This is a post from the-scientist referring to a work published on page 627 in SCIENCE VOL 319, 1 Feb 2008, by Peer et al. regarding advances in delivering siRNAs.
New drug hopes for RNAi?
the-scientist.com
Posted by Alla Katsnelson
[Entry posted at 31st January 2008 09:01 PM GMT]
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Researchers report that they have overcome one of the major roadblocks to using small interfering RNA (siRNA) therapeutically - they have developed a new method to deliver siRNA to silence genes in specific cells in vivo, according to this week's Science.
"I'm really actually quite excited about the paper," said John Rossi, who works on siRNA therapeutics and gene therapy at City of Hope in Duarte, California, and who was not involved in the research. "I really think this is a big breakthrough."
In the same issue of the journal, two other groups of researchers announce that they have developed a technique using RNA interference to identify a new type of target for cancer therapeutics.
Researchers have lauded the promise of siRNA as a tool for studying gene function as well as a potential therapeutic technique, but difficulties with delivering siRNA molecules into cells has dogged the field. Motomu Shimaoka and colleagues combined two approaches used in the past to create a nanoscale particle that can target and transfect leukocytes - a notoriously difficult cell type to transfect.
The delivery vehicle consists of a liposome, or lipid vesicle, covered with two layers. A coating made of hyaluronan, common in the extracellular matrix of many tissues and often used as a biomaterial, stabilizes the molecule and maintains its tiny dimensions. A second layer uses antibodies to direct the molecule to its destination, where "the inside of the siRNA will release its payload quite fast," explained Daniel Peer, the study's lead author, based at Harvard. He noted that the technique was simple enough to be done in any lab.
In the past, researchers have used liposomes for siRNA delivery, but the molecules tended to be large and toxic. Researchers have also used antibodies to direct siRNAs to specific targets, but were only able to attach small numbers of siRNA to the antibody carriers. "The advance here is that you can package a greater amount of siRNA," said Francis Szoka, a drug delivery researcher at the University of California, San Francisco, who wrote the accompanying commentary to the study. What made that advance possible, said Rossi, was combining liposome and antibody approaches in a smart way.
The researchers used their approach to knock down the gene for the protein CyclinD1, known for its role in cancer, and showed that blocking its function specifically in lymphocytes regulated cytokine levels and reduced inflammation in a mouse model of colitis. "The fact that this has potential in treating inflammatory diseases is really exciting," said Rossi.
Shimaoka told The Scientist that his lab was looking into testing the technology in clinical trials "in the near future." But both Szoka and Rossi cautioned that clinical applications may be a ways off, because injecting antibodies creates the risk of harmful immune responses.
In the other set of papers, Steve Ellegde, a Harvard geneticist, Greg Hannon at Cold Spring Harbor, and colleagues used a library of short hairpin RNA (shRNA) to knock down the function of thousands of genes with known involvement in cell proliferation and survival.
"Our philosophy," said Elledge, "is that [oncogenes] aren't the only cancer targets out there." Other genes which cancer cells need to survive might be involved in the many stresses a cancer cell undergoes, such as DNA damage, high reactive oxygen levels, aneuploidy, or the effects of chromosome deletions.
"It was much easier to make a normal cell grow faster [than a cancer cell], so we're finding potential tumor suppressors in that category," said Elledge. The group also identified genes that play a larger role in cancer cells than normal cells, with distinct groups of genes providing a "lethality signature" for that type of cancer. "This is a pilot experiment - we only looked for a few thousand genes, but there's ten times more genes to explore," said Elledge, adding that the aim is to create a method that any lab can use.
"Conceptually, we knew this kind of approach would work," said Michael Green, a cancer genetics researcher at the University of Massachusetts Medical School in Worcester, who was not involved in the research, but who uses the shRNA library developed by Elledge and Hannon in his own work. Such screens have been done on a smaller scale, he said, "but what they've done is put together an elegant set of technologies that allows this to be done on a genome-wide level and in many cell-types."
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comment:
A lot of fundamental bias in such as apparently epochal research!
by Sergio Stagnaro
[Comment posted 2008-02-02 05:28:19]
In my opinion, based actually on 51-year-long CLINICAL experience, there is a lot of fundamental bias in such as apparently epochal research, unfortunately! The authors consider erroneously that the only DNA, playing an importante role in oncogenesis, is n-DNA. Clearly, they overlook the role played by mit-DNA, really paramount, as I underlined more than 30 years ago, from the CLINICAL viewpoint (See www.semeioticabiofisica.it). Admittedly, ameliorating therapy against cancer is preisworthy. However, I say once again, we all have to pay accurate attention to the BEST therapy above all others: Primary Prevention performed on very large scale with the aid of clinical tool! As a matter of fact, suspiciously enough, there are to Scientists all around the world, who are ignoring Oncological Terrain and INHERITED Oncological Real Risk, although my theories are accepted and posted by farsighted, open-minded Editors, among them (See Bibliography in above cited website)Editors of The Lancet, Annals Intern Med., Ann. Family Medic., PLOS, World Journ. Surgic. Oncology, NYAS.com, Cancer Cell International ..... and, of course, THE SCIENTIST.com |
