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Tekmira Gets Grant for Combo Ebola, Marburg Drug; Others Secure RNAi, microRNA Funding

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The National Institutes of Health this month awarded roughly $1.4 million in grant money to researchers at the University of Texas and Tekmira Pharmaceuticals to support their development of a single RNAi-based drug that can treat both Ebola virus and Marburg virus infections.

The agency also awarded nearly $500,000 to City of Hope investigators to fund their efforts to test the effects of chemotherapy with an investigational shRNA-incorporating lymphoma-associated AIDS therapy, and just over $300,000 to a Henry Ford Health System scientist examining the effect of a specific microRNA on the restoration of neurological functioning following stroke.

Tekmira and the University of Texas have been working closely together on developing RNAi-based drugs to fight filovirus infections for nearly 10 years — an effort that has yielded TKM-Ebola, a compound that delivers siRNAs against the virus in lipid nanoparticle carriers. With the support of a US Department of Defense contract worth up to $140 million, Tekmira recently moved a next-generation version of the drug into phase I testing.

Meanwhile, Tekmira has been exploring treatments for other filovirus-associated hemorrhagic fevers including those caused by Marburg virus infection. Late last year the company released data showing that treatment with the preclinical candidate TKM-Marburg led to 100 percent survival in non-human primates exposed to the most lethal strain of the virus.

But according to their recently awarded grant, Tekmira and the University of Texas are also working to combine TKM-Ebola and TKM-Marburg into a single, broad spectrum agent that would target the most clinically relevant strains of the two viruses.

The resultant product would then be combined with either one of two other investigational treatments including a recombinant vesicular stomatitis virus-based post exposure vaccine being developed by the University of Texas and Profectus Biosciences, or fully human anti-filovirus monoclonal antibodies that the university is creating.

"This combinatorial strategy is intended to provide an effective and complementary treatment of filovirus infection that is more effective than each therapeutic alone," Tekmira Chief Technical Officer Ian MacLachlan noted in the grant's abstract.

Development of the dual-targeting RNAi drug will involve identifying siRNAs that are highly active against one or more Ebola and Marburg strains, and then combining them within single lipid nanoparticle formulations.

To reduce the number of different siRNAs within the cocktail, the collaborators will use of universal neutral bases capable of pairing with multiple nucleosides. "Incorporation of one or more neutral bases in our siRNA sequence will allow targeting regions of incomplete sequence conservation among filovirus species," MacLachlan wrote.

The most active drug formulation will then be tested in non-human primates.

The one-year grant began on March 1.

Also pulling in NIH funding is City of Hope's John Zaia, who has been working for a number of years on a novel treatment for AIDS in lymphoma patients that involves treating a patient's stem cells to combat their condition.

Specifically, the stem cells are mobilized using granulocyte colony stimulating factor. Once the stem cells begin circulating peripherally, they are collected, isolated, and genetically modified with a lentiviral vector containing three therapeutic genes: DNA that encodes for shRNAs targeting the tat-rev exon, a ribozyme that cleaves the mRNA for CCR5, and a nucleolar-localizing TAR decoy.

The patients undergo full chemoablation, killing the regenerative cells of the bone marrow and lymphoma cells. Then, the modified stem cells are infused back into their bloodstreams so that they can migrate to, and engraft in, the marrow. The idea is that the stem cells will carry the anti-HIV shRNAs and, when they mature into other cells such as macrophages and monocytes, these will be resistant to the virus. The ribozyme and TAR decoy components of the treatment are designed to enhance the inhibitory effect of the shRNA.

Having obtained promising safety and efficacy data on this treatment approach from small clinical trials, Zaia and his collaborators are setting out to see whether a chemotherapeutic regimen known as R-EPOCH that is designed for B cell and T cell lymphomas can be used safely prior to the stem cell AIDS therapy.

The grant began on March 1 and runs for three years. It is worth $465,641 in its first year.

The NIH also awarded a grant to Henry Ford's Jieli Chen, who has been studying the role of miR-126 in the brain's ability to regain function after stroke — a condition that is up to four times more likely to occur in diabetics.

Previously, she and her colleagues discovered type II diabetes is associated with a downregulation of miR-126 and the growth factor antiopoietin-1, which the miRNA is known to regulate, in the circulation and ischemic brains of diabetic mice.

Meanwhile, treating diabetic mice that have experienced a stroke with human umbilical cord blood cells (HUCBCs) boosts recovery of neurological function, as well as the expression of the miR-126 and angiopoietin-1.

In light of these findings, she and her team aim to see whether delivery of miR-126 mediates HUCBC treatment-induced neurorestorative effects after stroke in diabetic mice, theorizing that the miRNA mediates the cells' ability to improve vascular integrity, axonal outgrowth, and white matter remodeling.

They also plan to test their hypothesis that miR-126 is generated by HUCBCs and transferred to brain endothelial cells and parenchymal cells in exosomes/microvesicles, and whether the miRNA's regulation of angiopoietin-1 is responsible for HUCBC's neurorestorative effects after a stroke.

The grant began on March 1 and runs until Dec. 31, 2018. It is worth $324,844 in the first year.

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