RNA hopes hyped?

DNA's cousin will yield therapies, but not yet.

9 May 2003

HELEN R. PILCHER

RNA can stop HIV replicating in cultured cells. © GettyImages

The potential of DNA's cousin, RNA, to provide new therapies for conditions from cancer to AIDS may have been over-hyped, experts warned at a symposium last week in Black Point Inn, Maine.

"The field has over-promised and under-delivered with respect to the therapeutic applications," said Gerry Joyce of the Scripps Research Institute in La Jolla, California. There are many basic questions that need to be answered before RNA can be used in the clinic, he warned.

Like DNA, RNA is made from a four-letter molecular alphabet - although only three of those letters are also found in DNA. In DNA, sequences of letters make genes; RNA classically helps to convert genes to proteins.

The excitement began 20 years ago, when researchers discovered that single RNA strands can stick to DNA and block key genes. These pieces of 'antisense' RNA can switch off disease-causing genes in the laboratory.

Then, in 1988, RNA interference - or RNAi - was born. Short stretches of double-stranded RNA were found to switch genes off up to ten times more quickly than their single-stranded counterparts.

The next decade saw RNAi widely adopted as a basic lab tool to help researchers decipher gene functions. For example, the genes involved in human fat storage were identified using RNAi, as well as the jobs of more than 1,500 worm genes.

These developments did not go unnoticed. In 2002, Science magazine hailed RNAi as the biggest scientific achievement of the year. It has caused scientists to rethink their understanding of the cell, they claimed, and should uncover new leads for treating diseases caused by errors in the genetic code.

Already the technique has shrunk mouse tumours and halted HIV replication in cultured human cells. Yet scientists are still struggling to translate the method from bench to bedside, said delegates at the symposium, entitled Understanding the RNAissance.

One problem is that RNA is fragile - a million times more so than DNA. In solution, it breaks apart in minutes, so researchers need to find ways to stabilize the molecule for long enough for it to take effect in the human body.

Another challenge is fathoming the best combination of constituent chemical letters to treat specific diseases. "We need to make sure that the RNA does not act off target" and damage healthy cells, said Richard Griffey of Ibis Therapeutics, a drug-discovery firm based in Carlsbad, California.

A further challenge is to ensure that RNA reaches the right part of the right cell in the right part of the body. "Delivery is the key issue if we are going to keep the promises we made," said Joyce.

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2. Lee, N. S. et al. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nature Biotechnology, 20, 500 - 505, (2002). |Article|