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With Brain Delivery Tech, BiOasis Takes Aim at RNAi Therapeutics Field

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NEW YORK (GenomeWeb) – Canadian biopharmaceutical firm BiOasis last week announced that it has thrown its hat into the RNAi therapeutics ring and aims to advance an siRNA-based drug into Phase I testing before the end of next year.

While BiOasis hasn't made a final decision on what will be its first RNAi candidate, the firm recently presented limited data showing that its delivery technology could successfully carry siRNAs targeting Nox4, a gene involved in the generation of reactive oxygen species, across the blood-brain barrier (BBB).

According to BiOasis CEO and Chairman Rob Hutchison, Nox4 represents an attractive candidate for two indications in particular: stroke and Alzheimer's disease.

Nox4 has been shown to be responsible for nerve cell death following stroke. A number of groups have generated data showing that the gene's suppression can mitigate the damage caused by stroke-related oxidative stress in animal models of the condition. Similarly, Nox4 has been associated with the neuronal loss caused by Alzheimer's disease, making it a potential therapeutic target in that disorder.

Hutchison said that animal studies are underway in both indications and should conclude around the end of the year, at which point BiOasis will decide whether to pursue one of them or another undisclosed disease under consideration. An investigational new drug application is expected to be filed in 2015.

BiOasis' core delivery technology is known as Transcend and was developed by researchers at the University of British Columbia. It is based on the discovery of an endogenous receptor located on the blood vessels that compose the BBB that shuttles an iron-transport protein called p97, or melanotransferrin, across the barrier.

In 2008, a team led by UBC's Wilfred Jefferies, who is the scientific founder of BiOasis, published a paper in PLOS One demonstrating that the p97 system could be used to carry therapeutic agents from the blood stream and into the brain. In that report, human p97 was covalently linked with one of two chemotherapeutics, paclitaxel or adriamycin (ADR). The conjugates were then administered intravenously into mice with tumor cells growing subcutaneously or intracranially.

The conjugates were found to cross the brain capillary endothelium within a few minutes after administration. After 24 hours, total p97 accumulation in the brain reached one to two percent of the injected dose, equivalent to the ratio of brain to body weight, according to the paper.

Notably, the p97-ADR conjugates and unmodified ADR both inhibited the growth of subcutaneous cancer cells, but only the conjugates affected the survival of animals with either subcutaneous or intracranial tumors.

Taken together, the findings demonstrate the potential of p97 to "ferry normally excluded therapeutic compounds through the battlements of the BBB, thereby allowing [the] cargo to traverse from the blood and emerge in the brain," Jefferies and his team wrote.

Having acquired the p97 delivery technology from UBC, BiOasis began developing it under the name Transcend as a method for carrying anti-cancer drugs into patients with inoperable brain tumors. However, the company has had success using it with a variety of other molecules including siRNAs, prompting its interest in the RNAi field.

Recently, however, the company and its academic collaborators identified a peptide in p97 that drives the protein's ability to bind to receptors on the BBB. Dubbed Transcendpep, the peptide has not only proven cheaper to manufacture, but also more effective than the Transcend protein.

"To manufacture 150 grams of the protein, it was close to around $1 million and [took] a year," Hutchison said. "To make 150 grams of the peptide takes about two weeks and $1,400." Meanwhile, the peptide has proven to transport to the brain more effectively than the full-length protein.

In terms of siRNA delivery, BiOasis has not released too many details on the Transcendpep, although it has said that it was able to reduce expression of Nox4 in the brains of animals by between 40 and 50 percent after a single intravenous dose. Based on these and other data, BiOasis aims to use Transcend-pep with its RNAi candidate.

Hutchison told Gene Silencing News that while BiOasis is prepared to run a Phase I trial of its siRNA drug alone, he expects that it will find a partner for the program based on the interest received from both RNAi firms, as well as pharmaceutical companies.

Beyond that, he said that BiOasis has also been fielding inquiries from other players in the RNA medicines space, including an unnamed firm that has asked to see data on Transcendpep's performance carrying microRNAs into the brain.

Those studies, Hutchison said, are currently underway.

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