Regulus Therapeutics presents new data on oncology, immune disease and HCV therapeutic programs

Regulus Therapeutics Inc. today announced that new pre-clinical data from multiple therapeutic programs were presented at the “RNA Silencing: Mechanism, Biology and Application” Keystone Symposium held January 14 – 19, 2010 in Keystone, Colorado. Regulus and its collaborators presented data showing microRNA target regulation by anti-miRs, as well as data from therapeutic programs focused on oncology, immune disease and hepatitis C virus (HCV) infection.

“The field of microRNA discovery and therapeutic development is growing exponentially and at a tipping point”

“The field of microRNA discovery and therapeutic development is growing exponentially and at a tipping point,” said Peter S. Linsley, Ph.D., chief scientific officer of Regulus. “The company’s innovative chemistries and unique understanding behind the biology of diseases caused by microRNA dysregulation positions Regulus to lead the development of a new class of high-impact medicines based on microRNA.”

Oncology

In a poster titled “microRNA mimics as cancer therapeutics,” Regulus scientists presented in vivo data demonstrating delivery of miR mimics and microRNA target repression in an orthotopic liver tumor mouse model. Using lipid nanoparticles developed by collaborators at Alnylam Pharmaceuticals, Regulus scientists demonstrated effective delivery of a miR-34a mimic to both the normal liver cells and human hepatocellular carcinoma cells growing as tumors within the liver. Microarray profiling of the livers from mice treated with the miR-34a mimic displayed a significant down-regulation of messenger RNA targets of miR-34a. Within the tumors, Regulus scientists saw a similar down-regulation of messenger RNA targets. When Regulus scientists further analyzed the down-regulated messenger RNAs for functional significance, it was discovered that several cell cycle progression and cellular division genes were over represented. This demonstrates the potential utility of a miR-34a mimic delivered by lipid nanoparticles for the treatment of liver cancer.

anti-miR target regulation in immune cells

Regulus, in an alliance with GlaxoSmithKline, presented data from immuno-inflammatory disorders program in a poster titled “Inhibition of microRNA function in macrophages by anti-miRs”. The study provided the initial demonstration of a pharmacological effect in immune cells by specific microRNA inhibition. The study showed that systemically delivered anti-miRs distribute to immune cells and show functional target regulation, as measured by a statistically significant de-repression of seed-matched messenger RNA transcripts. Characterizing microRNA targets using this approach is uncovering the role that microRNAs play in cells of the immune system, and opening the door for microRNA therapies in immuno-inflammatory diseases.

Autoimmunity and Cancer

In a presentation titled “Myeloproliferative disease, autoimmunity and cancer in mice with targeted deletion of miR-146a gene” Regulus scientists and collaborators from the California Institute of Technology demonstrated the biological role of miR-146a by establishing loss- and gain-of-function mouse models. miR-146a knockout mice are born normal, however at the age of 6 months they start to develop a spontaneous autoimmune-like disorder leading to premature death. The study showed additional immune phenotypes of miR-146a mutant mice, including loss of immunological tolerance and macrophage hyperresponsiveness to bacterial lipopolysaccharides. The study established that this microRNA is involved in determining immune cell fate. Moreover, aging miR-146a knockout animals develop frank tumors in the secondary lymphoid organs, suggesting that miR-146a can function as a tumor suppressor in the context of the immune system. Taken together, the findings suggest that miR-146a plays a key role as a molecular brake of inflammatory response and oncogenic transformation of the immune cells.

HCV

In a poster titled “Identification of miR-122 conserved targets in liver affecting cholesterol regulation” Regulus scientists presented expression profiling data from livers of anti-miR-122-treated cynomolgus monkeys, mice, and rats. The company is developing an anti-microRNA targeting miR-122 as a novel treatment for HCV infection. Regulus and other groups have shown that miR-122 inhibition in monkeys results in a potent reduction of plasma cholesterol levels. However, the molecular mechanisms contributing to this phenotype are not known. Analysis of the messenger RNA expression profiling data revealed target regulation in all species with a common set of up-regulated, seed-matched messenger RNA targets in pathways related to cellular transport. This research suggests miR-122 in hepatocytes might indirectly activate cholesterol efflux by suppressing targets that prevent transport.