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NIH Doles out Nearly $1.5M in RNAi, miRNA Small Business Research Grants in September

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By Doug Macron

When it comes to handing out research funding, September was a busy month for the National Institutes of Health, which awarded nearly $1.5 million in one-year Small Business Innovation Research grants to companies playing in the RNAi and microRNA fields.

Leading the pack is antisense shop Isis Pharmaceuticals, which was awarded $463,365 to continue an ongoing grant project investigating chemical modifications capable of improving RNAi drugs.

While the potential of the gene-silencing technology "has largely been realized in cell culture using cationic lipids to introduce substrates for the RNAi pathway into mammalian cells, the widespread application of RNAi technology to gene inhibition in animals remains elusive, according to the grant's abstract. "This is largely due to the poor pharmacokinetic properties of RNAi based drugs such as small interfering RNAs."

Because of the poor pharmacokinetics of RNA, including its instability in biological fluids, Isis aims to "design analogs which have the potential to exhibit improved PK properties, yet maintain the high intrinsic potency of the RNAi mechanism" using its "knowledge of the structure-activity relationships of RNAi drugs."

With the support of the NIH funding, the company intends to evaluate the improved designs in preliminary pharmacokinetic and pharmacology studies to assess their ability to serve as leads for the development of RNAi-based therapeutics, the abstract adds. "Because of our focus on a novel target relevant to cancer chemotherapy, we will also generate therapeutic leads appropriate for preclinical drug development activities," with the goal of developing "optimized, chemically modified motifs for RNAi drugs which should be widely applicable to the modulation of gene expression in animals as well as a lead siRNA compound targeting Eg5."

Aparna Biosciences also picked up some additional funding from the NIH last month, receiving a $235,400 grant to continue development of a nanoparticle reagent for the in vivo determination of cancer gene function.

"With the growing success of targeted therapeutics, it has become clear that a greater understanding of [non-small cell lung cancer] biochemistry and pathology is a crucial bottleneck in identifying new and better treatments," the grant's abstract states.

RNAi has proven to be a major advance for the field, "but this revolutionary capability to characterize gene function has been confined largely to cell culture studies, with limited methods for in vivo administration in animal disease models … and none available as a research reagent," it notes. "Our hypothesis is that we can adapt our cationic polypeptide nucleic acid nanoparticle technology, which we have found effective for in vivo delivery of RNAi agents to a primary breast cancer xenograft model, for a set of metastatic and primary NSCLC xenograft tumor models."

Should the company be able to develop an effective agent for the delivery of an RNAi agent to in-house metastatic and primary NSCLC xenograft models, it aims to "undertake commercial development of a reagent for in vivo RNAi for NSCLC xenograft model gene-function target validation with capabilities including metastatic cancer."

Armagen Technologies received a $195,742 infusion from the NIH for an ongoing project developing a targeted, intravenous delivery technology for siRNAs.

The company's approach involves an siRNA "mono-biotinylated in parallel with the production of a fusion protein of avidin and a receptor-specific monoclonal antibody," according to the grant's abstract.

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The fusion protein is specifically made of avidin and a mouse/rat chimeric mAb to the mouse transferrin receptor, and is designed to act as a "molecular Trojan horse," carrying the siRNA across any target cell membrane that expresses TfR, which the company noted is highly expressed on the blood-brain barrier.

Also in September, Omm Scientific was awarded $167,231 from the NIH to develop a novel miRNA-detection technology.

The project will use an "emerging surface plasmon-coupled emission technology in a … ratiometric, confocal format to detect microRNA analogs," the grant's abstract states. "The very limited, surface-confined detection volumes of SPCE … create an opportunity to develop a very low background, highly sensitive … inexpensive detection technology."

The abstract notes that the limit of detection is expected to be cut at least 10-fold over existing methodologies. Ultimately, the company expects to develop prototype devices for sale with an array capable of detecting miRNAs expressed in Drosophila and other organisms.

Startup TekShifa garnered $153,215 from the NIH last month to develop an approach to use exosomal miRNA profiles as biomarkers of ovarian cancer.

In the grant's abstract, the company noted that while the over-expression of multiple miRNAs has been used to diagnose ovarian cancer and correlate with poor patient survival, its application is limited to evaluation of tissue biopsies.

To address this shortcoming, the company is developing a method to use circulating, tumor exosome-associated miRNAs as diagnostic and screening biomarkers. In preliminary studies, the company has demonstrated that miRNA signatures of such exosomes derived from ovarian cancer patients "parallel the profiles of microRNAs expressed in the corresponding tumor," the abstract states.

Hypothesizing that the identification of miRNAs associated with circulating ovarian tumor-derived exosomes can be used as early-stage markers of disease, the company intends to "initially isolate and quantitate circulating exosomes from patients with ovarian serous adenocarcinoma at various stages and grades and compare [them] with similar material isolated from women diagnosed with benign ovarian masses," the abstract notes. The miRNAs associated with the exosomes will be profiled, and the presence of specific miRNAs will be correlated with the presence or absence of malignant disease.

Another newcomer to the RNAi space, Optimum Therapeutics, was awarded $125,561 from the NIH to develop an intraperitoneally delivered siRNA-based cancer therapy.

The company has pinpointed high tumor-cell density as a key barrier to intra-tumoral transport, and has since developed the tumor priming technology to promote particulate delivery and interstitial transport in solid tumors," according to the grant's abstract. "This technology uses [the chemotherapeutic] paclitaxel to induce apoptosis, expand the interstitial space, and consequently promote greater penetration and more even dispersion of particulates in tumor matrix."

With the support of the NIH funding, Optimum plans to evaluate the feasibility of using this so-called tumor-priming microparticles technology to "promote delivery and penetration of liposomal siRNA into tumors," the abstract notes. It will then "test whether the established technologies can enhance the therapeutic efficacy of [survivin-targeting] siRNA in the treatment of intraperitoneal tumor."

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Lastly, Effigene Pharmaceuticals was awarded $115,422 in September to develop small molecules capable of improving the therapeutic profiles of siRNA drugs.

"To address these difficulties associated with siRNA therapy, we have identified an RNAi-enhancer that can raise siRNA efficacy, lower the required siRNA dose, and prolong its silencing effect," the grant's abstract states. "If successfully developed, these enhancers could be used as an adjuvant therapy with siRNA drugs."

In its NIH-funded research, the company will see whether this compound, dubbed RNAi-E, can enhance the efficacy of siRNAs to treat age-related macular degeneration in a mouse model.

Should this proof-of-concept work prove successful, Effigene plans to determine "the optimal concentration of an RNAi-enhancing compound to potentiate chemically modified siRNA molecules in an in vitro system and determine the feasibility of RNAi-E for enhancing siRNA efficacy in vivo."

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