New Research Could (Finally) Remove RNAi’s Commercial Limitations

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[Corrected 11/17/14, 12:30pm. See below.] If nothing else, the acronym RNAi, which stands for ribonucleic acid interference, should be familiar to biotech observers as something that won two researchers the Nobel Prize in 2006, and that a few companies have tried to turn into drugs. Alnylam Pharmaceuticals (NASDAQ: ALNY) is the most well-known. But in treating human disease, its promise has outpaced its utility.

In Nature Biotechnology today, University of California, San Diego researcher Steve Dowdy and colleagues have published a paper that Dowdy says could be the foundation that drug developers use to overcome the biggest obstacle keeping them from delivering upon RNAi’s promise.

Or perhaps it’s better to say: the foundation that one drug developer uses. That’s because Dowdy’s work is the exclusive property of San Diego-based Solstice Biologics, a two-year-old, venture backed firm that Dowdy cofounded. I’ve written about Solstice and its dramatic history before, most recently in June when it hired Lou Tartaglia away from Third Rock Ventures to become CEO.

Dowdy, Tartaglia, and others involved in Solstice believe they’ve cracked a very important code—how to get RNAi drugs into all manner of cell types. They have voiced that belief for some time now, and some of the specifics of Dowdy’s work are well known. But the paper published today provides a more intricate look under the hood, and supplemented with conversations with Dowdy, Tartaglia, and Solstice chief scientific officer Curt Bradshaw, also gives a clearer idea of what Solstice still needs to do to turn its ambition into breakthrough RNAi medicines.

Turning the fascinating mechanism of RNAi into a widely deployed weapon against cancer, infectious disease, and more would indeed be a breakthrough. To date, Alnylam and a few others have only advanced drugs to treat liver and eye disease, the only tissue types relatively amenable to RNAi delivery. (Nothing yet has been approved; Alnylam’s most advanced program, aimed at a genetic disease called TTR amyloidosis, is in Phase 3.)

In fact, those delivery problems bedeviled other early enthusiasts, often with much deeper pockets: Roche and Novartis ((NYSE: NVS), two of Alnylam’s first development partners, dropped their programs after a few years; and Merck & Co. ((NYSE: MRK), which bought Alnylam’s rival Sirna Therapeutics for $1 billion in 2005, ended up selling those assets in 2014 for $175 million (of which only $25 million was cash)—to Alnylam, no less.

It’s easy to see why so many companies spent so much money within a few years of RNAi’s emergence. The overarching concept is simple and elegant. The DNA code of life must be transcribed, transported out of the nucleus, and ferried to the main part of the cell, the cytoplasm, where ribosomes await to turn the code into proteins.

The bridge between DNA and protein is RNA, or, because of the nature of its job, messenger RNA (mRNA). You’ve heard people say “Don’t shoot the messenger”? Substitute “hijack and slice up” for “shoot,” and there you have RNAi: If the mRNA is hijacked and destroyed on its way to the ribosome, the protein in question never gets produced. (A common description of RNA interference is “gene silencing.”)

How that happens inside a cell is complex and includes more than one form of RNA and enzymes that do the slicing and dicing.

It’s a mechanism that helps cells defend against intruders like viruses, whose genomes are encoded in RNA, not DNA. And the therapeutic implications are obvious: Use the mechanism to prevent the production of disease-causing proteins, like the ones tumor cells make to survive; or the ones that cause rare diseases; or the ones viruses use to infect cell after cell (which I suppose you could call hijacking the hijackers).

As Dowdy describes RNAi, “it’s like a gift from God or whoever’s upstairs.”

As with anything in biology, however, the complications pile up quickly—the “dirty little tricks,” Dowdy says, that have kept that gift mainly beyond our reach. Many of them stem from this fact: RNA—or the RNA-like strands that companies have engineered to do therapeutic work—aren’t meant to be outside a cell, which makes getting them into the body and to the right spot a very frustrating exercise.

RNA molecules are fragile. Floating around in the bloodstream, they’re like foreign invaders, but not particularly tough ones. The body’s defenses recognize and chew them up easily. (Eye and liver cells are less problematic to reach and penetrate, which is why those areas have seen some clinical success.) Even if they evade detection, RNA have the same negative electric charge as cell membranes. Similar charges repel each other, as anyone knows after playing with magnets. It’s really hard to get RNA into a cell.

The big takeaway from Dowdy’s work is that he and colleagues have created RNA-like strands that hide from the body’s defenses and slip into cells more easily. They have a neutral charge, so the researchers have dubbed them RNNs, or ribonucleic neutrals. And they build upon a concept used by a lot of other pharmaceutical research programs: conjugation. Most notably, Seattle Genetics (NASDAQ: SGEN) and Immunogen (NASDAQ: IMGN)—and their larger partners Genentech, now part of Roche, and Takeda Pharmaceutical—have brought to market antibody-drug conjugates: cell-killing drugs chemically bonded to antibodies, which serve as homing devices that deliver the drugs into tumor cells.

Solstice wants to conjugate RNNs to similar homing devices—“targeting agents” is the term of art—that not only get them to the right cell, but hide them from the body’s defenses on the long journey. Once they’re … Next Page »

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One response to “New Research Could (Finally) Remove RNAi’s Commercial Limitations”

  1. cvrichard says:

    Tissue targeting is the holy grail of drug delivery very few have achieved. Most targeting companies ended up ‘targeting’ liver (including Dowdy’s latest paper) because that’s where most of these (larger) molecules end up anyway.

    siRNN availability inside the cell is another big issue. In his paper, Dowdy claims his “siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses.” Yet, Solstice’s molecule would get stuck in endosome, inaccessible to thioesterase. These conflicting observations indicate two different cell entry pathways. In my opinion, the Solstice/Dowdy team has a loooong way to go before they sort out the exact nature of their molecules.

    The path to targeted drug delivery and intra-cellular delivery of large molecule is littered with the skeleton of failed companies. I wish these guys the best of luck.