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NIH Awards $1.2M in Grants to Four Companies Developing RNAi, miRNA Cancer Drugs

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Four companies developing RNAi/microRNA therapeutics received a combined $1.2 million in funding from the National Institutes of Health in September to develop their respective cancer drug candidates.

Among the firms are RXi Pharmaceuticals, Optimum Therapeutics, Ensysce Biosciences, and Mirna Therapeutics.

Since undergoing a major corporate restructuring to become a much smaller company earlier this year (GSN 5/10/2012), RXi has focused all of its efforts on developing a wound-healing drug based on its core self-delivering RNAi technology.

Dubbed sd-rxRNAs, the molecules are modified with proprietary chemistries to facilitate their uptake into a cell's cytoplasm without the need for a delivery vehicle. RXi's first focus with the technology is RXI-109, which is currently under phase I testing for use in reducing surgical scarring (GSN 9/27/2012).

However, RXi had also been examining the use of the technology in retinal diseases, and last month received a six-month, $292,272 grant from NIH to develop an sd-rxRNA treatment for retinoblastoma and other malignancies.

In its grant abstract, the company noted that tumor suppressor mutations account for nearly 80 percent of all cancer mutations, but are not amenable to drugs that inhibit gene expression. However, recent work in the lab of Memorial Sloan-Kettering Cancer Center researcher David Cobrinik indicates that retinoblastoma is not only driven by mutations in retinoblastoma proteins, but also by normal signal circuitry of retinal cone precursors.

“This normal circuitry includes extremely high expression of murine double minute oncogene, V-myc myelocytomatosis viral related oncogene, thyroid hormone receptor beta 2, and retinoic acid receptor gamma nuclear receptor,” the abstract states. “The expression of these genes is critical to retinoblastoma cell growth and survival, suggesting that they may be effective therapeutic targets despite the fact that they are not genetically altered in retinoblastoma.”

Of these four genes, MYCN is an especially attractive target because it is implicated in a variety of cancers, and its transient down-regulation appears well tolerated, although it has heretofore proven undruggable by conventional approaches, the abstract adds.

In rodent testing, RXi has found that intravitreal injection of sd-rxRNAs completely penetrate the retina and are efficiently taken up into tumors. Based on these and other data, the company is developing a portfolio of sd-rxRNAs targeting MYCN, as well as other backup retinoblastoma targets.

The NIH funding will be used to explore the compounds' distribution via intravitreal and inta-arterial injection, as well as to measure in vivo target mRNA knockdown in retinoblastoma cell tumors seeded into the eye. Additional studies will involve an examination the effect of the sd-rxRNA agents on tumor progression in a human xenograft mouse model.

“The most potent compounds will be moved into preclinical development with a focus on developing a data package sufficient to support” the filing of an investigational new drug application, RXi said in the abstract.

The grant began on Sept. 25 and runs until Feb. 28.

Also developing an RNAi-based cancer therapy is Optimum, although that company is interested in using siRNAs delivered using a pegylated cationic lipid carrier as a means to increase patient sensitivity to existing chemotherapeutics.

Optimum is focusing its effort on non-muscle-invading bladder cancer, the most common form of the disease and one that is managed via surgery and immunotherapy or chemotherapy, according to the company's grant abstract.

The most common chemotherapeutics used are mitomycin C and doxorubicin, but these are limited by the sensitivity of patients, primarily those with aggressive tumors, to treatment.

Noting that survivin is an established marker for bladder cancer aggressiveness and recurrence, Optimum said in its grant abstract that it has developed siRNAs against survivin that can inhibit target protein expression in cells and tumor-bearing animals, while boosting the activity of chemotherapy, when delivered using the lipid carrier.

With the support of a one-year, $344,460 grant from NIH, Optimum plans to identify the “optimal conditions” for combining the RNAi drug and a chemotherapeutic, and to identify the appropriate administration route for the therapeutic cocktail, namely intravesical instillation and/or submucosal injection.

Optimum's grant project began on Sept. 8.

Ensysce is also looking to siRNAs as a treatment for cancer, but is taking a novel approach to delivery through the use of single-walled carbon nanotubes, or SWCNTs.

Carbon nanotubes are highly elongated tubular nanostructures composed of sp2-hybridized carbon atoms covalently bonded into six-membered rings. Their high surface area, conductivity, high tensile strength, high aspect ratios, and potentially greater adsorption abilities make them a promising material for biomedical applications, according to the company.

Ensysce has been exploring the combination of carbon nanotubes and siRNAs for some time, and has found that such complexes cause little to no toxicity when delivered intravenously to mice, accumulate in tumors, produce tumor target-protein knockdown, and show anti-tumor activity, it states in its grant abstract.

With a one-year grant from NIH worth $298,072, Ensysce now plans to evaluate different formulations of its SWCNT/siRNA constructs to “determine their tumor and tissue distribution following intravenous administration,” it said in the abstract. “The preparation with the most promising tumor versus tissue distribution will be further examined for anti-tumor efficacy using [siRNAs against] for KRAS,” a gene that is involved in tissue signaling and which is mutated in many cancers.

“There is no treatment for KRAS and finding effective therapies for KRAS is arguably the single most important unmet medical need in cancer today,” Ensysce said in the abstract. “Therefore reducing its presence with siRNA delivered by SWCNT provides approach to this deadly problem.”

The grant runs from Sept. 25 until Aug. 31, 2013.

Taking a slightly different, albeit related, approach to treating cancer is Mirna, which is developing miRNA replacement therapies to counteract dysregulation of the non-coding RNAs in various malignancies.

The company's lead candidate is MRX34, a mimic of miRNA-34a that is slated to enter phase I testing next year for various cancers, with a particular focus on liver cancer (GSN 5/3/2012).

The drug is formulated with Marina Biotech's Smarticle liposome particle-based technology, but Mirna is also exploring the use of other delivery approaches and has now received a one-year grant, worth $299,999, from NIH to examine a chitosan nanoparticle-based delivery vehicle for its miRNA drug.

According to the company's grant abstract, it has generated much data demonstrating the anti-tumor activity of miR-34a in mouse models of human primary and metastatic prostate cancer, but is lacking a “clinically relevant delivery technology” to bring a treatment into the clinic for this indication.

Working in collaboration with researchers from the University of Texas, Mirna will use its NIH funding to develop functionalized chitosan nanoparticles that show enhanced properties for miRNA delivery and low toxicity, it said.

“We will determine biodistribution and half-life of these nanoparticles in plasma and various tissues test for delivery to orthotopic prostate tumors and most importantly, inhibition of primary and metastatic tumor growth,” the company added. “We believe these studies will help developing a delivery technology that enables the systemic administration of therapeutic miRNAs to prostate tumors and potentially other solid tumors and will advance the development of therapeutic miRNAs closer to the clinic.”

The grant runs from Sept. 21 until Aug. 31, 2013.

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