[ Back to EurekAlert! ]

PUBLIC RELEASE DATE:
16-Dec-2013

[ | E-mail ] Share Share

Contact: Jennifer Charlston
info@mirimus.com
516-882-7111
Mirimus Inc.

Elite technology for gene silencing

Mirimus develops enhanced tools for reversible gene suppression

IMAGE: The improved miR-E backbone enhances gene silencing through better processing of precursor molecules.

Click here for more information.

Cold Spring Harbor, New York, December 16, 2013 -- The team of Christof Fellmann at Mirimus Inc., Cold Spring Harbor, New York, developed new technology to address the remaining limitations of RNA interference (RNAi), a powerful method that enables functional gene annotation in normal homeostasis and disease. Through an improved molecular design, the scientists at Mirimus were able to suppress target genes with massively enhanced efficiency and accuracy. These results are reported in the recent issue of Cell Reports (http://dx.doi.org/10.1016/j.celrep.2013.11.020), published online on December 12th, and will help accelerate drug target identification and validation.

Over the last decades, RNA interference (RNAi) has become an indispensable tool for functional genetic studies by harnessing the power of a cell intrinsic mechanism enabling reversible gene silencing. Indeed, gene silencing can mirror gene loss during disease progression or mimic pharmacological target inhibition even where no such drug currently exists. In both cultured cells and animals, RNAi thus promises to rapidly advance our understanding of disease and search for new therapies.However,the design of potent and specific RNAitriggers is nottrivial, limiting the practical potential of RNAiforresearch and clinicalsettings.

Evolution driven design

Christof Fellmann, Johannes Zuber and coworkers at Cold Spring Harbor Laboratory (CSHL), USA, came up with strategies to improve RNAi technology when both were still working there. "The molecular underpinnings of efficient gene silencing are yet to be fully understood. Potent RNAi triggers are rare and have to be identified among hundreds to thousands of possibilities for each gene. To advance current techniques, we looked at the evolutionary conservation of natural RNAi triggers to build enhanced synthetic analogues", Fellmann describes their approach. He continued to evolve this concept at Mirimus, a spin-off company from CSHL, while Zuber went on to found his own lab at the IMP, Austria.

One particularly powerful RNAi method pioneered among others by Gregory Hannon and Scott Lowe at CSHL relies on embedding synthetic short hairpin RNA (shRNA) sequences into naturally occurring microRNA backbones. The resulting RNA molecules mimic natural triggers and are processed by cell intrinsic pathways. Yet, the efficiency of current reagents designed in this manner remains limited.

Fellmann and his team analyzed a specific microRNA backbone across various species, including opossum, chicken, elephant, rat and human, to identify sequence motifs that remain unchanged, indicating possible functional importance. The researchers then found that some of these sequences had been modified in one of the most commonly used synthetic RNAi backbones. By inverting these sequence regions back to their natural form and establishing a new shRNA backbone termed "miR-E", Fellmann and his team succeeded in greatly enhancing the efficiency of synthetic RNAi tools.

Realizing the full potential of RNAi

"This advancement is highly relevant to reduce to practice the great promise of RNAi for drug discovery and biomedical research", Fellmann summarizes. While current methods require laborious and lengthy testing of many predictions to find an RNAi trigger that is sufficiently potent, the optimized "miR-E" backbone drastically increases the success rate through better processing of the precursor molecules. Importantly, the new miR-E backbone can easily be integrated into current technologies to improve high-throughput RNAi screens and RNAi- based mouse models of human disease. Looking forward, Fellmann's study will open a promising avenue for generating focused and genome-wide shRNA libraries that will truly cover each gene with multiple effective shRNAs and constitute a validated and versatile tool for high-throughput functional genetics in the post-genomic era.

###

Original Publication

C. Fellmann, T. Hoffmann, V. Sridhar, B. Hopfgartner, M. Muhar, M. Roth, D.Y. Lai, I.A.M. Barbosa, J.S. Kwon, Y. Guan and J. Zuber: An optimized microRNA backbone for effective single-copy RNAi. Cell Reports 5: 1-10, December 16, 2013. http://dx.doi.org/10.1016/j.celrep.2013.11.020

About MirimusInc.

Mirimus specializes in developing tools for in vitro and in vivo research by harnessing the power of RNA interference (RNAi). Using the most advanced platforms of RNAi design for potent gene silencing and speedy mouse modeling, Mirimus generates unique tools for rapid target identification and validation. Mirimus offers customized mouse models with reversible gene silencing capabilities that will serve as superior preclinical models for target discovery and toxicology research in our combat against human health issues.

About Christof Fellmann

Christof Fellmann is the Chief Scientific Officer at Mirimus Inc., a Cold Spring Harbor, New York based Biotechnology Company developing advanced RNAi reagents for accelerated drug development. Following undergraduate training in Molecular Biology at the University of Basel, he received a Masters of Engineering degree from the Ecole Supérieure de Biotechnologie Strasbourg. In 2007 he joined the laboratory of Scott Lowe at Cold Spring Harbor Laboratory (CSHL) as a PhD student, to establish a high-throughput "Sensor" assay for the functional optimization of RNAi triggers for large-scale loss-of-function screens and RNAi-based mouse models of human disease. While obtaining his doctorate from the University of Zurich, he co-founded Mirimus Inc. in 2010 to make optimized RNAi reagents available to the broader research community.

About Johannes Zuber

Johannes Zuber is a Group Leader at the Research Institute of Molecular Pathology (IMP) in Vienna where he founded his own lab in 2011. Following his Medicine studies at the Humboldt University in Berlin and a thesis in basic cancer research, he did a four year clinical residency at the Department of Hematology and Oncology at the Charité University Hospital in Berlin, where acute leukemias became the focus of his clinical work and scientific interest. In 2005, he joined Scott Lowe's lab at Cold Spring Harbor Laboratory (CSHL) as a postdoc, where in 2009 he became the CSHL Clinical Research Fellow. His scientific work focuses on the development and use of innovative RNAi technologies and cancer mouse models to systematically explore therapeutic targets in leukemias and other cancers. His most recent contributions to the discovery of BRD4 as new therapeutic target have been selected by Nature medicine as "Notable Advance in Cancer Research 2011".

Press contact

Public Relations
Jennifer Charlston
Mirimus Inc.
1 Bungtown Road
Cold Spring Harbor, NY 11724
USA
Phone: (516) 882-7111
E-mail: info@mirimus.com



[ Back to EurekAlert! ] [ | E-mail Share Share ]

 


AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.