Regulus Therapeutics, GSK announce new collaboration on microRNA therapeutics targeting microRNA-122

Regulus Therapeutics, GSK announce new collaboration on microRNA therapeutics targeting microRNA-122


25. February 2010

Regulus Therapeutics Inc. today announced the establishment of a new collaboration with GlaxoSmithKline (GSK) to develop and commercialize microRNA therapeutics targetingmicroRNA-122 in all fields with Hepatitis C Viral infection (HCV) as the lead indication. Under the terms of the new collaboration, Regulus will receive additional upfront and early-stage milestone payments with the potential to earn more than $150 million in miR-122-related combined payments, and tiered royalties up to double digits on worldwide sales of products.

“This new collaboration with GSK demonstrates the clear scientific leadership that Regulus has established in advancing a whole new frontier of pharmaceutical research. microRNA therapeutics target the pathways of human diseases, not just single disease targets, and hold considerable promise as novel therapies across a broad range of unmet medical needs,” said Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus. “It also further validates Regulus’ microRNA product platform built on fundamental biology of human diseases and intellectual property, and also extends the therapeutic scope of our existing collaboration formed with GSK in 2008. Furthermore, the funding from this alliance supports Regulus’ efforts in advancing high impact, novel medicines based on microRNA biology to patients.”

The collaboration provides GSK with access to Regulus’ comprehensive and robust intellectual property estate. Regulus exclusively controls patent rights covering miR-122 antagonists and their use as HCV therapeutics in the United States, Europe, and Japan, including but not limited to the patent families which encompass: the ‘Sarnow’ patent pertaining to the method of use of anti-miR-122 to inhibit HCV replication, the ‘Esau’ patent application claiming the use of anti-miRs targeting miR-122 as inhibitory agents, the ‘Tuschl III’ patent claiming composition of matter for miR-122 and complementary oligonucleotides, and the ‘Manoharan’ patent claiming antagomirs, including antagomirs targeting miR-122.

miR-122 is a liver-expressed microRNA that has been shown to be a critical endogenous “host factor” for the replication of HCV, and anti-miRs targeting miR-122 have been shown to block HCV infection (Jopling et al. (2005) Science 309, 1577-81). In earlier work, scientists at Alnylam and Isis demonstrated the ability to antagonize miR-122 in vivo using chemically modified single-stranded anti-miR oligonucleotides. Further, work by Regulus scientists and collaborators showed that inhibiting miR-122 results in significant inhibition of HCV replication in human liver cells, suggesting that antagonism of miR-122 may comprise a novel “host factor” therapeutic strategy. Regulus scientists have shown in multiple preclinical studies a robust HCV antiviral effect following inhibition of miR-122. Regulus plans to identify a clinical development candidate in the second half of 2010 and file an investigational new drug (IND) application in 2011.
SOURCE Regulus Therapeutics Inc.

What is MicroRNA?


MicroRNAs are a class of post-transcriptional regulators. They are short ~22 nucleotide RNA sequences that bind to complementary sequences in the 3’ UTR of multiple target mRNAs, usually resulting in their silencing. MicroRNAs target ~60% of all genes, are abundantly present in all human cells and are able to repress hundreds of targets each. These features, coupled with their conservation in organisms ranging from the unicellular algae chlamydomonas reinhardtii to mitochondria, suggest they are a vital part of genetic regulation with ancient origins.


MicroRNAs were first discovered in 1993 by Victor Ambros, Rosalind Lee and Rhonda Feinbaum during a study into development in the nematode ''C. elegans'' regarding the gene lin-14. This screen led to the discovery that the lin-14 was able to be regulated by a short RNA product from lin-4, a gene that transcribed a 61 nucleotide precursor that matured to a 22 nucleotide mature RNA which contained sequences partially complementary to multiple sequences in the 3’ UTR of the lin-14 mRNA. This complementarity was sufficient and necessary to inhibit the translation of lin-14 mRNA. Retrospectively, this was the first microRNA to be identified, though at the time Ambros et al speculated it to be a nematode idiosyncrasy.


It was only in 2000 when let-7 was discovered to repress lin-41, lin-14, lin28, lin42 and daf12 mRNA during transition in developmental stages in c elegans and that this function was phylogenetically conserved in species beyond nematodes, that it became apparent the short non-coding RNA identified in 1993 was part of a wider phenomenon.


Since then over 4000 miRNAs have been discovered in all studied eukaryotes including mammals, fungi and plants. More than 700 miRNAs have so far been identified in humans and over 800 more are predicted to exist.


Comparing miRNAs between species can even be used to delineate molecular evolutionary history on the basis that the complexity of an organisms phenotype may reflect that of the microRNA found in the genotype.


When the human genome project mapped its first chromosome in 1999, it was predicted it would contain over 100,000 protein coding genes. However, only around 20,000 were eventually identified (International Human Genome Sequencing Consortium, 2004) and for a long time much of the non-protein-coding DNA was considered "junk", though conventional wisdom holds that much if not most of the genome is functional. Since then, the advent of sophisticated bioinformatics approaches combined with genome tiling studies examining the transcriptome, systematic sequencing of full length cDNA libraries and experimental validation (including the creation of miRNA derived antisense oligonucleotides called antagomirs) have revealed that many transcripts are for non protein coding RNA of which many new classes have been deducted such as snoRNA and miRNA. Unfortunately, the rate of validation of microRNA targets is substantially more time consuming than that of predicting sequences and targets.


Due to their abundant presence and far-reaching potential, miRNAs have all sorts of functions in physiology, from cell differentiation, proliferation, apoptosis to the endocrine system, haematopoiesis, fat metabolism, limb morphogenesis. They display different expression profiles from tissue to tissue, reflecting the diversity in cellular phenotypes and as such suggest a role in tissue differentiation and maintenance.