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

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in the cell, enzymes cut the targeting agent away from the RNN—the oligonucleotide is now active and can do its interference work.

One of Alnylam’s earliest employees who asked not to be named called Dowdy’s paper “a great advance” but cautioned that there’s much work to do to hone the principle into therapeutics.

Solstice’s executives would undoubtedly agree, and, although generally circumspect, they outlined several areas in which they have been building on top of the Dowdy work.

For example, if RNNs getting into cells will leave behind a lot of snipped-off waste, is there a safety risk? “You have to account for the potential toxicity of that entity,” says Tartaglia, and so far in preclinical tests, he says there have been no worrisome signals.

And what about those targeting agents that get the RNN into the cell? “We can place ‘handles’ anywhere we want on the structure and then conjugate whatever we want,” says Dowdy, and lists the various attributes of antibodies, ligands, synthetic molecules, and peptides. “All four are readily ‘conjugatable’ to the RNN backbone,” he says.

Solstice chief scientific officer Curt Bradshaw says, “We’re interested in all those, but we think we can also write some new rules when it comes to oligonucleotide delivery.”

There will be several factors to understand and fine-tune: size, ability to mask the payload as it travels to the target, and interaction with the target itself. Another big problem Dowdy continues to work on, and Bradshaw says Solstice is pursuing independently, is what happens after the molecules get past the cell membrane. At that point, an RNN is about as scot-free as the jewel thief who picks the front door lock, walks inside, and finds himself in a foyer full of trip-wire alarms. The cell has another layer, the endosome, from which very little escapes. “Getting out of the endosome is important for increasing efficiency,” says Tartaglia. “We’re in the early stages in trying to consider what our own proprietary methods would be in that space.”

It’s important not just for a more effective drug, but to lower the amount injected into a patient. The less drug that a patient needs, the better the safety potential—and the lighter the cost of goods to produce.

Solstice’s RNN backbone needs not only to hold onto a targeting agent but also an “endosomolytic agent”—something that can punch a hole through the endosome. This is not a new concept, and plenty of labs in academia and industry are working on the “endosome escape” problem.

Arrowhead Research (NASDAQ: ARWR), for example, calls its construct a “dynamic polyconjugate” and uses a synthetic polymer to crack open the endosome. (Arrowhead released disappointing interim Phase 2 results in October for its lead candidate, for Hepatitis B, and the stock has yet to recover.)

Dowdy more than once has touted RNNs as a way to go after diseases driven by rapid mutations, such as cancer or infectious viruses. That’s because nucleic acids are relatively easy to program to match to a disease-causing genetic code, then quickly synthesize. “Pull any sequence out of a hat,” says Dowdy, and within five days his lab team will “hand you those oligos”—meaning the backbone of the RNN.

When I ask Tartaglia how that rapid-response approach fits into Solstice’s plans, he taps on the brakes. “How regulatory agencies will handle drug approvals for mutating tumors or viruses when you have to introduce new sequences, and hence a new drug, rapidly is not clear,” he says. “Regulatory agencies will continue to weigh the benefits and risks as this technology becomes more available. It is safe to say our earliest therapeutic programs will not be based on this.”

Tartaglia declines to discuss the targets and tissue types Solstice is considering, although he reels off a long list of cell types—B cells, T cells, macrophages, lung, muscle, and more—that potential partners said they’d like to see targeted.

Since signing on as CEO in June, Tartalglia has been on what might be described as a listening tour to hear what those drug firms have in mind. It’s important to note that Solstice’s main backer is venBio, a fairly young venture firm based in San Francisco whose modus operandi is to build companies around assets that customers want. And the customers are drug companies with pipelines to fill, so Tartaglia and colleagues are paying close attention.

VenBio and Swiss investor Aeris Capital were behind Solstice’s $18 million Series A; the final $6.5 million slice of that cash flowed to Solstice last month after it hit undisclosed milestones, which means the need to raise more cash is not imminent, says Tartaglia.

I asked Tartaglia if the negative experiences of so many Big Pharma—Roche, Merck, Novartis—with RNAi programs in the past decade colored the reaction he got as he explained the RNN concept this summer. “We would have gotten cold shoulders, so to speak, if we were … 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.