More support for RNAi in clinic

Nanoparticles studded with short RNA molecules can silence target genes in melanoma patients, demonstrating the clinical feasibility of these techniques for the first time, according to research published online today (March 21) in __Nature.__ NanoparticlesImage: Wikimedia/Nandiyanto"This is a breakthrough for the field," said John Rossi from the City of Hope Cancer Center, who was not involved in the study. It's the first clinical proof that "RNA is entering the tumor cells and delivering the goods" needed to reduce the expression of target cancer-genes, he said. While the result is clearly a boon for the fields of RNA interference (RNAi) and nanobiology, it remains to be seen whether the new therapy improves patient outcomes, scientists said. RNAi functions by binding to the mRNA transcript of a gene before it is translated into a protein and cutting it at a specific point in the sequence, thereby reducing the amount of protein the gene can produce. Earlier trials for other diseases had injected patients with short interfering RNAs (siRNAs), resulting in improved patient health. But whether this improvement was the result of the siRNA-induced gene knockdown or a product of immune system activation due to the presence of the siRNA molecules in the bloodstream, which the body recognizes as a sign of infection, was unclear. To get to the bottom of this question, Mark Davis from the California Institute of Technology and colleagues attached the siRNAs to nanoparticles, which effectively hide the genetic material from the immune system. The researchers also attached a ligand for a receptor that is more abundant on cancer cells to ensure that the nanoparticles were taken up predominantly by those cells. Once inside, the nanoparticles are designed to disintegrate, releasing their siRNA payload into the cells. As part of a Phase I human clinical trial, the team looked at cancer samples of three melanoma patients injected with the siRNA-studded nanoparticles. Over several treatments, the researchers observed an increasing accumulation of the particles and a corresponding reduction in the levels of the mRNAs and proteins targeted by the siRNAs, suggesting that the siRNAs successfully interfered with gene expression in the cancer cells. The results are "important because delivery [of the siRNAs] is the major obstacle to therapeutics," said Judy Lieberman of Harvard Medical School, who writes about RNAi in the upcoming April issue of The Scientist. "I was impressed with the degree of [mRNA] knock-down that they were able to achieve," she added. In addition, the presence of mRNA fragments cut at the intended location indicated that the siRNA was functioning inside the cell as expected. "That's why this study is beautiful," said Sancy Leachman, a physician scientist at the University of Utah Health Sciences Center. "The mRNA is clipped in the right spot." The study did not, however, provide an indication that the therapy was controlling the cancer, Lieberman said. "Were there fewer dividing cells, [and/or] was there any apoptosis [in the cancer cells]?," she asked. The study did not show evidence of either, and the results from the clinical study, including the results from about 12 additional patients with a variety of cancers, aren't expected for several months at least, Davis said. Because both the receptor ligand that helps the nanoparticles traffic to cancer cells, and the gene that is targeted for knockdown by siRNA "are fairly ubiquitous" across cancer types, this therapy has the potential to work in many cancer types, said Davis. But some cancers are more or less dependent on this particular gene for survival; thus they may not be as susceptible to the genetic knock-down as others. "Ultimately we'd want a more specific targeting ligand and more specific genes," said Davis. Still, "this is a very, very exciting finding," said Leachman. "This was a proof of principle experiment in a person," that demonstrated the feasibility of the approach. **__Related stories:__***linkurl: Milestone for RNAi therapeutics?;http://www.the-scientist.com/blog/display/54395/ [29th February 2008]*linkurl:The Human Genome: RNA Machine;http://www.the-scientist.com/2007/10/1/61/1/ [October 2007]*linkurl:An RNAi Rogue's Gallery;http://www.the-scientist.com/article/display/52978/ [April 2007]

More support for RNAi in clinic

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