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UMMS' Mello Bullish on RNAi Rx Field as Colleagues See Bright Future for miRNA Modulation

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By Doug Macron

Despite some of the setbacks experienced by the RNAi drugs field over the past 12 months, the technology is advancing well and is expected to begin fulfilling its promise as a new therapeutics modality, University of Massachusetts Medical School investigator and Nobel laureate Craig Mello told RNAi News earlier this month.

At the same time, the related field of microRNA modulation, benefitting from work done in the RNAi and antisense fields, is also progressing quickly and could yield a commercialized drug even before its gene-silencing cousin, Mello's UMMS colleague and Alnylam Pharmaceuticals co-founder Phillip Zamore said.

Since RNAi was first discovered by Mello and his colleague Andrew Fire in 1998, the technology has been touted as one of the biggest scientific breakthroughs in decades. Yet while it has proven to be so as a research tool, its clinical utility has been less clear-cut.

RNAi for research applications "really is very reliable and it works very well," Mello said. "I think where it was over-hyped is this notion that you can just give a patient RNA and expect them to get better.

"I'm not saying that the hype was completely unreasonable," he added. "I think that it was over-sold in part because it was working so well in the laboratory and people thought, 'Well, it's going to work just like that in humans and be incredible.'"

Ultimately, as with any therapeutic technology, RNAi's development "is going to take time," he said. "People shouldn't be impatient or say, 'RNAi didn't work because they injected it in and it wasn't enough or it gave a subtle effect.'"

To Mello, less-than-robust efficacy with current RNAi drug candidates is primarily the result of delivery hurdles, which remain the field's biggest challenge. Still, "these are things that, to some extent, are already solved at certain levels and are going to be solved by advances that are coming down the line.

"Bit by bit, we're going to get better delivery to additional tissues, and RNAi is going to become an actual therapy that, hopefully, will have beneficial effects for many patients where conventional medicines just aren't available," he said.

Already, RNAi has crossed the threshold from a preclinical technology to one being tested in humans. But there have been some notable failures, including the decision to halt development of what had been the industry's most developed RNAi drug candidate: the wet age-related macular degeneration drug bevasiranib.

Owned by Opko Health, the siRNA drug was designed to inhibit vascular endothelial growth factor. Although bevasiranib had shown promise in earlier human trials, Opko halted its development earlier this year after determining that it was unlikely to meet the primary endpoint of a phase III trial (see RNAi News, 3/12/2009).

A few months later, a spokeswoman for Allergan confirmed that her company had also stopped developing its own siRNA-based AMD drug, which had been acquired from Sirna Therapeutics, because of poor clinical data (see RNAi News, 5/28/2009).

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In July, Alnylam announced that its siRNA-based treatment for respiratory syncytial virus, ALN-RSV01, met the primary endpoint of a phase II study, but indications of efficacy were less dramatic than some industry watchers had expected (see RNAi News, 7/23/2009).

Tellingly, Cubist Pharmaceuticals, which acquired the rights to ALN-RSV01 in January (see RNAi News, 1/19/2009), said last month that it had handed the drug's rights back to Alnylam and would instead focus on a follow-on agent, ALN-RSV02 (see RNAi News, 11/12/2009).

But for Mello, these setbacks are confirmation that all first-generation technologies will run into pitfalls. "The initial clinical trials were with unmodified siRNA and so on," he said. But "there are much better triggers now for RNAi, so we should expect to see better clinical results with these highly active compounds."

In light of the hype surrounding RNAi, "people are going to be disappointed [that the commercialization of an RNAi drug] hasn't happened already," Mello, who is also the co-founder of RXi Pharmaceuticals, added. "But I don't think anyone who's being fair should have expected it to have been easy."

miRNA Medicines

Though less advanced than its RNAi counterpart, the miRNA drug space has also been making significant strides and saw its first candidate, Santaris Pharma's hepatitis C therapy SPC3649, complete a phase I trial earlier this year (see RNAi News, 5/7/2009).

The majority of efforts to modulate miRNA are based on an antisense-type approach, and Zamore noted that while "antisense inhibition of messenger RNA is hard … antisense inhibition of microRNAs turns out to be easy.

"I fully expect an antisense inhibitor of microRNA function to be in clinical use before an siRNA because the whole path is laid out already," he told RNAi News. "The amount of experience people have in making chemical modifications that safely stabilize antisense molecules, that reduce their length, that deliver them specifically to the appropriate target — that's much more work … than anything our community has done with RNAi."

And while there is concern in the field that miRNA inhibition could trigger unintended effects since the small, non-coding RNAs regulate the expression of multiple genes, "in general, most microRNAs are not required for viability in model organisms, and I suspect the same is true in humans," Zamore said.

As such, "if you block a single microRNA, in the vast majority of cases, the side effects of that will be far less severe than the disease you're trying to improve," which is also something that is common with small-molecule drugs, he noted.

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At the same time, in certain cases "there are homeostatic mechanisms that compensate and eventually the side effects go away, even in chronic use," he pointed out. "If you look at what people are discovering about microRNA function, generally, they are involved in … tuning, adjusting the levels of transcripts or proteins to be just right. That's something [for which] cells usually have multiple redundant mechanisms."

The problem of off-target effects is likely to be even less an issue for approaches involving the introduction of a miRNA mimic to tissues where its expression is missing, UMMS researcher and miRNA pioneer Victor Ambros added.

In this situation, the miRNA is "going to now engage in the processes it normally engages in … [and] have the same repertoire of activities it normally does," he told RNAi News. "The danger would be if the microRNA is delivered non-specifically … [and be] present in cells where it normally shouldn't be. You're going to get these effects of it regulating genes it shouldn't.

"We keep coming back to this problem of delivery," he added.

Indeed, all three UMMS researchers agree that, as with RNAi drugs, delivery will be the key challenge for miRNA therapeutics.

"The real limitation is just finding diseases where blocking a microRNA is effective in a tissue you can deliver to," Zamore said.

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