Monday, Sept. 28, 2009 | The cause is as simple as it is lethal. Huntington’s Disease slowly destroys brain cells, eventually leaving sufferers unable to talk, think clearly or even walk by themselves.

The culprit is a defective copy of a single gene — one out of more than 25,000 in the human genetic code. If the defective gene could be magically switched off, it would stop the disease dead in its tracks.

Yet finding a way to switch off genes that are behaving badly has been an elusive goal for scientists. But now, thanks to an ongoing revolution in the understanding of RNA, they are getting closer than ever before. And much of this pioneering research is happening in San Diego.

RNA was long thought to serve as little more than DNA’s messenger boy. But in recent years scientists have discovered new types of RNA that help regulate genes.

These new types of RNA could lead medical science away from the so-called cure that is worse than the disease, researchers say. Put simply, RNA therapies could make cells behave differently, a better solution than treatments like chemotherapy that damage both healthy and diseased cells.

To be sure, RNA-based therapies are still largely unproven. But researchers are enthusiastic about its potential to tackle some of medical science’s most vexing diseases like cancer, Huntington’s and HIV. And several local companies, along with the pharmaceutical industry writ large, are betting hundreds of millions of dollars that the potential will be realized.

“What RNA therapeutics represents is a fundamental shift,” said Kleanthis Xanthopoulus, president and CEO of Carlsbad’s Regulus Therapeutics. “These big ideas don’t come in biotech very often.”

The two-year old company last year entered into a $600 million partnership with GlaxoSmithKline to develop RNA therapies for various types of cancer, rheumatoid arthritis and cardiovascular disease. Regulus was formed through a joint venture involving locally based Isis Pharmaceuticals.

Isis also struck a $325 million bargain with Genzyme Corporation in 2008, and has partnered with Bristol-Myers Squibb and OrthoMcNeil, among others, on developing RNA therapies.

RNA drugs have only become possible thanks to a revolution in biology over the last decade, which revolves around gene regulation, that’s changing how science understands the workings of the genetic code itself.

Killing the Messenger

The human genome is a chemical code some 3 billion letters long, stored in a molecule shaped like a spiral ladder called DNA. Each gene in the genome is a coded recipe for a protein, the giant molecules that perform the real work in cells. Different proteins do everything from carrying oxygen in the bloodstream to generating the force that causes muscles to contract.

By determining what proteins get made and when, the genetic code acts like a master program installed in the nucleus of every cell. Differences in the genetic code account for a host of important traits: Your gender, your height, the color of your hair.

To make a protein, the code in a gene gets copied onto a type of RNA called messenger RNA, and then the messenger RNA travels out into the cell. Even though RNA is similar in structure to DNA, its key role is as a courier for its famous cousin, carrying the instructions stored in DNA where they need to go.

In recent years, however, scientists have found that RNA is capable of much more. Most importantly, some kinds of RNA help to regulate genes. Certain sections of DNA that don’t code for proteins — once dismissed as “junk DNA” — have been found to produce previously unknown types of RNA. The two new types of RNA that have drawn the most attention are microRNAs and siRNAs.

Both use a powerful process called RNA interference (RNAi) to intercept messenger RNAs for a specific gene and knock them out of action, essentially silencing the gene by tackling its messengers. MicroRNAs are produced inside the cell and are possible drug targets, while siRNAs enter cells from outside and are used by researchers as tools to turn off a gene.

“We didn’t know, basically, that there was a whole world of these small RNAs,” said Tariq Rana, professor and director of the program for RNA biology at the Burnham Institute for Medical Research. “And this gives us now another switch to control some of these conditions.”

Most drugs work by attaching to a specific protein. Many related proteins, however, have similar shapes, so the drug knocks out these unintended targets — causing unpleasant or even fatal side effects. Aspirin, for example, latches onto a protein involved in inflammation. It also binds a closely related protein that helps produce mucus to protect the digestive tract, which is one reason why aspirin can increase the risk of stomach ulcers.

RNA-based drugs, by contrast, have the potential to be precise, silencing a single gene without bruising innocent bystanders. This could give scientists the ability to hit targets that remain out of reach for conventional drugs. With a genetic disorder like Huntington’s Disease, for example, disabling a few defective genes could mean a cure.

Cancer is a tempting target. In cancer cells genes that are ordinarily active have been damaged or silenced, while other genes have become too active. Switching off the right genes would bring the cancer cells back in line with their law-abiding neighbors. The greatest advantage would be the lack of side effects.

RNA offers a property that no other known cancer therapy has come close to, said Steven Dowdy, Howard Hughes Medical Institute investigator and professor of cellular and molecular medicine at UCSD School of Medicine.

“When you talk about personalized anticancer therapy, RNAi is the only thing on the table,” he said.

Drugs that exploit RNAi, Dowdy believes, offer an opportunity to tailor the treatment to the tumor — and stay a step ahead of the fast-evolving enemy.

HIV is also a strong candidate for RNA therapy. When HIV hijacks a cell, it inserts its genes into the genome of its hapless host — like adding a few snippets of code to a computer program to change its function entirely. By using RNAs to switch off genes in infected cells, scientists could finally get a grip on the virus.

“Any time you target the virus directly, the virus evolves around it,” said Kevin Morris, an assistant professor of molecular and experimental medicine at Scripps Research Institute. “So we target the house the virus lives in instead.”

Can It Deliver?

For all of the promise, however, a major hurdle still exists: how to deliver an RNA drug to the target cells. The small molecules in most drugs can seep through cell membranes; RNA molecules are too large to make that journey. An effective RNA drug needs a way to trick target cells into opening their doors.

“You need a delivery vehicle,” Dowdy said. “If you don’t solve the delivery problem, all the other potential will cease to exist. Delivery is the problem.”

Also, since some viruses are RNA-based, RNA therapies can provoke an immune reaction. Some companies and researchers use hollow globules of fats to smuggle the RNA through the bloodstream.

Like many researchers, Rana’s team at the Burnham Institute is grappling with another common problem with RNA therapies — too much of the drug ends up in the liver. If the drug is absorbed by the liver instead of the diseased tissue, it could fail to achieve an effect.

UCSD’s Dowdy has devised a technology that deals with the delivery issue, and formed a company around it. The company, called Traversa, raised $5 million in a second financing round earlier this year.

A Danish company in the RNA field, Santaris, recently announced plans to establish a San Diego-based subsidiary as well.

“Everything we’re doing with RNAi today you can see as version 1 or 1.5,” Dowdy said. “My hope is that in 5 or 10 years, we’re going to see the next generation.”

Whether the results will justify that initial enthusiasm remains to be seen; the field is changing fast, and some of the same mechanisms that RNA-based therapies exploit were unknown just 10 years ago.

One thing’s for sure, said Rana: “We have a lot to learn.”

Jonathan Parkinson is a San Diego-based freelance writer. Please contact him directly at or set the tone of the debate with a letter to the editor.

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