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Startup AuraSense Aims to Commercialize Northwestern U Tech for siRNA Delivery to Skin

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Researchers from Northwestern University this month published data showing that proprietary spherical nucleic acid, or SNA, nanoparticle conjugates could be used to deliver siRNAs topically into uncompromised skin cells with no apparent toxicity, opening the door to a new route of administration for therapeutic RNAi agents.

SNAs have already been commercialized for diagnostic applications by Nanosphere, which was co-founded by Northwestern researcher and study co-author Chad Mirkin. Another company called AuraSense Therapeutics, which was co-founded by Mirkin last year, is now advancing the technology for therapeutic applications.

“We've had tremendous interest” from potential drug-development partners, he told Gene Silencing News this week, noting that AuraSense has already inked deals with a number of big pharmas.

Although the nature and scope of those arrangements remain undisclosed, Mirkin did point out that one of AuraSense's investors is Abbott Biotech Ventures, a subsidiary of Abbott, which has been playing in the RNAi field since at least 2006 (GSN 7/13/2006).

SNA nanoparticle conjugates are essentially gold cores surrounded by a dense shell of highly oriented DNA or RNA “so that you get a spherical display of nucleic acids covalently attached to a particle in the middle,” Mirkin explained.

“It turns out that when you take DNA or RNA and arrange it in that manner, you end up getting a structure that exhibits properties that are very different, on a sequence-for-sequence basis, [from] linear nucleic acids,” he said.

Ordinarily, when linear nucleic acids are delivered directly to cells, they are unable to penetrate the cell wall “to a significant extent” because of their negative charge, Mirkin said. However, “if you take the same linear nucleic acids and arrange them in a spherical format, they can be added to the exact same cells … and get in better than any material known to man.”

As Mirkin and colleagues first described in a paper in Science in 2006, “when you create this three-dimensional presentation, [the molecule] is large enough to recognize scavenger proteins that facilitate endocytosis,” he said this week. “You hijack a natural material — these scavenger proteins — and use it to get these nucleic acids into cells.”

“What you have is the only single-entity agent known, [which] can be made pure … because you can dissolve the core in certain cases, that can be delivered to cells and get a large amount of genetic material inside them with almost no immune response,” he added.

In the 2006 paper, Mirkin and his team used the SNA nanoparticles to deliver antisense molecules, and last year they reported on using the nanoparticles to deliver microRNA mimics.

In PNAS this month, they extended their findings to topically delivered siRNAs, which could “penetrate almost 100 percent of keratinocytes in vitro, mouse skin, and human epidermis within hours after application.

“Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses,” the team wrote.

To demonstrate the effectiveness of the delivery system, the researchers used SNA nanoparticles bearing siRNAs against epidermal growth factor receptor, which plays a role in epidermal homeostasis, and found that they were over 100-fold more effective than siRNAs delivered with commercial lipids in knocking down their target in cultured keratinocytes.

Topical delivery to hairless mouse skin, meantime, “almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40 percent,” according to the paper. “Similarly, EGFR mRNA in human skin equivalents is reduced by 52 percent” after 60 hours.

Treated skin showed no signs of toxicity, and no cytokine activation in mouse blood or tissue samples was observed. After three weeks of topical skin treatment, the SNAs were “virtually undetectable” in internal organs.

To Mirkin, topical siRNA delivery represents “a holy grail" in the field.

“Currently the way people do [delivery to the skin] is use things like microinjection, which is extraordinarily painful … and therefore horribly impractical,” he said. “But when you have the ability to carry these types of entities through the stratum corneum and into the skin, you have the ability to think about all sorts of new therapies for many diseases of the skin including things like psoriasis [and] melanoma, and ailments like wound healing.”

The delivery approach also represents “a fundamental change in the way we think about RNAi and antisense therapeutics,” he added.

“The entire field focuses on using some sort of vector — positively charged material, a polymer, a virus particle, a peptide — complexing it with a nucleic acid, and effectively tricking cells into picking up the nucleic acid,” Mirkin said. “The negative of that approach is that you are limited by the toxicity and effectiveness of that co-carrier.

“We've come along and said, 'Let's forget this idea that negatively charged entities won't enter cells because when you make the spherical nucleic acid network, they will.' … And have not only the ability to get nucleic acids in, but you don't need a co-carrier.”