Alnylam公司揭示分子扭转RNA干扰疗法的效果

StephenW

Alnylam reveals molecule to reverse effect of its RNAi therapies
October 20, 2015 | By Varun Saxena


Alnylam ($ALNY) unveiled two new additions to its RNAi drug delivery arsenal at the meeting of the Oligonucleotide Therapeutics Society in Leiden, Netherlands, as it strives to be first biotech to commercialize a therapeutic that leverages the naturally occurring pathway.

At the meeting, senior scientist Ivan Zlatev described the company's internally developed Reversir molecules for the reversal of siRNA silencing activity. Or as COO Barry Greene put it during an interview, "What our scientists invented was a technology to reverse the pharmacology of an RNAi-mediated therapeutic program."

Greene said the breakthrough is a feature that makes Alnylam's RNAi drug delivery platform more powerful, although he stressed the company has not yet created a Reversir molecule for any of its specific programs or candidates.
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Subcutaneous injection of a Reversir molecule is designed to stop an Alynlam RNAi therapeutic from achieving its normal biologic effect on the body, Greene said, citing data presented at the conference showing that the molecules were well-tolerated and reversed siRNA-conjugate activity in rodents after about 10 days.

Hypothetical benefits of Reversir molecules could include the ability to stop drug activity before a surgery or after an inadvertent injection, Greene said, adding "I can imagine us integrating this into our programs over the next couple of years."

Greene explained the Reversir molecules bind to antisense strands in functional RNAi-induced silencing complexes (RISCs) to prevent mRNA cleavage, enabling the normal "DNA makes RNA makes protein" process to continue.

In addition, Alnylam presented data on its bis-RNAi conjugate molecules for the simultaneous silencing of two genes with a single molecular entity. The drug delivery technology delivers two strands of siRNA to the cell, potentially improving the therapeutic benefits of Alnylam candidates.

Alnylam evaluated two designs of bis-RNAi with different linker structures, and has developed a screening system to evaluate various conjugates, according to a poster on its website. Early results of bis-RNAi on human whole blood assays and mice models show promising signs of efficacy and demonstrate that molecules do not induce a cytokine response, the poster says.

The company expects to advance its first bis-RNAi candidate as soon as next year, and says the platform advance has applications to its cardio-metabolic and hepatic infectious disease therapeutic areas.

Although neither breakthrough has worked its way into a particular Alnylam candidate yet, the company is advancing therapies through its pipeline that use its second-generation "ESC" GalNAc conjugate technology, including a Phase III hemophilia candidate. And during the conference, Alnylam presented preclinical data on one of its ESC candidates for TTR-mediated amyloidosis.

Greene said that the second generation platform improves patient safety, efficacy and convenience because it enables stronger drug potency and less frequent subcutaneous dosing.

Alynlam's platform enhancements come as RNAi is threatened with becoming a victim of its own success, as clinicians and investors impatiently await a clinical and economic payoff in the form of a successful commercial therapeutic.

The naturally occurring paradigm's discovery in 1998 earned scientists Andrew Fire and Craig Mello a Nobel Prize in 2006 to great fanfare, and subsequent investments from Big Pharmas Roche ($RHHBY), Novartis ($NVS) and Merck ($MRK), all of whom subsequently canceled their programs due to the difficulty of drug delivery of RNAi candidates across cell membranes.

Greene defended his company last year by going on the offensive, telling FierceDrugDelivery that Big Pharma "has been a miserable barometer of high-impact technologies" and "has never been able to innovate" after Novartis' RNAi pullout sent Alnylam's stock down 20% amid a renewed wave of nervousness.

As another sign of decreased (popular) interest, the Economist magazine notes that Google searches for "RNAi" have been steadily decreasing since peaking around 2005. But pointing to the strong pipelines and innovative drug delivery strategies of Alynlam and competitors Dicerna and Benitec Biopharma, the article concludes that the herd likely gave up on RNAi a little too early.

- read the release about the two new features | here's more about Alnylam's preclinical candidate (ALN-TTRsc02)
- here are presentation slides about Reversir molecules | and a poster about bis-RNAi

StephenW

Alnylam公司揭示分子扭转RNA干扰疗法的效果
二零一五年十月二十〇日|通过Varun的Saxena先生


Alnylam公司（$ ALNY）发布了两款新增加的RNA干扰药物输送阿森纳寡核苷酸治疗协会在荷兰莱顿的会议，因为它努力成为第一个生物技术商业化的治疗，利用自然产生的途径。

会上，资深科学家伊万Zlatev介绍，公司内部开发的Reversir分子的siRNA沉默活性的逆转。或者担任COO巴里·格林把它在接受采访时，“我们的科学家发明了一种技术来扭转的RNAi介导治疗方案的药理学。”

格林说，突破是一个功能，使得Alnylam公司的RNA干扰药物交付平台更强大，但他强调，公司尚未建立一个Reversir分子的任何具体计划或候选人。
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皮下注射Reversir分子被设计为停止Alynlam RNAi的距离实现对身体的正常生物效应的治疗，格林说，援引数据在会议表明该分子被良好耐受提出和颠倒的siRNA结合物活性的啮齿动物后约10天。

Reversir分子的假设的好处可能包括停止药物活性的术前或无意的注射后的能力，格林补充说，“我可以想像我们这个集成到我们在未来几年计划。”

格林解释Reversir分子与反义链在功能的RNAi诱导沉默复合物（位RISC），以防止mRNA的乳沟，使正常“的DNA，使RNA，使蛋白质”的过程继续。

此外，奥尼拉姆提出的数据在其双 - 缀合物的RNAi分子的两个基因的一个单一分子实体同时沉默。药物递送技术提供的siRNA两条链的细胞，有可能提高奥尼拉姆候选的治疗益处。

Alnylam公司评估双RNA干扰的两种设计不同的连接体结构，并开发了一个筛选系统，以评估各种结合物，根据其网站上的海报。二RNAi对人全血化验和小鼠模型的早期结果显示疗效令人鼓舞的迹象，并表明分子不诱导细胞因子的反应，发帖者说。

该公司预计，一旦明年推进其第一个双RNA干扰的候选人，并表示该平台已经提前应用到它的心脏代谢和肝脏感染性疾病的治疗领域。

虽然没有突破，曾的方式进入一个特定的奥尼拉姆候选人的是，该公司正在推进通过其管道使用的第二代“ESC”半乳糖胺结合的技术，包括第三阶段血友病候选疗法。而且在会议期间，Alnylam公司提出了第ESC候选人TTR介导的淀粉样变1临床数据。

格林说，第二代平台提高了患者的安全性，有效性和方便，因为它使强药效，减少频繁皮下给药。

来作为RNA干扰Alynlam的平台增强的威胁成为其自身成功的受害者，为临床医生和投资者迫不及待地等待临床和经济回报的一个成功的商业治疗的形式。

天然存在的范式的发现在1998年赢得了科学家安德鲁·法尔和克雷格·梅洛诺贝尔文学奖于2006年大张旗鼓，以及后续投资的大型制药企业罗氏（$ RHHBY），诺华（$ NVS）和默克（$ MRK），所有的人随后被取消其方案由于RNAi的候选人的跨细胞膜的药物递送的难度。

格林捍卫了他的公司去年通过去在进攻上，告诉FierceDrugDelivery的大型制药公司“一直是高影响力的技术，一个悲惨的晴雨表”和“始终无法创新”后，诺华公司的RNA干扰撤军发送Alnylam公司的股票下跌了20％。市场重新波紧张。

作为降低（流行）的兴趣又一个迹象，经济学人杂志指出，谷歌搜索“RNA干扰”以来峰值2005年左右，但指向的Alynlam和竞争对手Dicerna和Benitec公司生物制药的强劲管道和创新药物递送策略一直在稳步下降，文章的结论是，牛群很可​​能放弃了RNA干扰有点太早了。

- 阅读有关的两个新功能的发布|这里更多的是Alnylam公司的临床前候选（ALN-TTRsc02）
- 这里是关于Reversir分子演示幻灯片|而关于海报双RNA干扰