Gene Therapy Yields to RNA Interference

Over the past 2 decades, physicians heard a lot about the promise of gene therapy. Then, suddenly, it stopped. Years of work added up to little more than 1 tough lesson after another on the complexity of therapeutic DNA fixing. Deaths in 1998 and 2002 in 2 gene therapy trials particularly contributed to its fall from favor. In frustration, many researchers and pharmaceutical companies abandoned their efforts altogether.

Others turned to alternative gene therapy, focused not on fixing DNA but on blocking its effects. Ribozyme and antisense gene therapy targeted messenger RNA (mRNA) transcripts to prevent reproduction of a mutated gene's protein. Ribozyme therapy used a single-stranded RNA molecule designed to cleave specific RNA molecules and act as an enzyme. Antisense therapy used a single strand of RNA or DNA designed to pair with a specific known mRNA sequence. Again, these approaches were largely disappointing. The RNA used in both methods had low potency and a short half-life in the body. Also, promising early clinical results from antisense therapy were later found to have resulted from increased production of interferons by the immune system in response to high doses of foreign RNA; at lower doses, the clinical benefit largely disappeared.

Now, some scientists are taking a new approach to stop genes from making unwanted disease proteins: RNA interference (RNAi). Many believe that RNAi is the most promising approach of all and will lead at last to effective new therapeutics. This is because RNAi harnesses a natural biological process, identified in the early 1990s in plants and in the late 1990s in mammals, wherein RNA silences specific genes. “We're capitalizing on a natural process to control gene expression that the cell already has provided for us,” said Beverly L. Davidson, PhD, a professor of internal medicine, physiology, and biophysics and neurology …