病毒性疾病。

press release               
                               

                                        Sept. 7, 2011, 7:15 a.m. EDT                               

                                Santaris Pharma A/S Showcases microRNA and mRNA Research Advancements Utilizing its Proprietary Locked Nucleic Acid Technology at Oligonucleotide Therapeutics Society Meeting                                - Santaris Pharma A/S provides update on the development of miravirsen, a microRNA-targeted drug inhibiting miR-122, which is currently in Phase 2 clinical trials to treat patients infected with the Hepatitis C virus (HCV) - Scientists at Santaris Pharma A/S demonstrate specificity of "tiny" 8-mer LNA-based compounds, which have shown to successfully inhibit entire microRNA families providing potential new approach for treating cancer, viral infections, cardiovascular and muscle diseases - Data presented by scientists at Santaris Pharma A/S demonstrate successful "naked" delivery uptake of LNA-based compounds, a key advantage over other RNA-based technologies that require complex delivery vehicles - Versatility of the LNA Drug Platform allows Santaris Pharma A/S to develop both microRNA and mRNA-targeted drugs with excellent specificity and increased affinity to drug target, providing improved potency and favorable tissue-penetrating properties                       
               
       
       
       
                                 
                                             
                           
                           

HOERSHOLM, Denmark and SAN DIEGO, Sept. 7, 2011 /PRNewswire via COMTEX/ --Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the research and development of mRNA and microRNA targeted therapies, today announced advancements from the company's RNA-targeted research programs utilizing its proprietary Locked Nucleic Acid (LNA) Drug Platform. In addition to a presentation on the Company's microRNA-targeted drug miravirsen, a total of six abstracts/posters are being showcased at the 7th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) held September 8-10 in Copenhagen, Denmark.                                                       

   

                                                       

                           

The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates that can selectively inhibit mRNA and microRNA targets for a range of diseases including metabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders.                                                       

                           

"Santaris Pharma A/S is pleased to have the OTS hold its annual meeting here in Denmark this year as it recognizes the groundbreaking RNA-targeted research and development being conducted in Denmark from companies such as Santaris Pharma A/S as well as public institutions and research centers," said Henrik Oerum, Ph.D., Vice President and Chief Scientific Officer of Santaris Pharma A/S.                                                       

                           

"Santaris Pharma A/S is excited to showcase its microRNA and mRNA-targeted research advancements utilizing its proprietary Locked Nucleic Acid Drug Platform," Dr. Oerum added. "The Company is providing an update on the progress of its lead microRNA-targeted drug candidate, miravirsen, for the treatment of Hepatitis C; presenting data on the use of Santaris Pharma A/S proprietary 'tiny' LNA-based drugs to inhibit entire microRNA-targeted families and highlighting data demonstrating 'naked' delivery uptake of LNA-based drugs, a key advantage over other RNA based technologies. This collection of data attests to the versatility of the LNA Drug Platform and clearly supports Santaris Pharma A/S leadership position in discovering and developing RNA-targeted medicines."                                                       

                           

In a talk titled, "Targeting miRNA-122 for the Treatment of HCV," Dr. Oerum will provide an update on the development of miravirsen, the first microRNA-targeted drug to enter clinical trials, which is now in Phase 2 studies to assess the safety and tolerability of the drug in treatment-naïve patients infected with HCV. Data from Phase 1 clinical studies with miravirsen in healthy volunteers show that the drug is well tolerated.                                                       

                           

Previously published data in Science demonstrated that miravirsen successfully inhibited miR-122 and dramatically reduced Hepatitis C virus in the liver and in the bloodstream in chimpanzees chronically infected with the Hepatitis C virus(1). Because of its unique mechanism of action and tolerability profile, miravirsen has the potential to be an effective treatment option for patients with HCV.                                                       

                           

In addition, scientists at Santaris Pharma A/S will present data using proprietary bioinformatics techniques to demonstrate the specificity of "tiny" 8-mer LNA-based compounds, which have shown to successfully inhibit entire microRNA families providing potential new approach for treating a range of diseases including cancer, viral infections, cardiovascular and muscle diseases. Recent data published in Nature Genetics showed that the high affinity and target specificity of tiny LNA-based compounds enabled functional inhibition of entire microRNA families in a range of tissues without off-target effects(2).                                                       

                           

MicroRNAs have emerged as an important class of small regulatory RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression associated with many diseases. Because they dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets in the treatment of many disease processes.                                                       

                           

Santaris Pharma A/S also will present data demonstrating successful "naked" delivery uptake of LNA-based compounds, an advantage over other RNA-based technologies that require complex delivery vehicles. Data showed that LNA-based compounds readily enter cells in an active form allowing in vitro prediction of potent therapeutically active compounds as well as in vivo distribution to manifold cell types and tissues. Without the need for using complex delivery vehicles, the versatility of the LNA Drug Platform is the key for scientists to develop both microRNA and mRNA-targeted drugs with excellent specificity and increased affinity to drug target, providing improved potency and favorable tissue-penetrating properties.                                                       

                           

The Santaris Pharma A/S LNA Drug Platform is the only RNA technology with both mRNA and microRNA targeted drugs in clinical trials, demonstrating the broad utility of the proprietary platform. In September 2010, Santaris Pharma A/S successfully advanced miravirsen, a lead microRNA drug candidate targeting miR-122, into Phase 2 studies for the treatment of patients infected with the Hepatitis C virus. In addition, Santaris Pharma A/S also advanced two mRNA-targeted drugs, SPC5001 targeting PCSK9 and SPC4955 targeting apoB, for the treatment of high cholesterol into Phase 1 in May 2011.                                                       

                           

With its partners, Santaris Pharma A/S has a robust product pipeline consisting of mRNA and microRNA drug discovery and development collaborations. These include partnerships with Pfizer, Inc. (delivery of lead candidates against up to 20 targets), miRagen Therapeutics (cardiovascular diseases), Shire plc (rare genetic disorders), GlaxoSmithKline (four viral disease drug candidates) and Enzon Pharmaceuticals (eight cancer targets successfully delivered - three are now in Phase 1 clinical studies).                                                       

                           

About Locked Nucleic Acid (LNA) Drug Platform                                                       

                           

The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to target pathways previously considered inaccessible. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.                                                       

                           

About Santaris Pharma A/S                                                       

                           

Santaris Pharma A/S is a privately held clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The Company's research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The Company has strategic partnerships with miRagen Therapeutics, Shire plc, Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the Company holds exclusive worldwide rights to all therapeutic uses of LNA. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit  www.santaris.com     for more information.                                                       

                           

(1) Lanford et al, Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327 (5962): 198-201                                                       

                           

(2) Obad, et al. Silencing of microRNA families by seed-targeting tiny LNAs. Nature Genetics 10.1038/ng.786.                                                       

                           

SOURCE  Santaris Pharma A/S                                                       

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