Despite all the work done during 2003, many working in the RNAi field see more questions than answers in store for 2004.
Delivery to target cells or tissues remains as perhaps the biggest challenge for RNAi researchers, especially those exploring the use of the technology as a therapeutic, and the upcoming year is expected to include a lot of focus on this front.
“The next frontier is to go broadly into a wide range of primary cells and difficult cell types, and going beyond the lipofection-based methods,” Chris Echeverri, CEO and CSO of Cenix BioScience, told RNAi News. “It’s clear there is a good variety of commercially available lipid-based transfection tools out there now … but being able to go after the tougher cell lines is now what needs to be addressed.”
“Simple knockdowns everybody can do,” Dmitry Samarsky, director of business development at Sequitur, added. “If you need to work with more complex cell lines — primary cells, non-adherent cells — in many cases there are no reliable protocols existing for delivery of RNAi compounds, and that’s going to be a challenge that [needs] to be resolved.”
For Echeverri, the key to solving the delivery problem will be to find the most phenotypically silent transfection approach. “Any time you use something to get your molecules into a cell, that triggers certain aspects of the biology. Each method has its own baggage, and you just want to minimize that baggage,” he said.
Establishing efficient and cost-effective methods for high-throughput RNAi, especially in difficult to transfect cells, also needs to be dealt with in 2004, Samarsky told RNAi News.
Echeverri agrees. “It’s quite straightforward for us to do [high-throughput RNAi] in a wide range of cell lines, but we want to constantly expand that range of cell lines for which that’s possible,” he said.
Behind the Science, the IP
The RNAi intellectual property landscape continues to be one of the most uncertain areas related to the technology, said John Rossi, from the Beckman Research Institute of the City of Hope Cancer Center.
“[An] issue, of course, is the intellectual property rights for different aspects of this technology, and how many companies are actually going to end up being viable in the end,” he said.
Richard Warburg, a partner with the law firm of Foley & Lardner, told RNAi News that “the [RNAi IP] field is extremely fast moving — at last count, I think there were close to 30 companies working in the area, and they’re all filing their own IP, most of which we don’t know about.”
He noted that “many people outside the IP field think that it’s the science that drives it all. It’s proven that while the science might be great, the IP is what’s going to dominate — you must have access to that IP to be able to play in the field,” Warburg said.
“Things are up in the air” right now, he said, but 2004 will likely see many of the issues shake out. Warburg said he expects to see some RNAi companies address the IP issue through consolidation, a move Alnylam made in mid-2003 when it merged with Ribopharma.
“I would think that you’d see some sort of consolidation as people learn what’s going on,” he said. “Money is very short [in] biotech, and there’s been consolidation all around the industry — I think that this is a ripe time for 30 companies to consolidate down to maybe 20.”
Warburg also said that he thinks that companies will turn to collaborations and alliances as a means to settle patent disputes.
“I would hope that we’d see some more things like the Benitec/CSIRO [deal],” he said, referring to the recent settlement of a dispute over the ownership of a key patent covering DNA that transcribes double-stranded RNA and a subsequent RNAi effect. (See RNAi News, 12/12/2003).
“I think that the more people take notice of what everyone else is doing, the more they’re going to hopefully spend money on collaborations rather than fighting,” Warburg said.
Aside from all the questions and uncertainty, some RNAi players made predictions for what they expect to see in 2004.
Both Echeverri and Samarsky expect to see the publication of truly genome-wide RNAi screens in human cells some time in the upcoming year.
“This is what I’ve been waiting for since 1998, basically,” Echeverri said. “We’ve progressed from genome wide in worms, then genome wide in Drosophila — [it] was the hope, the dream, the expectation that we’d be able to do it directly in human cells and, yes, those are underway now and those will become public next year.
Additionally, Samarsky expects libraries of RNAi compounds that can knock down almost all human genes to become available by the end of 2004.
John Maraganore, president and CEO of Alnylam Pharmaceuticals, said that he is predicting significant developments in in vivo applications of RNAi to occur during 2004, but hesitated to forecast the initiation of phase I trials of RNAi-based therapeutics.
“I think there are certainly claims being made already about companies starting clinical trials in 2004,” he told RNAi News. “Hopefully, people promoting those claims are being thoughtful of how they do drug development — it’s easy to get a molecule into the clinic, [but] it’s easy to put the wrong molecule into the clinic, as well, and end up having a product failure that occurs two years down the line.”
For the record, Maraganore said that Alnylam expects to have a compound in phase I testing in “a couple of years.”
Rossi expressed similar doubts.
“I think that it’s not going to happen this year,” he said. “I think it’s still going to be another year and a half or so before things actually enter into the clinic.” The delay, Rossi added, will likely result from regulators’ efforts to take care with a mechanism as powerful and new as RNAi.