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As Delivery Challenges Continue to Confound RNAi, Copernicus Looks at DNA Nanoparticles for siRNAs

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As delivery continues to be a major hurdle for RNAi-based drugs, Copernicus Therapeutics has begun exploring whether its DNA nanoparticle technology, designed for gene therapy, can be used to deliver siRNAs.

Although the company is just beginning in vivo experiments in RNAi, it expects to have data ready for presentation in about a year.

Copernicus was founded in 1997 to commercialize technologies developed at Case Western Reserve University, including one that compresses single molecules of DNA to their minimum possible size in order to facilitate entry into cells. But as the RNAi field began heating up, the company has started looking into whether its technology can be used with other small nucleic acids, namely siRNAs.

"We've been getting approached by people out there that recognize … that the whole problem with siRNAs is not just off-target toxicities but the ability to deliver them effectively into cells in a human being," Copernicus President and CEO Robert Moen told RNAi News this week. In light of this interest, "we have just started in the last few months working with siRNAs, both as small oligomers as well as expressed off of plasmid DNA."

According to Moen, once DNA molecules are compacted with the company's technology, they bind to a cell membrane protein called nucleolin, which transports the resulting nanoparticles into the nucleus through a pathway that does not involve endosomes or lysosomes, side-stepping degradation issues.


"We think the first uses of our technology [in RNAi] will be in delivery to the lung airway cells. For an siRNA application, [it] would be most effective against viral infections."

Although nucleolin is present in most cells, Moen said, it resides on the surface of only certain kinds such as ocular and neural cells, which somewhat limits the scope of the delivery technology. "It doesn't look like we can get into … regular blood cells and regular endothelial cells," he said. "We [also] don't seem to get into liver cells," although the addition of targeting ligands to next-generation versions of the technology may change this.

The cells lining pulmonary airways, however, appear particularly amenable to the delivery technology, and the company's primary focus has been to develop an aerosolized gene-replacement therapy for cystic fibrosis, which it has already tested in humans.

As such, "we think the first uses of our technology [in RNAi] will be in delivery to the lung airway cells," Moen said. "For an siRNA application, [it] would be most effective against viral infections" such as influenza and SARS.

Given the company's experience with plasmid DNA, it has a greater "comfort level" developing the technology for expressed RNAi applications, Moen said. "We're [only] learning how to work with siRNAs at this point."

Still, Moen is optimistic about Copernicus' efforts, noting that the company expects to have data ready to present to the biotechnology community by next year's American Society of Gene Therapy meeting, being held in Seattle May 30 through June 3.

He also noted that Copernicus has already established a manufacturing process for its nanoparticles, giving it an edge over some other firms developing nucleic acid-delivery methods.

"It doesn't matter if it works in tissue culture if you can't actually do it in a commercializable pharmaceutically relevant system," Moen said. "We've been able to work out how to manufacture [our nanoparticles] so you don't end up with hundreds or thousands of these things in a big aggregate complex. We end up with something that's essentially uni-molecular, much more discrete, [and] well-defined."

Should its technology prove effective with siRNAs, Copernicus expects that it will establish a collaboration with an RNAi drug developer looking for a delivery solution, rather than develop its own therapeutics.

Although the company has a portfolio of issued and pending patents covering its delivery approach, including its use with small nucleic acids, its intellectual property estate is not RNAi-specific.

Therefore, "the wise choice for a company our size … would be to marry our delivery technology with companies that have IP in the siRNA field, whether that's the oligo or expressed forms," he said.

— Doug Macron ([email protected])

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