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InteRNA, Collaborators Secure €1.2M Grant for microRNA Cancer Drug Development

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InteRNA Technologies announced this week that it and collaborators from industry and academia have received a €1.2 million ($1.6 million) grant from the European Union to form a consortium to develop its microRNA-based treatment for head and neck cancer.

Called MiRacle, the effort will combine a miRNA mimic identified by InteRNA for its ability to kill cancer cells with a delivery technology created by Israeli firm Quiet Therapeutics.

Other participants in the two-year consortium are BioSpring, which will provide miRNA synthesis services; OctoPlus, which will offer guidance on drug formulation; the Laboratory of Pharmacology and Toxicology, which will lead toxicology studies on the drug candidate; and VU University Medical Center, which has expertise in oncology.

According to InteRNA CEO Roel Schaapveld, MiRacle builds off of the work the company and VU Medical Center have conducted under a previous collaboration, which yielded six potential miRNA candidates for the head and neck cancer program.

As the partners reported in Clinical Cancer Research last month, they applied a retroviral expression library of human miRNAs to head and neck squamous cell carcinoma, or HNSCC, cell lines and normal oropharyngeal keratinocytes to identify tumor-selective lethal miRNAs. Potential downstream gene targets of these miRNAs were then identified by gene expression profiling and validated by functional assays.

Six miRNAs — miR-181a, miR-323, miR-326, miR-342, miR-345, and miR-371 — were found to significantly decrease cell proliferation in the HNSCC cell lines, but not in primary keratinocytes. Further analysis revealed that the expression of the miRNAs had a similar effect on colon cancer and glioblastoma cells, " although there was a considerable variation in the lethal phenotype between cell lines of different origin."

Gene-expression profiling and 3' UTR assays indicated that the ataxia telangiectasia mutated, or ATM, gene is a common target for at least two, and likely three, of the miRNAs. Notably, specific inhibition of ATM triggers a tumor-specific lethal effect similar to that achieved with miRNA expression, while the phenotype was reverted in rescue experiments.

With these data, along with the EU grant, in hand, InteRNA and its consortium partners will now conduct additional research on the two most promising miRNAs culled from the six identified in Clinical Cancer Research. Schaapveld said that the two miRNAs are not yet being made public.

Specifically, the funding will support in vivo proof of efficacy studies, he noted, which are expected to yield a formal preclinical candidate that can be moved into investigational new drug application-enabling studies in combination with Quiet's delivery vehicles.

Called Gagomers, the vehicles are lipidated glycosaminoglycan particles that can encapsulate nucleic acids or small molecules. The glycosaminoglycan used, hyaluronic acid, is anionic and non-sulfated, and can be distributed widely throughout connective, epithelial, and neural tissues, according to Quiet.

One of the primary receptors of hyaluronic acid is CD44, a cell surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration and is expressed in many cells, the company said.

"High-affinity forms of activated CD44 splice variants are highly expressed in cancer and in inflammation," it added. With this as their shell, gagomers are "naturally targeted to cells expressing these specific activated receptors."

In 2011, researchers from Tel Aviv University, which licensed the gagomer technology to Quiet, reported that the particles could be loaded with the chemotherapeutic paclitaxel and delivered directly to CD44-expression head and neck cancer cells in a mouse tumor model.

Schaapveld said that MiRacle consortium members will retain the rights to their respective technologies, adding that InteRNA owns intellectual property on the miRNA drug candidates themselves.

Elsewhere in the pipeline

While InteRNA's efforts in head and neck cancer has gotten a boost from the EU grant, its melanoma program remains its primary focus.

As reported by Gene Silencing News, that effort centers on miR-3157, a miRNA the company has validated for its ability to inhibit proliferation and induce apoptosis in tumor cells (GSN 10/25/2012). It is believed that the miRNA functions by counteracting the effects of BRAF, a protein kinase that regulates cell growth and proliferation but which is mutated in about half of patients with melanoma.

Although InteRNA had expected to have a miR-3157 agonist, which uses an undisclosed delivery system, ready for the clinic by the end of 2013, Schaapveld this week that said an IND isn't expected to be ready until 2015.

The company also continues to work on a microRNA mimic that inhibits angiogenesis, which could be developed as a treatment for cancer and, potentially, eye diseases. It has already established in vivo proof of concept in a glioblastoma model, but it expects that its initial indication will be kidney cancer.

Any work in ocular disorders would only be conducted with a partner, Schaapveld said.

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