20年等待后基因沉默技术终首获制药批准
青岛希尼尔翻译咨询有限公司（www.sinosenior.com）整理发布 2018-8-19
青岛希尼尔翻译公司（www.sinosenior.com）2018年8月19日了解到：U.S.
regulators have approved the first therapy based on RNA interference (RNAi),
a technique that can be used to silence specific genes linked to
disease. The drug, patisiran, targets a rare condition that can impair
heart and nerve function.
美国监管机构已经批准了第一种基于RNA干涉技术（RNAi）的治疗方法，这项技术可以使得与疾病相关的特定基因不在活跃。由此技术研制的药物
patisiran可用于治疗一种可能伤害心脏和神经功能的罕见疾病。
The approval, announced by the U.S. Food and Drug Administration on 10
August, is a landmark for a field that has struggled for nearly two
decades to prove its worth in the clinic. Researchers first discovered
RNAi 20 years ago, sparking hopes of a revolutionary new approach to
medicine. Since then, however, a series of setbacks has lessened those
expectations.
这项由美国食品药品管理局于8月10日公布的批准对于这个近二十年来一直努力证明其价值的领域来说具有里程碑意义。研究人员在20年前首次发现了RNAi，激起了人们对于医学界革命性的新疗法的希望。然而自那之后一系列的挫折降低了人们的期望。
“This approval is key for the RNAi field,” says James Cardia, head of
business development at RXi Pharmaceuticals in Marlborough,
Massachusetts, which is developing RNAi treatments. “This is
transformational.”
“这项批准对于RNAi研究领域很关键，”詹姆斯.卡地亚（James Cardia）,一直在从事RNAi治疗技术研发的马萨诸塞州马尔堡RXi制药公司商务运营部长说，“这是变革性的。”
Patisiran works by silencing the gene that underlies a rare disease
called hereditary transthyretin amyloidosis. In that illness, mutated
forms of the protein transthyretin accumulate in the body, sometimes
impairing heart and nerve function.
Patisiran可以使可能引起一种称为“遗传性运甲状腺素蛋白介导淀粉样变”的罕见疾病的基因成分沉默。这种疾病会引起蛋白质转甲状腺素蛋白的突变形式在体内集聚，有时会造成心脏和神经功能损伤。
The drug’s approval means that pharmacology textbooks will need to be
rewritten, says Ricardo Titze-de-Almeida, who studies RNAi at the
University of Brasilia. “We are inaugurating a new pharmacological
group,” he says. “We will have many more such drugs in the coming
years.”
“这种药物的批准意味着药理学教科书可能要重编了，”理查德.泰泽.阿尔梅达（Ricardo Titze-de-Almeida）说，他在巴西利亚大学研究RNAi。“我们在开辟一个新的药物学组合，”他说，“未来几年我们将会开发出更多这样的药物。”
This was the hope when Alnylam, the company in Cambridge, Massachusetts,
that developed patisiran, launched in 2002. Four years later, the Nobel
Prize in Physiology or Medicine was awarded to two RNAi pioneers: Andrew
Fire of Stanford University School of Medicine in California and Craig
Mello of the University of Massachusetts Medical School in Worcester.
2002年位于马萨诸塞州剑桥市的医药公司Alnylam研制出了patisiran,从而给了人们希望。四年之后，诺贝尔生理学江颁发给了两位RNAi先驱：来自加州斯坦福大学医学院的安德鲁.福尔（Andrew
Fire）和来自伍斯特市马萨诸塞州立大学医学院的克雷格.梅罗（Craig Mello）。
But to make RNAi into medicine, developers would first need to determine
how to deliver delicate molecules of RNA safely to their target organs.
They needed a way to shield the RNA from degradation in the bloodstream,
prevent it from being filtered out by the kidneys, and allow it to exit
blood vessels and spread through tissues. “That proved to be a
substantially harder problem than we anticipated,” says Douglas
Fambrough, chief executive of Dicerna, an RNAi-focused company in
Cambridge, Massachusetts.
但是为了能用RNAi技术制成药物，研发人员首先需要确定如何将精细的RNA分子安全地传递到它们的靶器官。他们需要一种方法来保护RNA免受血液的降解，防止它被肾脏过滤掉，并能使它从血管中解析出来并通过组织传播。“事实证明，这比我们预期的要困难的多。”Dicema
的CEO道格拉斯.樊布劳（Douglas Fambrough）说。Dicema是马萨诸塞州剑桥市一家专注于RNAi研究的公司。
As researchers grappled with the delivery puzzle, investors began to
lose confidence. In 2008, analyst Edward Tenthoff of investment bank
Piper Jaffray in New York City advised his clients to stop buying
Alnylam stock. “We saw the promise in the technology, but the delivery
was lacking,” he says.
当研究人员受困于解决RNA分子传递难题时，投资者们开始失去信心了。2008年纽约Piper
Jaffray投行的分析师爱德华.藤瑟夫（Edward
Tenthoff）就建议他的客户别再购买Alnylam公司股票了。“我们得到了技术上的承诺，但却迟迟无法兑现。”他说。
By 2010, large pharmaceutical companies were also losing their appetite
for RNAi, severing collaborations and ending internal research
programmes. “By and large, big pharma left RNAi for dead,” says
Fambrough. Safety concerns dealt the field another blow in 2016, when
Alnylam abandoned one of its leading RNAi programmes after finding a
possible link to patient deaths in a clinical trial.
到2010年大型制药公司也开始失去对RNAi的兴趣了，中止了合作，也停止了内部研究计划。“总的来说，大型制药公司放任RNAi自生自灭了。”樊布劳（Fambrough）说。2016年安全问题又给了这个领域一次打击，当时Alnylam公司在临床试验中发现这种技术可能导致病人死亡，之后便中止了她的一个领先性的RNAi项目。
But gradually, some RNAi companies began to iron out the kinks in their
delivery systems, and Tenthoff started to encourage investors to buy
stock again. Alnylam experimented with a number of delivery routes and
target organs, encasing some of its RNA molecules in fatty nanoparticles
orchemically modifying the RNAs to help them survive the perilous
journey through the bloodstream.
但渐渐的一些RNAi公司开始解决了他们传递系统中的问题，藤瑟夫（Tenthoff）也开始鼓励投资者再次去买股票了。
Alnylam实验了许多传递方法和靶器官，将一些RNA分子包裹在脂肪纳米颗粒中，以化学方式改进了RNA，帮助它们在危险的血液穿越过程中存活下来。
RNAs protected in this way and injected into the bloodstream tended to
accumulate in the kidneys and liver. This led the company to look at
transthyretin, which is produced mainly in the liver. In a clinical
trial in 225 people with hereditary transthyretin amyloidosis who showed
signs of nerve damage, average walking speed significantly improved in
those who received the treatment. Walking speed declined in the placebo
group.
以这种方式保护并被注入血液的RNA分子开始能够在肾脏和肝脏中聚集。这引起了制药公司对于甲状腺素这种主要产生于肝脏中的的关注。在由225名患有遗传性运甲状腺素介导淀粉样变病并表现出神经损伤症状的病人参加的临床试验中，接受RNAi治疗的参与者的平均行走速度得到了显著提升。安慰剂组的病人行走速度又减慢了。
In the future, Alnylam and others will be able to move beyond the liver,
says company co-founder Thomas Tuschl, a biochemist at Rockefeller
University in New York City. Quark Pharmaceuticals of Fremont,
California is testing RNAi therapies that target proteins in the kidneys
and the eye. Alnylam is developing ways to target the brain and spinal
cord, and Arrowhead Pharmaceuticals of Pasadena, California, is working
on an inhalable RNAi treatment for cystic fibrosis.
未来Alnylam和其他公司的研究将不止限于肝脏，公司联合创始人、纽约洛克菲勒大学生物化学家托马斯.拖施尔（Thomas
Tuschl）说。加利福尼亚州弗里蒙特市的Quark 制药公司正在测试肾脏和眼睛中蛋白质的RNAi疗法。 Alnylam正在开发针对大脑和脊髓的治疗方法，加利福尼亚州帕萨迪纳市的箭头制药公司正致力于研究囊性纤维化的可溶性RNAi治疗法。
“I’ve never been more optimistic about the future of RNAi,” says
Fambrough. “All of those tear-your-hair-out days were worth it to get to
today.”
“我从没有像现在一样对RNAi的未来感到乐观，”樊布劳（Fambrough）说，“能有今天的成果，所有那些绞尽脑汁冥思苦想的艰苦日子都是值得的。”
来源:Scientific American
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