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Northwestern Group Reports on AuraSense Tech for Delivering siRNAs to Brain Tumors


A research team from Northwestern University this week published new data showing that a class of novel nanoparticle conjugates, which have been exclusively licensed to startup AuraSense Therapeutics, can be used to deliver cancer-fighting siRNAs into the brains of mice.

The findings, which appeared in Science Translational Medicine, come a little more than a year after the same group, which includes AuraSense founder Chad Mirkin, reported that the technology could deliver siRNAs topically into uncompromised skin cells (GSN 7/12/2012).

The nanoparticle conjugates, called spherical nucleic acids, or SNAs, are essentially gold cores surrounded by a dense shell of highly oriented DNA or RNA. The result is a "spherical display of nucleic acids covalently attached to a particle in the middle," Mirkin told Gene Silencing News last year.

When arranged in this manner, nucleic acids that would ordinarily be unable to penetrate cell walls due to their negative charge are recognized by scavenger proteins and endocytosed, he added.

In 2006, Mirkin and his colleagues first reported on SNAs in Science, and in 2011 they published a report demonstrating their ability to deliver microRNA mimics. About a year later, they extended those findings to topically delivered siRNAs, showing in a Proceedings of the National Academy of Sciences paper that SNAs could “penetrate almost 100 percent of keratinocytes in vitro, mouse skin, and human epidermis within hours after application" — key findings given AuraSense's interest in skin disorders.

Now, Mirkin and his team have released data on another area of interest to the company: glioblastoma multiforme.

Also known as GMB, the disease is the most prevalent and lethal form of malignant brain tumors. Existing therapies have had limited success in extending patient survival, and are hampered by drug-drug interactions and systemic toxicity, the Northwestern scientists wrote in Science Translational Medicine. Further complicating treatment is the difficulty in delivering drugs across the blood-brain barrier, blood-cerebrospinal fluid barrier, and the blood-tumor barrier.

Given the past successes with SNAs, the researchers sought to test their ability to deliver therapeutic siRNAs into GBM tumors. They selected the apoptosis-suppressing oncogene Bcl-2-like 12 as the target of their drug candidate, noting that it localizes to chromosome 19q13, a region frequently amplified in the cancer.

"Furthermore, cell-based assays and expression analyses have identified [Bcl-2-like 12] as a putative oncogene with consistent and prevalent mRNA and protein upregulation in GBM relative to normal brain," they added.

In vitro experiments confirmed that SNAs could efficiently enter primary and transformed glioma cells without the need for additional transfection agents or chemical modifications. Bcl-2-like 12 inhibition was also observed and confirmed through 5' RACE to be a result of siRNA-triggered RNAi.

Additional analysis showed that the gene knockdown sensitized glioma cell to chemotherapy-induced apoptosis, specifically by enhancing caspase and p53 activities.

The investigators then looked in vivo, testing whether SNAs could penetrate glioma tissue in glioma-bearing severe combined immunodeficient mice following either local or systemic administration.

Intracranial injections of SNAs led to a 10-fold greater accumulation of the nanoparticles in tumor tissue versus non-tumor brain regions. Meanwhile, intravenous administration of SNAs led to their selective infiltration into the glioma mass in comparison to adjacent non-cancerous tissue.

"SNA accumulation in brain tissue of non-tumor-bearing mice was extensive, with about 1x1010 SNA particles per gram of tissue," according to the Science Translational Medicine paper. "Tumor and adjacent normal brain in glioma-bearing mice, however, revealed an almost three orders of magnitude higher SNA accumulation" — an effect likely due to a compromised blood-brain/blood-tumor barrier in the animals.

No significant toxicity was observed in connection with the SNAs and, more importantly, treatment with nanoparticles carrying Bcl-2-like 12 siRNAs resulted in target mRNA and protein knockdown of 26 percent and 40 percent, respectively, in the mouse models' glioma cells.

The drug also reduced tumor burden and progression, while it significantly increased intratumoral apoptosis, in the mouse models — all of which contributed to increased survival.

Taken together, the data provide proof of concept that systemically administered SNAs can cross the blood-brain/blood-tumor barrier in GBM cell and mouse models, infiltrate tumor parenchyma, silence genetic lesions of established GBM in vitro and in vivo, and effectively reduce tumor burden, the study's authors concluded.

Further, they wrote, the findings suggest that the nanoparticles might represent a new class of therapeutic gene-regulation agents — something that AuraSense is banking on.

Although it has not released specific details about its pipeline, the company has stated that it has programs based on its SNA technology in skin disorders, brain tumors and other cancers, organ transplants, and respiratory diseases.

It also says it has established collaborations with "several pharma partners" to test the molecules in multiple "disease-specific applications," although the exact nature of those arrangements remains undisclosed.