Global Trend

RNA Runs Interference for New Therapeutic Solutions

At the same time stem cells are promising unprecedented hope for conditions requiring replacement of tissue, another new technology called “RNA interference” may be even bigger. This technology promises to address the one-third of human maladies that are the result of genetic glitches that can’t be fixed by stem cells or by any of today’s “conventional” therapies.

We’re referring to those conditions where either a gene is not doing its job, as when diabetics stop producing insulin, or those where a gene is doing a job that should not be done, as when cancer cells grow out of control.

Scientists have long dreamed of being able to get into the genetic mechanism and turn it on or off, depending on the disease. Finally, crucial trends in genetic research are turning that dream into reality, and the implications promise to be huge.

To understand these trends and why the implications are so enormous, a bit of history is in order:

In the late 1980s, a geneticist was working on enhancing the color of petunias. He wanted to deepen the purple color and so he introduced a special gene. Instead of getting a deep purple as expected, he got white flowers or ones with white patches, indicating that certain genes had been suppressed.

At first, scientists thought this was a quirk of the petunia’s makeup. But then, according to an article in the Electronic Journal of Biotechnology,1 other researchers demonstrated the same sort of gene suppression in other life forms, such as fungi. They began wondering how far they could take this technique, which became known as “post-transcriptional gene splicing,” or PTGS.

A flurry of research in the early 1990s proved that PTGS worked in a number of species, and by 1995, scientists had demonstrated the most efficient way to achieve it was through what is now called “RNA interference.”

How does it work? A gene’s main function is to produce specific proteins for various life functions. RNA is the messenger molecule that takes instructions from the gene and gives them to the cell’s biological factory, where the protein is made. RNA interference stops production of the protein before it occurs.

RNA interference essentially introduces a few strands of modified RNA, which effectively jam the signal that would normally be carried from the gene by the original RNA in the patient. The offending RNA is cut up into about two-dozen pieces and destroyed, so no message it sent. This technique offers for the first time the possibility of therapies for hundreds of diseases.

According to an article in the January 10, 2005 issue of Fortune,2 this understanding has set in motion a race involving researchers, research institutions, and venture capitalists, as well as pharmaceutical and biotech companies, to be the first with patentable commercial technologies exploiting RNA interference. The Trends editors have identified three of the most promising companies in this field: Ambion, Alnylam Pharmaceuticals, and Acuity Pharmaceuticals.

Ambion is one of several companies offering laboratory technologies to construct the type of RNA used to jam messages and silence genes. This is a crucial foundational technology for any real-world applications.

One of the first of these applications involves using RNA interference to stop the production of excess cholesterol. According to the November 11, 2004 issue of the journal Nature,3 researchers at Harvard have used RNA interference to silence a gene in mice that produced too much cholesterol.

Working with Alnylam Pharmaceuticals, the new leaders in this field, the Harvard researchers actually used a genetically modified cholesterol molecule to carry the “Trojan Horse” RNA into the cells. The therapeutic RNA then interrupted the signals that produce too much cholesterol. The mice experienced a 37 percent drop in their cholesterol levels.

It is this type of exciting result that has people scrambling to exploit this new technique. Alnylam was founded in 2002 by the scientists who first pioneered RNA interference at MIT, the Scripps Institute, and Rockefeller University, where they were among the first to demonstrate that they could selectively turn off genes that cause disease. One of the scientists, Philip Sharp, won a Nobel Prize.

Researchers at Alnylam are working on two parallel courses. One, called Direct RNAi, targets individual genes directly at local sites in the eye, brain, or lung, for example. The other, called Systemic RNAi, is under development and would allow doctors to inject the RNA into the bloodstream, where it would find its way to the appropriate site by itself.

Under the Direct RNAi program, the company is already collaborating with Merck to develop a treatment for macular degeneration in elderly people. In this disease, blood vessels behind the retina grow out of control and leak, causing blindness. This excess growth is caused by a gene producing too much vascular endothelial growth factor, or VEGF.

The researchers are using their patented RNA interference technology to turn off that gene and stop the degeneration. The program will enter phase one clinical trials later this year.

As Alnylam’s Systemic RNAi products come on line, they will be targeted at inflammatory, metabolic, and infectious diseases, as well as cancer. Numerous small start-up companies are attempting to carve out part of the RNA interference territory for themselves, but Alnylam holds eight patents that it says are the key to commercializing those therapies, according to statements from its CEO, John Maraganore.

But they’re not alone in the field, by any means. The University of Pennsylvania and its researchers spun off a company called Acuity Pharmaceuticals in 2002 specifically to use RNA interference to treat macular degeneration and the blindness caused by diabetes, called diabetic retinopathy.

Their first product, called Cand5, like Alnylam’s, acts by shutting down the VEGF gene. Since about 30 million people worldwide suffer from macular degeneration and another 20 million suffer from diabetic retinopathy, the market potential for the winning drug is in the $7 billion to $8 billion range.

To sum up, the RNA interference revolution is based on trends in science and therapeutics that will completely change the face of medical intervention in the next 10 to 20 years and, along with the parallel trends in stem cell therapy, it will rewrite the medical textbooks, transform the way we view disease, and alter forever the way diseases are treated.

Based on these trends, we offer the following six forecasts for your consideration:

First, starting this year, a scramble to define the playing field with an effective RNA interference therapy will result in clinical trials beginning at institutions throughout the world, aimed at treating everything from diabetes to blindness to Parkinson’s disease. Pressure will mount for the FDA to expedite approval. Competing RNA interference therapies will quickly emerge as potential winners in each of the major disease categories, and the field will be crowded for some time.

Second, within five years of their initial FDA approval, clear leaders will emerge in each of the therapeutic categories. Such leaders will typically come from a start-up like Alnylam partnering with ? and eventually being purchased by ?a giant such as Merck, and collaborating with big-name hospitals, universities, or other institutions. However, even as specific companies take control of certain segments, we don’t expect a major shakeout to come for a decade or more. There are so many diseases, that there will still be plenty of market to go around. Many small companies will reap the benefits of a broad field during this phase.

Third, despite the number of opportunities, a shakeout will inevitably occur after 2020. By 2025, we expect the shakeout will be complete, leaving a few major players, mostly belonging to established drug companies, dominating the field of RNA interference therapy. At that point, the dominant entrepreneurial opportunities will be in delivery systems.

Fourth, starting with the next few years, the now-troubled pharmaceutical industry will grow with renewed vigor on the backs of breakthrough biotech developments in both stem cell and RNA interference technology. As explained in the February 2005 issue, the Trends editors are bullish on this whole industry sector, which will benefit from the intersection of unstoppable demographic trends, powerful political trends, and promising technology trends.

Fifth, and perhaps most important, millions of patients suffering from dozens of diseases worldwide will benefit from RNA interference therapy, which promises to unlock the key to finding cures for HIV and cancer, among many others. This will lead to longer, healthier, and more productive lives.

Sixth, pharmaceutical companies will begin to phase out many traditional drugs, as RNA interference and stem cell therapies prove their efficacy. Some widely accepted treatments of today, such as cancer chemotherapy, are likely to disappear by 2015.

References List :
1. Electronic Journal of Biotechnology, April 15, 2003, Vol. 6, No. 1, “RNA Interference Revolution,” by Archana Thakur. ⓒ Copyright 2003 Universidad Catolica de Valparaiso ? Chile. All rights reserved.2. Fortune, January 10, 2005, “Genetic Medicines Next Big Step,” by John Simons. ⓒ Copyright 2005 by Time Warner, Inc. All rights reserved.3. Nature, November 11, 2004, “Therapeutic Silencing of an Endogenous Gene by Systemic Administration of Modified siRNAs,” by Jurgen Soutschek, Akin Akinc, Birgit Bramlage, Klaus Charisse, Rainer Constien, Mary Donoghue, Sayda Elbashir, Anke Geick, Philip Hadwiger, Jens Harborth, Matthias John, Venkitasamy Kesavan, Gary Lavine, Rajendra K. Pandey, Timothy Racie, Kallanthottathil G. Rajeev, Ingo Rohl, Ivanka Toudjarska, Gang Wang, Silvio Wuschko, David Bumcrot, Victor Koteliansky, Stefan Limmer, Muthiah Manoharan, and Hans-Peter Vornlocher. ⓒ Copyright 2004 by The Nature Publishing Group. All rights reserved.