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Review Highlights the Need for Biocompatibility, Biodistribution Work in RNAi Drug Field

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NEW YORK (GenomeWeb) – Despite extensive preclinical research into polymeric siRNA delivery vehicles, clinical translation of such work has been lacking, largely due to issues of biocompatibility and difficulties in tracking biodistribution, according to a review published this month.

Since the discovery of RNAi, the number of publications on siRNA delivery has steadily grown to over 1,500, with a significant portion dedicated to polymeric delivery approaches. Yet "the number of publications does not reflect the rather small number of clinical trials," the review, appearing in the Journal of Controlled Release, noted.

To Olivia Merkel, a co-author of the report and an investigator at Wayne State University, this is in part due to a discrepancy in the interests of academia, which is often focused on basic research, and the interests of industry, which typically handles clinical trials.

"Oftentimes in academia, we're happy when we can cure a mouse or when we have publishable results," she told Gene Silencing News this week. "That sometimes does not address all the problems." In many cases, there simply has not been enough biocompatibility work done on a particular delivery system to lay the groundwork for human testing.

Among the biggest problems when it comes to biocompatibility is the accelerated blood clearance phenomenon, which occurs with repeated administration of polyethylene glycol, a polyether that is added to nanomedicines to slow clearance and reduce toxicity. Of greater concern is complement activation, an immune response that can, at its worst, be fatal.

Several studies covered in the Journal of Controlled Release review did examine in vivo biocompatibility with single and multiple doses, but in most cases the effects of chronic dosing with polymeric siRNA carriers remain unclear.

Meanwhile, a lack of understanding about a delivery vehicle's biodistribution has hampered the translation of promising technologies from the lab to the clinic. This is not for lack of interest, Merkel said, but rather a lack of enabling technologies.

"A lot of people, even in academia, are interested in biodistribution," she said. But it wasn't until 2007 when Mark Davis and colleagues from the California Institute of Technology reported on the biodistribution of siRNA nanoparticles using in vivo imaging that the field had its first real report on the subject.

Since then, work by a number of groups, including Merkel during her time in the lab of Thomas Kissel, who co-authored the Journal of Controlled Release review, has provided new tools and approaches for studying where siRNA nanocarriers travel throughout the body.

Still, "too few studies focus on the biodistribution of the carrier both in regards of body distribution, but also concerning intracellular distribution," Merkel and Kissel wrote. "We do not know if we would possibly overload a patient’s body with 'plastic' if we had to administer polymeric carriers chronically."

They concluded that there are "many questions to answer on the way to successful translation of RNAi therapeutics. However, we should keep in mind that several approaches have entered clinical trials and that well planned preclinical studies can eventually make a difference."

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