Exploding Microbubbles, RNAi, and RXi

The Haystack saw a press release yesterday out of Worcester, Mass.-based RNAi therapeutic firm RXi Pharmaceuticals that was intriguing. The company has signed a pact with Royal Philips Electronics to explore “image-guided therapy concepts based on RNAi.” What the heck does that mean? We were curious so we reached out to RXi for a primer, which turned into a bit of an update on where the company has come in the last year.

Before we get into translating the mouthful of techno-speak from Philips and RXi, a few words to explain RXi’s delivery approach. Most folks in the RNAi therapeutics world are focused on encapsulating the siRNA in a lipid nanoparticle or polymer-based system: the formulation (in theory) guides the drug to its target cell and, once inside, releases its therapeutic payload. Check out our article on siRNA delivery for more details on the challenges and current limitations of that strategy.

RXi is working on “self delivery” technology, which it bought from Boulder, Co.-based Advirna. As the company’s CSO (and Advirna co-founder) Anastasia Khvorova told me yesterday, the company is combining oligonucleotides, short single-stranded strings of nucleic acids, with small bits of double-stranded siRNA. RXi makes hydrophobic modifications to that hybrid molecule that stabilize the structure and allow it to be taken up by the cell of interest. They wind up with a large complex that has been tricked out to behave like a small molecule.

So what does Philips bring to the table? RXi hopes to improve the potency of its self-delivery RNAi molecules using Philips’ formulation technology, which traps drugs inside “microbubbles” that are sensitive to ultrasound pulses. After a drug is dosed, it travels to the tissue of interest and an ultrasound pulse is applied, causing the bubbles to explode and the drug to be released. It all sounds rather futuristic, but RXi thinks it could significantly improve the potency of its molecules by one-to-two orders of magnitude.

“Our RNAi molecules are very good at getting into cells once they’re kind of in the proximity, whereas their technology helps us get into the right organs,” RXi’s CEO Noah Beerman says.

It’s cool stuff, but will it work? It remains to be seen, but it’s nice that some outside-the-box thinking is getting play in the RNAi arena. As mentioned, many companies continue to beat the lipid nanoparticle drum, but that technology has yet to work across a wide range of diseases. The need for chemistry and engineering to step in and come up with some innovative approaches to RNAi delivery is great.

It’s worth noting that all this shiny new technology is a bit of a departure from what RXi was focused on just a year ago. Before bringing in the Advirna technology, the company was touting its glucan-encapsulated particle delivery technology.

Now that it has settled into its self-delivery approach, look for the company to provide details about its overall strategy during its presentation next Thursday at the Jefferies Global Life Sciences Conference. “One of the things we’ve been working on very hard here is defining the core therapeutic areas to focus on,” Beerman says. “We’re now turning that page and focusing in on a handful of areas that will roll out next week at the Jefferies conference.”

Author: Lisa Jarvis

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  1. That ultrasound facilitates gene transfer using microbubbles has been known since at least 1996. That isn’t a cool cutting edge breakthrough in my opinion.

    Hum. Gene Ther. 1996, 7, 1339-1346.

    Does someone else have an earlier reference?

  2. Hi Mitch– Thanks for the reference article. The reason for highlighting the pact (and their new strategy for RNAi even without the help of Philips) is that it is, well, not lipid nanoparticles or polymers. Many companies (both biotechs and pharmas who are licensing technologies) are focused on lipid nanoparticles or polymers for delivery (check out the chart in the article I link to)–though its yielded some small successes, there are serious limitations for what types of tissues you can reach. Even companies with high profile deals to explore lipid nanoparticle delivery have told me that chemistry and engineering need to step it up if we ever want to see systemic delivery of siRNA. I’ve pointed to a few companies on the blog who think they can expand the diseases RNAi can address by using a delivery vehicle that targets a specific cell type (see our post on Traversa, for example), I haven’t seen much from companies in the way of pure engineering approaches. I”m guessing this technology has advanced (on both ends–both the microbubbles and the RNAi molecules themselves) since the ’90s, so it could be interesting to revisit the idea. Carbon nanotubes is another area that people in the know have told me is worth taking a look at….

  3. I should point out that I don’t mean to infer this Philips technology will enable systemic delivery–however, it could enable cardiovascular disease and more types of cancer to be addressed, which for siRNA would be an advance.

  4. Thank you for pointing out the C&EN article, I hadn’t read it previously. I’m no longer a nuclear chemist, I am now working in gene delivery for my postdoc. In the next 2 weeks I will be injecting mice with various formulations of nanoparticles (not lipids, but supramolecular formulations) encapsulating luciferase plasmids and measuring transfection efficiencies. The chemists are coming.

  5. Ooh, keep us posted on your work, Mitch!