RNA动力学被解构：新技术为RNA分子水平的改变提供详细的信息
May 03, 2011 No Comments
RNA在指引蛋白质合成方面起着至关重要的作用，但是RNA的使命不仅限于携带DNA信息那么简单。布罗德研究所（Broad Institute
of Harvard and
MIT）的研究人员开发的新方法能够帮助他们更全方位地研究这个关键分子的生命周期，同时有助于其他科学家研究细胞出现异常的前因后果。他们将这个具有高分辨率以及全面适用性的新方法发表在4月24日的《自然生物技术》（Nature
Biotechnology）杂志的在线版上。
“人们越来越多地了解到了RNA的生命周期在疾病核心问题中所起的作用，但是，相对于其它细胞过程来说，我们对RNA生命周期的了解还是比较少的，”Aviv Regev说。他是美国布罗德研究所的负责人，也是论文的共同资深作者。
Regev等人研发出了一种新方法，通过检测信使RNA生成和降解的数量就可以对RNA生命周期的不同阶段进行解释。RNA生产和降解过程的平衡决定了在一个细胞中RNA水平会随着时间发生变化，就如同出生和死亡率决定了一个国家的总人口数一样。
RNA水平是动态的——在对某些刺激做出反应时，它们总是会发生变化。在这个研究中，研究人员就选择参与人体免疫反应的树突状细胞作为模型。他们将这些细胞暴露在类似于一个病原体的刺激物中，然后观察暴露前和暴露后的RNA水平的改变。
“我们想要掌握细胞是如何调控RNA水平的，调控是发生在RNA分子生成、降解阶段，还是处理过程中呢？” 说。他是该论文的第一作者，也是布罗德研究所的研究生。“每一个步骤都有可能影响细胞内活性RNA分子的水平。当事情发生异常时，如果你想要了解到底发生了什么，你就必须了解它们正常工作是如何进行的。”
研究人员的新方法有助于我们观察一个特定的细胞类型以及所有基因的表达变化。这个方法的广泛适用性以及特异性有助于我们全面观察RNA随着时间是如何变化的。“如果我们想要观察大脑中特定的神经细胞或者肺部位于其它细胞间的特异细胞，这个新方法可以帮助我们放大在数百万其它细胞中的一个细胞的一个过程。在许多疾病中，都出现过一个特异细胞短路的情况，现在，我们有更好的工具来发现它，”Ido Amit说，他是该文章的共同资深作者。
科学家利用一种现有的技术，再加上用于mRNA分子技术的基于测序方法的技术来追踪新生成RNA的命运。研究人员得到了一些有关mRNA剪接或者加工两个步骤之间的意外发现。“这就是测序方法之美：它能向你展现一些你意想不到的广阔景象，”Regev说。
该方法的关键方面是研究人员能够在非常短的时间间隔里获得RNA水平的“快照”。这些快照串联在一起不仅能够揭示RNA数量是如何变化的，也能用于其它方法无法进行的对短时、中间阶段RNA生命周期的检测。“这为我们进入RNA世界提供更多的窗口，”Amit说。这个新方法的一个关键作用是可用于未来疾病的研究，例如，用于了解在癌症或其它疾病中，能影响RNA生命周期的突变基因。“在过去，你可能知道存在着一个突变基因，并对这个基因的功能有质疑，但是却很难观察在细胞中突变体对这些类型进程的影响，”Regev说。研究人员希望，这项新技术有助于其它研究人员更深入了解基因突变是如何扰乱RNA水平，进而影响蛋白质合成的。
“我们现在将这些RNA水平分解成多个单独的步骤来研究，以便了解在每个步骤中发生了什么，以及不同的步骤是如何相互作用，从而产生最后结果的，”Rabani表示。“这是一个非常复杂的系统，但是掌握它最终将有助于我们掌握当出现异常时，是哪里出错了。”
文章来源：http://www.physorg.com/news/2011-04-rna-dynamics-deconstructed-technique-view.html
文章题目：RNA dynamics deconstructed: Technique offers detailed view of how RNA levels change
小芳/编译
“人们越来越多地了解到了RNA的生命周期在疾病核心问题中所起的作用，但是，相对于其它细胞过程来说，我们对RNA生命周期的了解还是比较少的，”Aviv Regev说。他是美国布罗德研究所的负责人，也是论文的共同资深作者。
Regev等人研发出了一种新方法，通过检测信使RNA生成和降解的数量就可以对RNA生命周期的不同阶段进行解释。RNA生产和降解过程的平衡决定了在一个细胞中RNA水平会随着时间发生变化，就如同出生和死亡率决定了一个国家的总人口数一样。
RNA水平是动态的——在对某些刺激做出反应时，它们总是会发生变化。在这个研究中，研究人员就选择参与人体免疫反应的树突状细胞作为模型。他们将这些细胞暴露在类似于一个病原体的刺激物中，然后观察暴露前和暴露后的RNA水平的改变。
“我们想要掌握细胞是如何调控RNA水平的，调控是发生在RNA分子生成、降解阶段，还是处理过程中呢？” 说。他是该论文的第一作者，也是布罗德研究所的研究生。“每一个步骤都有可能影响细胞内活性RNA分子的水平。当事情发生异常时，如果你想要了解到底发生了什么，你就必须了解它们正常工作是如何进行的。”
研究人员的新方法有助于我们观察一个特定的细胞类型以及所有基因的表达变化。这个方法的广泛适用性以及特异性有助于我们全面观察RNA随着时间是如何变化的。“如果我们想要观察大脑中特定的神经细胞或者肺部位于其它细胞间的特异细胞，这个新方法可以帮助我们放大在数百万其它细胞中的一个细胞的一个过程。在许多疾病中，都出现过一个特异细胞短路的情况，现在，我们有更好的工具来发现它，”Ido Amit说，他是该文章的共同资深作者。
科学家利用一种现有的技术，再加上用于mRNA分子技术的基于测序方法的技术来追踪新生成RNA的命运。研究人员得到了一些有关mRNA剪接或者加工两个步骤之间的意外发现。“这就是测序方法之美：它能向你展现一些你意想不到的广阔景象，”Regev说。
该方法的关键方面是研究人员能够在非常短的时间间隔里获得RNA水平的“快照”。这些快照串联在一起不仅能够揭示RNA数量是如何变化的，也能用于其它方法无法进行的对短时、中间阶段RNA生命周期的检测。“这为我们进入RNA世界提供更多的窗口，”Amit说。这个新方法的一个关键作用是可用于未来疾病的研究，例如，用于了解在癌症或其它疾病中，能影响RNA生命周期的突变基因。“在过去，你可能知道存在着一个突变基因，并对这个基因的功能有质疑，但是却很难观察在细胞中突变体对这些类型进程的影响，”Regev说。研究人员希望，这项新技术有助于其它研究人员更深入了解基因突变是如何扰乱RNA水平，进而影响蛋白质合成的。
“我们现在将这些RNA水平分解成多个单独的步骤来研究，以便了解在每个步骤中发生了什么，以及不同的步骤是如何相互作用，从而产生最后结果的，”Rabani表示。“这是一个非常复杂的系统，但是掌握它最终将有助于我们掌握当出现异常时，是哪里出错了。”
文章来源：http://www.physorg.com/news/2011-04-rna-dynamics-deconstructed-technique-view.html
文章题目：RNA dynamics deconstructed: Technique offers detailed view of how RNA levels change
小芳/编译
Isis Pharmaceuticals - Antisense Making Sense (ISIS)
Isis Pharmaceuticals (ISIS), based in Carlsbad, California, is a leader in something called "antisense technology." With approximately 1,600 patents issued globally, Isis Pharmaceuticals is the owner of one of the largest antisense and RNA patent estates in the pharmaceutical industry. The company has developed a drug discovery platform based on RNA-targeting as opposed to traditional protein targets. Isis Pharmaceuticals is building an impressive pipeline of more than 28 drugs that utilize this technology to treat diseases such as cardiovascular diseases, metabolic disorders, severe and rare diseases, and cancer.
Other smaller pharma companies developing RNA interference/RNAi and antisense drug applications include: Tekmira Pharmaceuticals (TKMR), Sarepta Therapeutics (SRPT), Alnylam (ALNY) and Bio-Path Holdings (OTC:BPTH). But Isis Pharmaceuticals was the first antisense player to date to receive regulatory approval back in 1998 for its antiviral drug Vitravene, and more recently, this January, Isis and Genzyme, a Sanofi company (SNY), received FDA approval for its drug Kynamro to treat inherited cholesterol disorder.
Kynamro, the first systemic antisense therapy to receive regulatory approval, was an important validation of Isis' deep antisense pipeline. Homozygous familial hypercholesterolemia (HoFH), the condition that Kynamro was approved to treat, is relatively rare, ocurring in 1 in a million births. Despite the limited patient population and competition from Aegerion's Juxtapid (AEGR), analysts still estimate Kynamro's peak market opportunity to be in the $200-400 million range. Part of the reason for the revenue opportunity - the high price. Sanofi's Genzyme unit has set a price for Kynamro of $176,000 year. This is actually cheaper than Juxtapid, which runs $235,000-$295,000 year, depending on the patient. The side-effect profiles are also different, perhaps favoring Juxtapid. But Kynamro has the marketing power of Sanofi/Genzyme behind it to help drive sales.
On its earnings call, the company predicted that 2013 was going to be a year of "substantial growth and maturation for Isis." Already in 2013, the company has received a $25 million milestone payment from Genzyme and a $7.5 million milestone payment from GlaxoSmithKline (GSK). With the commercial launch of Kynamro, a maturing pipeline of drugs, and more near-term opportunities for partnership revenue, 2013 is setting up to be a strong year of revenue growth for the company.
On February 28, the company reported a narrower than expected loss of $.03 per share, which was $.20 better than the Zack's consensus estimate. Revenues fell 38.6% year over year to $19.9 million, but this was also higher than the Zack's $16 million consensus estimate.
On April 8th, Isis Pharmaceuticals, Inc. announced that they have formed an alliance with Roche to develop treatments for Huntington's disease (an inherited brain disorder) based on Isis' antisense technology and Roche's "brain shuttle" technology developed to better penetrate the brain. Presently, there is no effective treatment or cure for the disease, and current treatments, such as Valeant's (VRX) drug Xenazine, only focus on reducing the severity of some disease symptoms.
About 30,000 Americans have Huntington's disease. A similar prevalance of 1/10,000 is believed to occur in the major countries in Europe. If all patients with the disease were prescribed a treatment, at a modest cost of $20,000 per patient, the total market opportunity could be as much as $4.2 billion across the patient population. Despite the challenges that lay ahead, the announced partnership with Roche is yet another validation of Isis' antisense drug delivery platform.
Isis Pharmaceutical does indeed have an impressive drug pipeline and some big strategic partners.
(click to enlarge)
The stock traded off late last year and dipped below $8 share on safety and competitive concerns related to Kynamro. But since the drug was approved in January, the stock has moved from $14 and moved up to test the $18 level. The stock is up more than 66% year-to-date versus only 17% for the AMEX Biotech Index (BTK). However, in the absence of earnings, if Isis' stock is going to move higher, it needs more strategic partnerships such as the one announced today. Isis Pharmaceuticals is a Jim Cramer, CNBC "Mad Money" mention and one of his favorite picks in the biotech space. Prior to today's announcement, Cramer stated on April 3's show that he would wait for a pullback before buying shares.
Despite the favorable terms of the recent Roche partnership, the announcement did not really move Isis Pharmaceutical stock - it traded up only 3 cents a share. However, with yet another lucrative strategic partnership deal inked for the company, on the heels of an important FDA approval, "antisense" may be starting to make sense as an investment opportunity.
Information provided, whether charts or any other statements regarding market, real estate or other financial information, is obtained from sources, which we and our suppliers believe reliable, but we do not warrant or guarantee the timeliness or accuracy of this information. Nothing in this article should be interpreted to state or imply that past results are an indication of future performance.
Disclosure: I am long AEGR.
Other smaller pharma companies developing RNA interference/RNAi and antisense drug applications include: Tekmira Pharmaceuticals (TKMR), Sarepta Therapeutics (SRPT), Alnylam (ALNY) and Bio-Path Holdings (OTC:BPTH). But Isis Pharmaceuticals was the first antisense player to date to receive regulatory approval back in 1998 for its antiviral drug Vitravene, and more recently, this January, Isis and Genzyme, a Sanofi company (SNY), received FDA approval for its drug Kynamro to treat inherited cholesterol disorder.
Kynamro, the first systemic antisense therapy to receive regulatory approval, was an important validation of Isis' deep antisense pipeline. Homozygous familial hypercholesterolemia (HoFH), the condition that Kynamro was approved to treat, is relatively rare, ocurring in 1 in a million births. Despite the limited patient population and competition from Aegerion's Juxtapid (AEGR), analysts still estimate Kynamro's peak market opportunity to be in the $200-400 million range. Part of the reason for the revenue opportunity - the high price. Sanofi's Genzyme unit has set a price for Kynamro of $176,000 year. This is actually cheaper than Juxtapid, which runs $235,000-$295,000 year, depending on the patient. The side-effect profiles are also different, perhaps favoring Juxtapid. But Kynamro has the marketing power of Sanofi/Genzyme behind it to help drive sales.
On its earnings call, the company predicted that 2013 was going to be a year of "substantial growth and maturation for Isis." Already in 2013, the company has received a $25 million milestone payment from Genzyme and a $7.5 million milestone payment from GlaxoSmithKline (GSK). With the commercial launch of Kynamro, a maturing pipeline of drugs, and more near-term opportunities for partnership revenue, 2013 is setting up to be a strong year of revenue growth for the company.
On February 28, the company reported a narrower than expected loss of $.03 per share, which was $.20 better than the Zack's consensus estimate. Revenues fell 38.6% year over year to $19.9 million, but this was also higher than the Zack's $16 million consensus estimate.
On April 8th, Isis Pharmaceuticals, Inc. announced that they have formed an alliance with Roche to develop treatments for Huntington's disease (an inherited brain disorder) based on Isis' antisense technology and Roche's "brain shuttle" technology developed to better penetrate the brain. Presently, there is no effective treatment or cure for the disease, and current treatments, such as Valeant's (VRX) drug Xenazine, only focus on reducing the severity of some disease symptoms.
About 30,000 Americans have Huntington's disease. A similar prevalance of 1/10,000 is believed to occur in the major countries in Europe. If all patients with the disease were prescribed a treatment, at a modest cost of $20,000 per patient, the total market opportunity could be as much as $4.2 billion across the patient population. Despite the challenges that lay ahead, the announced partnership with Roche is yet another validation of Isis' antisense drug delivery platform.
Isis Pharmaceutical does indeed have an impressive drug pipeline and some big strategic partners.
Pipeline
| Drug | Target | Partner | Phase |
| CARDIOVASCULAR | |||
| KYNAMRO™ | ApoB-100 | Genzyme | Phase III |
| ISIS-APOCIIIRx | ApoCIII | - | Phase II |
| ISIS-CRPRx | CRP | - | Phase II |
| ISIS-FXIRx | Factor XI | - | Phase II |
| ISIS-APOARx | Apo(a) | - | Phase I |
| ISIS-FVIIRx | Factor VII | - | Preclinical |
| SEVERE & RARE | |||
| KYNAMRO™ | ApoB-100 | Genzyme | Approved |
| Alicaforsen | ICAM-1 | Atlantic | Phase II/Named Patient Supply |
| ISIS-TTRRx | TTR | GSK | Phase III |
| ISIS-SMNRx | SMN2 | Biogen Idec | Phase II |
| ISIS-APOCIIIRx | ApoCIII | - | Phase II |
| ATL1103 | GHr | ATL | Phase II |
| ISIS-GCCRRx | GCCR | - | Phase I |
| ISIS-AATRx | AAT | GSK | Preclinical |
| ISIS-PKKRx | PKK | - | Preclinical |
| METABOLIC | |||
| ISIS-PTP1BRx | PTP-1B | - | Phase I |
| ISIS-GCCRRx | GCCR | - | Phase I |
| ISIS-GCGRRx | GCGR | - | Phase I |
| ISIS-FGFR4Rx | FGFR4 | - | Phase I |
| ISIS-DGAT2Rx | DGAT2 | - | Preclinical |
| CANCER | |||
| Custirsen | clusterin | Teva/OncoGenex | Phase III |
| ISIS-EIF4ERx | eIF-4E | - | Phase II |
| OGX-427 | Hsp27 | OncoGenex | Phase II |
| ISIS-STAT3Rx | STAT3 | AstraZeneca | Phase II |
| ISIS-AZ1Rx | Undisclosed | AstraZeneca | Preclinical |
| INFLAMMATION AND OTHER | |||
| ISIS-CRPRx | CRP | - | Phase II |
| ATL1102 | VLA-4 | ATL | Phase II |
| EXC 001 | CTGF | Pfizer | Phase II |
| iCo-007 | C-raf kinase | iCo | Phase II |
| Plazomicin | Aminoglycoside | Achaogen | Phase II |
| XEN701 | Undisclosed | Xenon | Preclinical |
| ISIS-GSK3Rx | Undisclosed | GSK | Preclinical |
Source: Isis Pharmaceuticals Company Website
Strategic Partnerships
Strategic partnerships are critical to Isis' future success. The company's partnership strategy has enabled it to build a broad product pipeline with its annuity of license fees, milestone payments and royalty payments. The other advantage of this strategy is that development expenses are limited and it allows the company to focus on research and development.Biogen-Idec
Isis formed three new strategic alliances with Biogen-Idec (BIIB) to develop and commercialize antisense drugs for severe and rare neurologic diseases. In total, the three alliances are valued at up to $1.2 billion.AstraZeneca
Isis formed a strategic alliance with AstraZeneca (AZN) to discover and develop antisense drugs against five cancer targets. The agreement comprises $31 million in upfront and near-term payments, including a $25 million payment Isis has received followed by a $6 million payment Isis is eligible to receive in the second quarter of 2013 assuming the research program is continuing. Isis is also eligible to receive milestone payments, license fees and royalties.GlaxoSmithLine
Isis and GlaxoSmithKline are pursuing an accelerated development plan for ISIS-TTRRx. As a result, Isis received a $2.5 million upfront payment and a $7.5 million milestone payment. Isis is also eligible to earn an additional $50 million in pre-licensing milestone payments.Roche
Isis and Roche (OTCQX:RHHBY) formed an alliance for Huntington's disease. Roche will make a $30 million upfront payment to Isis. Total payments related to license fee and pre- and post-licensing milestone payments are potentially $362 million, including up to $80 million in potential commercial milestone payments.Other Partnerships
Isis benefited as its partners advanced RNA-based technologies and products incorporating its technology.- Isis received $2.7 million from Alnylam as a result of Alnylam's licenses that included Isis' patents.
- Isis received $1.3 million from Pfizer triggered by Pfizer's decision to advance EXC 001 into a Phase 2 study.
Stock Price
So how has all this positive news flow translated to the stock's price year-to-date, and is there still near-term opportunity for upside?(click to enlarge)
The stock traded off late last year and dipped below $8 share on safety and competitive concerns related to Kynamro. But since the drug was approved in January, the stock has moved from $14 and moved up to test the $18 level. The stock is up more than 66% year-to-date versus only 17% for the AMEX Biotech Index (BTK). However, in the absence of earnings, if Isis' stock is going to move higher, it needs more strategic partnerships such as the one announced today. Isis Pharmaceuticals is a Jim Cramer, CNBC "Mad Money" mention and one of his favorite picks in the biotech space. Prior to today's announcement, Cramer stated on April 3's show that he would wait for a pullback before buying shares.
Despite the favorable terms of the recent Roche partnership, the announcement did not really move Isis Pharmaceutical stock - it traded up only 3 cents a share. However, with yet another lucrative strategic partnership deal inked for the company, on the heels of an important FDA approval, "antisense" may be starting to make sense as an investment opportunity.
Disclaimer
The opinions expressed above should not be construed as investment advice. This article is not tailored to specific investment objectives. Reliance on this information for the purpose of buying the securities to which this information relates may expose a person to significant risk. The information contained in this article is not intended to make any offer, inducement, invitation or commitment to purchase, subscribe to, provide or sell any securities, service or product or to provide any recommendations on which one should rely for financial, securities, investment or other advice or to take any decision. Readers are encouraged to seek individual advice from their personal, financial, legal and other advisers before making any investment or financial decisions or purchasing any financial, securities or investment related service or product.Information provided, whether charts or any other statements regarding market, real estate or other financial information, is obtained from sources, which we and our suppliers believe reliable, but we do not warrant or guarantee the timeliness or accuracy of this information. Nothing in this article should be interpreted to state or imply that past results are an indication of future performance.
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