GSOs and TLRs make antisense work

CAMBRIDGE, Mass.—Idera Pharmaceuticals Inc., a clinical-stage biopharmaceutical company developing nucleic acid therapeutics for patients with cancer and rare diseases, has announced the publication of promising preclinical data demonstrating the application of the company’s novel gene-silencing oligonucleotides (GSOs) to inhibit microRNAs implicated in neovascularization, a process that involves the proliferation of blood vessels in tissue and is crucial for recovery following cardiovascular events.

The studies were conducted by Drs. Paul Quax and Yaël Nossent of the Department of Surgery in the Einthoven Laboratory for Experimental Vascular Medicine at Leiden University Medical Center in the Netherlands as a collaboration with Idera. The paper, titled “Inhibition of 14q32 microRNAs miR-329, miR-487b, miR-494 and miR-495 Increases Neovascularization and Blood Flow Recovery after Ischemia,” appears in the current online edition of Circulation Research.

In this paper, Quax, Nossent and colleagues report on the identification of specific microRNAs that regulate genes in the pathway involved in neovascularization, including the 14q32 microRNA gene cluster. Idera’s proprietary GSO technology enabled inhibition of these specific microRNAs in both cell-based assays and animal models. Treatment with GSOs led to microRNA-specific down-regulation and hence up-regulation of the microRNA’s target genes. In a mouse model of double femoral artery ligation, treatment with specific GSOs targeting the identified microRNAs led to improved blood flow recovery after ischemia, increased perfusion and full recovery of tissue perfusion. These data show that GSOs targeting specific microRNAs have therapeutic potential for neovascularization.

“Historically, major limitations of antisense have included immunotoxicity, challenges related to delivery to target tissue and a limited therapeutic index,” states Idera CEO Sudhir Agrawal. “Based on extensive research, we understand that the human body recognizes antisense oligonucleotides as foreign nucleic acids, which can result in an immune response via toll-like receptors (TLRs) whose job is to recognize foreign nucleic acids.

“Idera’s insight into immunotoxicity and extensive research by Idera scientists has led to an understanding that certain structural components of antisense oligonucleotides play important roles. All nucleic acids have two distinctive ends: the 5’ (5-prime) and 3’ (3-prime) ends, and we understand that the 5’ end plays a critical role in interacting with the immune system through TLRs.”

Based on this research, Idera designed the novel third-generation GSO nucleic-acid structure to have no 5’ end, with the goal of mitigating the immunotoxicity observed with earlier generation technologies. Preclinical data with GSOs have demonstrated gene-silencing activity in multiple disease models upon systemic delivery. Based on these data, Idera plans to bring the first GSO drug candidates into clinical development in the second half of 2015.

“Another approach to gene silencing, small interfering RNA (siRNA), typically requires a delivery technology, such as a lipid nanoparticle,” Agrawal notes. “However, these delivery technologies often have important limitations. For example, most siRNA drug candidates currently in development focus on targets in the liver. Antisense oligonucleotides such as GSOs do not require a delivery technology.”

“GSOs are novel structures designed to overcome the limitations of the currently practiced antisense technology, with a goal of providing an increased therapeutic index,” said Dr. Walter Strapps, executive director of RNA Therapeutics for Idera. “We are very pleased with the results of our collaboration with Drs. Quax and Nossent, and that we were able to identify GSOs to inhibit specific microRNAs following systemic delivery. We are very encouraged with the emerging data, both internally and externally, supporting the potential of GSOs as third-generation antisense therapeutic agents able to overcome the hurdles of current technologies. We are continuing to advance our GSO platform and remain on track to initiate proof-of-concept studies with GSO drug candidates in two disease indications as early as the second half of next year.”

“Currently, we are conducting a prioritization analysis of disease indications,” notes Agrawal. “Considerations include evidence that a disease is caused by a specific protein, the unmet medical need for new treatments, clear criteria to identify a target patient population, a biomarker for early assessment of clinical proof of concept and an opportunity for a potentially rapid development path to approval.”

Idera’s gene silencing oligonucleotides (GSOs) are single-stranded RNA or DNA constructs with two exposed 3’ ends that are complementary to targeted mRNA sequences of therapeutic interest. In preclinical studies, GSOs have inhibited gene expression in vivo without requiring a delivery enhancement technology. GSOs are covered by issued (#8,431,544) and pending patents around the world.

Idera Pharmaceuticals is a clinical-stage biopharmaceutical company that has been active in antisense technology development since 1978. In the 1990s, 40 compounds went into preclinical development but inactivation was observed. Since then, the company has progressed to its third-generation development, which is five times more active than previous versions.