April 23rd, 2015- Webinar:  RNAi and CRISPR/Cas9-Based In Vivo Models for Drug Discovery-

http://www.criver.com/customer-service/education-training/educations/2015/04/rnai-and-crispr-cas9-based-in-vivo-models-for-drug

Genetically engineered mouse models (GEMMs) are a powerful platform for enabling the study of disease initiation and maintenance, the microenvironment and the responsiveness of disease to known or novel therapeutics. However, the long lead times and high costs required to develop, intercross and maintain models with various gene combinations have limited their practical utility in the drug discovery process. RNA interference (RNAi) is a rapid, cost-effective alternative to gene deletion that can be exploited experimentally to reversibly silence nearly any gene target not only in vitro, but also in live mice. Mirimus has developed a fast, scalable pipeline for the production of short hairpin RNA (shRNA) transgenic mice with potent reversible gene-silencing potential.

With the advent of new genome editing techniques such as CRISPR/Cas9, it has become possible to introduce additional sensitizing lesions to induce disease pathogenesis. In synergy with RNAi technology, complex multi-allelic ESC-based GEMMs can be generated without extensive intercrossing, resulting in the ability to model disease pathogenesis and mimic drug therapy in mice and enabling unprecedented capabilities for performing preclinical studies in vivo.

This webinar demonstrates how Mirimus’ RNAi technology, in combination with CRISPR/Cas9 genome editing, facilitates recapitulation of knockout mice phenotypes and further exploration of potential therapeutic approaches within the same model. This robust system provides a cost-effective, scalable platform for the production of mice with enormous predictive power that will shape development of better-tolerated therapies.

Presenter

  • Prem K. Premsrirut, PhD, Co-founder, President and CEO, Mirimus, Inc.

April 20th, 2015- Dr. Prem K. Premsrirut presents RNAi and CRISPR/Cas9 based in vivo models for drug discovery at the AACR Annual Meeting

Genetically engineered mouse models (GEMMs) are a powerful platform that enable the study of disease initiation and maintenance, the microenvironment and the responsiveness of disease to known or novel therapeutics; however, the long lead times and high costs required to develop, intercross and maintain models with various disease predisposing gene combinations have limited their practical utility in the drug discovery process. RNA interference (RNAi), a mechanism that controls gene expression, is a rapid and cost-effective alternative to gene deletion that can be exploited experimentally to reversibly silence nearly any gene target not only in vitro but also in live mice. By using our “Sensor assay” to biologically identify short hairpin RNAs (shRNAs) that induce potent gene suppression in combination with a new miRNA scaffold, miR-E, we have engineered a reliable system for in vivo gene suppression. Furthermore, by utilizing tetracycline-regulated miR-E based shRNAs with high efficiency ES cell targeting, we have developed a fast, scalable pipeline for the production of shRNA transgenic mice with reversible gene silencing. Recently, with the advent of new genome editing techniques, such as CRISPR/Cas9 technology, we are able to introduce additional sensitizing lesions to induce disease pathogenesis.  In synergy with RNAi technology, complex multi-allelic ESC based GEMMs can be generated without extensive intercrossing. Using this combination of CRISPR/Cas9 and RNAi technologies, we are able to not only model disease pathogenesis, but also mimic drug therapy in mice, giving us unprecedented capabilities to perform preclinical studies in vivo. Here, we demonstrate that RNAi in combination with CRISPR/Cas9 genome editing enables us to recapitulate the phenotypes of knockout mice and further explore potential therapeutic approaches within the same model. Using our robust system, we have created a a cost-effective and scalable platform for the production of complex GEMMs with RNAi silencing of nearly any gene - mice with enormous predictive power that will shape our development of better tolerated therapies.

 news

Feb. 19th, 2015- (Press Release): Mirimus Enters Into a Strategic Co-Marketing Alliance with Charles River Laboratories to Provide Superior Mouse Models:

 Mirimus Inc., a leader in RNA interference technology specializing in the creation of customized genetically engineered mouse models, today announced the formation of a cooperation agreement with Charles River Laboratories that seeks to speed the availability of superior genetically engineered mouse models for the pharmaceutical, biotechnology and academic research communities.

Charles River is a leading provider of drug discovery and early-stage development research products and services to global biopharmaceutical and biotechnology companies, government agencies, and leading academic institutions.

In this strategic alliance, Charles River will augment its service offerings to the scientific research community through co-marketing Mirimus’ in vitro and in vivo RNA interference products and services offerings. Mirimus, a company with roots in Cold Spring Harbor Laboratory’s ground-breaking RNAi research, has established itself as a leader in the rapid generation of complex genetically engineered mouse models.

“Unlike other RNAi reagent companies, we perform in depth screening of tens of thousands of shRNAs to identify the sequences that will achieve the most potent gene silencing knockdown.  Our goal is to significantly advance the drug discovery process. Together, Charles River can offer a full service portfolio that includes the genetic manipulation of research models designed to make them more predictive of the human condition,” said PremPremsrirut, PhD, Mirimus’ President and CEO.

Iva Morse, Charles River’s Corporate Vice President for North American Research Model Services, commented, “Our customers are using increasingly complex genetically altered models for greater confidence in the translational potential of their findings, but the time and level of expertise required to create and breed those models in-house can be a real barrier for many labs.  Through this partnership, Mirimus’ generates ES cells with shRNAs targeting the gene of interest, and our model creation supportlab performs the microinjection procedures that produce live mice from these cells.  This enables our customers to experience the benefits of complex genetic alterations on a much shorter time-scale.”

“We are delighted to offer the scientific research community our products and services through Charles River’s global reach,” said Louis Schure, Mirimus’ Director of Business Development.   “We are proud to add our RNAi tools to the quality and robust offerings that Charles River provides to the biotech, pharmaceutical and academic research communities.  All concerned will benefit from this valued collaboration.”

August 4th, 2014 National Institute of Health awards Mirimus with SBIR Grant-RNAi mouse models of FAP (Familial adenomatous polyposis)

  • AIM1: Generate a model of familial adenomatous polyposis using CRISPRs to mutate APC.
  • AIM2: Allow polyps to form and treat mice by Cox-2 inhibition using RNAi to mimic current therapy.

shRNA transgenic mice are generated where shRNAs against Ptgs2 are under control of a tet-responsive element and if these mice are intercrossed to mice with ubiquitous expression of the reverse tet-transactivator protein (rtTA), shRNA expression can be induced in all tissues in vivo via administration of doxycycline.

Since Apc will have been altered through CRISPR/Cas9 system, Familial Adenomatous Polyposis (FAP) will occur within these mice. We will allow for intestinal polyps to form and then, administer doxycyline (Dox) to the mice to induce shRNA-Ptgs2 expression to observe the effects of this therapeutic target on the polyps.

2014_news

December 16, 2013 (Press Release): An Optimized microRNA Backbone for Effective Single-Copy RNAi:Mirimus develops enhanced tools for reversible gene suppression. The team of ChristofFellmannat 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, published online on December 12th, and will help accelerate drug target identification and validation.

March 29, 2012 (Nature): Product focus on RNAi Research: Custom RNAi mouse models developed by Mirimus Inc., which are capable of reversible gene silencing gets featured on the March 29th issue of Nature.

May 20, 2011 (Long Island Business News): Medical research gets support from local scientists: Researchers at Cold Spring Harbor, PremPremsrirut and ChristofFellmann, have developed a method of gene knockdown in mouse models that has the capacity to revolutionize disease research.  Premsrirut and Fellmann’s company, Mirimus, Inc., develops knockdown mice that sell for a fraction of the cost of conditional knockout mouse models.

May 17, 2011 (Nature Review Genetics) Mastering RNAi in mice: Dr. Premsrirut and colleagues report new avenues for using mice to model disease. Their method gives researchers the ability to do more complex studies while avoiding time-consuming processes previously required.

May 3, 2011 (Newsday) $2M in venture capital for LI company: Mirimus Inc., the biotech company started by Drs. PremPremsrirut, ChristofFellmann, Scott Lowe, Gregory Hannon and Stephen Elledge received $2 million in venture capital funding to pursue genetic research that will enable pharmaceutical companies better information regarding disease therapies.

May 2011 (BioTechniques) The Strong, Silent Type: Until now, scientists have been unable to harness the silencing capacity of small-hairpin RNA due to their inability to effectively predict sequencing codes.  An innovative shRNA library, developed by Fellman and colleagues, facilitates a sensored approach to detecting potent shRNA silencers.

May 2011 (Molecular Therapy) Sensor and Sensitivity: A Screen for Elite shRNAs: RNAi technology can be successfully applied to drug development and the study of gene function once a potent, non-toxic trigger for RNAi has been developed.  Fellman and his colleagues are closing in on the potential of RNAi with the generation of anshRNA library that enables the identification of optimal shRNA and target site combinations.  Discerning these ideal matches allows researchers to pinpoint the most potent shRNAs for therapeutic applications.

April 28, 2011 (Nature Methods) Speeding up RNAi: Researchers at Cold Spring Harbor have collaborated to investigate the problems facing shRNA transgenic mouse development, particularly, the high variability of successful gene suppression and the inefficient process of mouse development. Using innovative methods, they generated eight transgenic RNAi mouse lines that demonstrated potent and reversible gene silencing in vivo.

April 1, 2011 (BioWorld Today): Method advancements bring shRNA potential up evolution’s ladder: Dr. Scott Lowe and his team at Cold Spring Harbor have discovered a method to harness the valuable power of shRNAs in living mammals.  In addition to streamlining the process of gene silencing in vivo, the team’s approach allows efficient study of complex diseases, as well as reversible gene knockdown.