When a Nobel Prize brings a shower of hype: the roller coaster ride of RNAi

When Nobel Prizes are announced next week, winning the biomedical discovery is sure to be showered with a lot of hype. And that could be a problem. The path of a bright laboratory for a real drug discovery is long and winding -. And sometimes, high expectations can be counterproductive

take the roller coaster ride interference RNA, a Nobel technology awards he has received a lot of praise and billions of dollars in funds, only to stumble badly when science does not deliver real drugs – at least not fast enough for investors.

A decade after the Nobel glory, RNAi is on the rise again: The first drug using technology to silence disease-causing genes could get federal approval as soon as next year. But his tortured career stands as a warning to other highly publicized and widely honrados- discoveries from cancer vaccines immune stimulation to optogenetics to CRISPR gene editing system is considered a serious contender for the next week Nobel.

Article continues after the announcement

“I assure you, God did not create RNAi for medicines out of it,” said John Maraganore, CEO of Alnylam Pharmaceuticals, which is working on RNAi in Cambridge, Mass. “We had to be that out. “

A search begins with roundworm

The story of RNAi begins with the nematode. In early 1990, a group of researchers studied how genes are expressed in these small worms – and found they could manipulate the process by interfering with RNA worms. A seminal article published in Nature by scientists Andrew Fire and Craig Mello demonstrated that roundworm genes could be silenced.

And we had great implications for medicine.

Many diseases are caused by the accumulation of proteins that are misshapen or do not work properly. conventional medicines often aim to clean these proteins in the body. RNAi therapies, however, could theoretically shut down the production of proteins completely dysfunctional -. silencing the gene encoding takes to make them

excited, researchers began to try to control genes in mammalian cells form the Fire and Mello had done in roundworms. That code was finally broken in 2001, and new biotech companies began working furiously to trigger RNAi in drugs.

In these early days, Maraganore said the team Alnylam includes a pair of researchers and plenty of patent attorneys – because RNAi technology was seen as so hot that the team wanted to engulf both intellectual property as may be possible. “A period of unbridled enthusiasm for RNAi.”

Patients, researchers and, above all, investors, observed the field as the next breakthrough in medical science. But the hype far exceeded the reality.

“I think most people did not understand at that time what they were really excited, and what is the way forward would be,” said Dirk Haussecker, an independent analyst who tracks carefully RNAi technology.

Loading a Nobel prize

Then came the Nobel prize.

Mello, a researcher at the University of Massachusetts, and fire, which by then was a professor at Stanford University won in 2006 – only eight years after his success in roundworms it was first announced to the world.

Field exploded. Venture capital and had gone RNAi dollars. Now, the financing of major drugmakers also flooded in -. Especially when Merck paid $ 1.1 million to acquire Sirna Therapeutics call home RNAi

“He put a lot of excited people, because they assumed that higher prices mean RNAi was really going to work – quickly,” Haussecker


“When it comes to the Nobel prize, there are two sides to the sword,” said Doug Fambrough, CEO RNAi Dicerna Pharmaceuticals, and an early investor in Sirna. “We were able to enjoy the benefits, but also face the burden of meeting expectations.”

soon became clear that RNAi had a long way to go.

Especially hard :. Figuring out how to deliver it to the cells that need

However, despite the clear obstacles, researchers were running ahead with the experiments, making drugs that had just validated in laboratory tests in humans.

“I think many of the first trials were poorly designed, with lots of people doing trials just to say they were the first,” said Mark Kay, a professor of gene therapy at Stanford. “I think most reasonable people who understand the field knew that these trials would not work.”

Experimental drugs caused harmful effects side in humans that had not been predicted by animal studies. It turned out that could not easily be delivered to the right cells in the body, and ended up being ineffective or harmful.

In 2010, the field was cratering.

Roche, having invested a half billion dollars in RNAi, decided to leave the field completely. Pfizer and Abbott Laboratories backed hastily. Alnylam had also reached a “valley”, though its executives were determined to keep pushing.

“The world thought we’d died,” Maraganore said.

But despite the pessimism, Maraganore said he was not particularly worried when he lost the pharmaceutical interest. “Large pharmaceutical companies are terrible on innovation – they really are,” Maraganore said. Large drug manufacturers “do not have the staying power or spirit to take a technology like RNAi, or CAR-T [immunotherapy] or CRISPR, and is a class of drugs.”

In 2014, Merck gave up and RNAi sold Sirna biotechnology company that had previously valued at $ 1 billion, only $ 175 million ahead in cash and stock.

Buyer :. Alnylam

John Maraganore
Keith Bedford / The Boston Globe John Maraganore, CEO Pharmaceuticals Alnylam

New Hope for revolutionary thought

These days RNAi is starting to pick up steam again, a decade after the underlying science was awarded the Nobel.

Where there were companies that pursue RNAi dozens, today only a handful. But big drugmakers are tiptoed back into the field :. just He amgen reached an agreement worth up to $ 647 million with the tip of pharmaceutical arrow to explore RNAi therapy in cardiovascular disease

And after more than $ 1 billion in research, Alnylam has finally come to human trials in late stage of an RNAi drug for a rare and potentially fatal disease resulting from the accumulation of misfolded proteins.

Maraganore is so confident the drug will win the approval of the Administration of Food and Drug next year, or that the company recently broke ground in a large manufacturing plant south of Boston.

The key lesson for investors and patients anxiously eyeing Nobel contenders this year?

Be patient.

Even the most promising technologies can take decades to develop. Take monoclonal antibodies, winning a trio of scientists the Nobel Prize in 1984. The discovery did not end up having therapeutic applications until almost two decades later. Today, monoclonal antibodies represent a market of billions of dollars, especially in cancer treatment .

Optogenetics, a technique that uses light control cells and CRISPR-Cas9, the gene editing tool, is widely expected to win the Nobel at some point. But the two are still in the early stages. Optogenetics now being tested in its first clinical trial, to try to reverse an inherited form of blindness. Researchers simply recently achieved the first of several regulatory approvals that will need to try to use CRISPR in humans.

As for RNAi, Nobel prize Phil Sharp says he hopes fully that to make a difference for patients -. Finally

Sharp, scientific co-founder of Alnylam, is a Nobel prize in its own right; He won in 1993 for his work in the 1970s in RNA splicing. It has been 15 years since it was demonstrated that it was possible to work RNAi in mammalian cells. If it takes a few years to reach patients, so that does not seem to be a reasonable wait for a revolutionary class of drugs.

“I’ve been in the science of 50 years, so this does not seem terribly long,” Sharp said. “I see this as a small step – I see this as a transformation in pharmacology.”

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