Cells constantly make mRNA—but not all mRNA reaches its destination. Often, a cell spots a gene that it chooses not to express,
such as a gene from a virus. In these cases, the gene is instead silenced through a process called RNA interference, or RNAi.
The process typically works well. But sometimes, cells don't recognize mutated genes. When that happens, the mRNA ferries
genetic information to the rRNA and allows for the expression of the genes for cancer and lupus and all sorts of other diseases.
For years, Big Pharma has tried to stop diseases by destroying the proteins made from bad genes, primarily through monoclonal
antibodies like Avastin. But these antibodies aren't easy to produce. And what's more, new research shows that the body may
be fighting the treatment it's receiving. Monoclonal antibodies can cause the body to produce more unwanted proteins, says
Steven Quay, CEO and president of Nastech Pharmaceuticals. That's because a cell may ratchet up production of malignant proteins
to compensate for the ones that are being destroyed.
But a growing crop of biotechs are showing a new direction in research by trying to stop the protein from being made in the
first place. They want to use the body's natural silencing mechanism to get rid of the mRNA strands that code for disease.
At the heart of that silencing mechanism is double-stranded RNA, or dsRNA, that helps the cell recognize "bad" mRNA and vaporize
it. Companies have already figured out how to engineer dsRNA—but delivering the molecules to cells has proved a big thorn
in developers' sides.
"I suspect that we will be working on optimizing delivery over a long period of time," said Alnylam Pharmaceuticals CEO John
dsRNA is a very charged molecule, which presents a problem. The polarity of the dsRNA is at odds with the cell membrane, making
it tough for the molecule to push through. "The best analogy is the oil-and-water challenge," said Maraganore. "You have to
get from the water side, which is where the RNA molecule would like to live, to another water side through this oil layer."
To solve the problem, Maraganore says Alnylam is following the grease trail by using liposome technology to put the dsRNA
in what amounts to a microscopic ball of fat, getting rid of the polarity issues involved in crossing the cell membrane. The
company's formula ALN-RSV01 is about to enter Phase II studies for respiratory syncytial virus (RSV), which is the leading
cause of US pediatric hospitalization and causes lower-respiratory-tract infections.
Alnylam's drug would directly interfere with the virus' ability to reproduce by stopping its genetic material from being translated
into proteins. "We can generate a very potent antiviral with this technology that goes after the virus itself," said Maraganore.
Besides the RSV formula, Alnylam believes its RNAi technology can treat hypocholesterolemia, liver cancer, Parkinson's Disease,
and cystic fibrosis.
Several other companies are exploring additional approaches, most notably Sirna and Merck. Their wet macular degeneration
drug, Sirna-027, is about to enter Phase II. Kylin Therapeutics recently bought a delivery system called pRNA—"packaging"
RNA complex—which allows dsRNA to pass through the cell membrane. Nastech Pharmaceuticals' delivery system attaches peptides
to the dsRNA. "The peptides will make cells drink in the liquid containing the dsRNA, maximizing the amount that infiltrates
the cells," Quay explained.
However, companies haven't yet solved the problem that's plagued monoclonal antibodies—formidable production costs. dsRNA
molecules are several times heavier than the traditional small molecules and, thus, more expensive to make. That's where the
partnership advantage comes in. Alnylam's currently playing prom queen, with recent partnerships with Roche and Novartis.
Merck bought RNAi-based biotech Sirna for $1.1 billion in 2006. AstraZeneca and Silence Therapeutics have formed an RNAi-based
bond as well, though AZ is currently tight-lipped about specific targets. Kylin and Nastech are still shopping around, but
both hope to get into the market soon. –ORIANA SCHWINDT