Nobel Laureate Thomas R. Cech, Ph.D. among prestigious Board Members

BOULDER, Colo., January 11, 2010 – miRagen Therapeutics, Inc., a biopharmaceutical company focused on improving patients’ lives by developing innovative microRNA (miRNA)-based therapeutics for cardiovascular and muscle disease, announced today the formation of the company’s world renowned Scientific Advisory Board (SAB). The SAB was established to provide miRagen with valuable guidance in developing an extensive pipeline of microRNA-based drugs and is comprised of leaders who are internationally recognized experts in their respective fields. The SAB is lead by miRagen’s Chief Scientific Advisor and Co-Founder, Eric N. Olson, Ph.D. The first appointed members include Nobel Prize in Chemistry winner Thomas R. Cech, Ph.D., Distinguished Professor at the University of Colorado-Boulder, Investigator of the Howard Hughes Medical Institute and Director of the Colorado Initiative in Molecular Biotechnology.

“We are delighted to have assembled such a distinguished team to help advise the company on its research and development pipeline,” said William S. Marshall, Ph.D., President and Chief Executive Officer of miRagen Therapeutics, Inc. “To have an SAB of this caliber intimately involved in miRagen’s drug discovery programs will be vital not only to the company’s success but also, and more importantly, to the millions of patients suffering from cardiovascular and muscle disease.”

“The science underlying miRagen’s therapies is highly innovative and represents a significant advancement in RNA research,” said Dr. Cech. “I look forward to working closely with my esteemed colleagues and miRagen’s team to translate breakthrough discoveries into therapies for patients who suffer from these debilitating diseases.”

“To collaborate with this team of thought leaders is an honor,” added Dr. Olson. “Each member brings unparalleled knowledge and experience to the table. Together, I believe we have an opportunity to create some truly unique RNA-based therapeutics. The SAB will be instrumental to the success of miRagen’s research and development pipeline.”

The members of miRagen’s Scientific Advisory Board are:

• Eric N. Olson, Ph.D., Chief Scientific Advisor and Co-Founder of miRagen Therapeutics; Professor and Chairman of Molecular Biology, Robert A. Welch Distinguished Chair in Science, Annie and Willie Nelson Professor in Stem Cell Research and Pogue Distinguished Chair in Research on Cardiac Birth Defects at the University of Texas Southwestern Medical Center

  Dr. Olson has received numerous awards for his pioneering research on the mechanisms of gene regulation in muscle development with particular emphasis on congenital and acquired cardiovascular disease and the subsequent creation of new therapeutic approaches for their treatment.

• Victor R. Ambros, Ph.D., Silverman Professor of Natural Sciences, Program in Molecular Medicine, University of Massachusetts Medical School

  Dr. Ambros and his co-workers were the first to discover microRNAs. Their seminal work has spawned an entirely new field of scientific investigation that promises to alter our understanding of gene regulatory pathways.

• Michael R. Bristow, M.D., Ph.D., Co-Founder of miRagen Therapeutics; Professor of Medicine and Co‐Director of the University of Colorado Cardiovascular Institute at UC Denver School of Medicine

  Dr. Bristow’s research has resulted in significant breakthroughs in the treatment of cardiovascular disease. His findings were instrumental in the development of ß-blocking agents as a therapeutic strategy for the treatment of chronic heart failure.

• Thomas R. Cech, Ph.D., Distinguished Professor at the University of Colorado-Boulder, Director of the Colorado Initiative in Molecular Biotechnology and Investigator of the Howard Hughes Medical Institute

  Dr. Cech most notably received the Nobel Prize in Chemistry for his groundbreaking work on the “catalytic properties of RNA.” His revolutionary findings demonstrated that RNA was not restricted to being a passive carrier of genetic information but could play an active role in cellular metabolism.

• Stephanie Dimmeler, Ph.D., Professor of Experimental Medicine and Director of the Institute of Cardiovascular Regeneration, Center for Molecular Medicine at the University of Frankfurt (Germany)

  Dr. Dimmeler’s award-winning research predominantly is focused on endothelial cell biology, including signal transduction, apoptosis and renewal by circulating endothelial progenitor cells in health and disease. Her scientific discoveries have culminated in current clinical trials of human progenitor cells for cardiovascular repair.

• Douglas L. Mann, M.D., Lewin Professor and Chief of the Cardiovascular Division at Washington University School of Medicine; Cardiologist-in-Chief at Barnes-Jewish Hospital

  Dr. Mann is an internationally renowned basic and clinical scientist whose work has garnered numerous awards. His research has centered on the basic cellular and molecular mechanisms that lead to cardiac decompensation, including the role that inflammatory mediators play in regulating cardiac structure and function.

• Jeffery D. Molkentin, Ph.D., Professor at the Cincinnati Children’s Hospital Medical Center of the University of Cincinnati and Investigator of the Howard Hughes Medical Institute

  Dr. Molkentin’s cutting-edge research program focuses on the identification of genes and signaling pathways involved in cardiac hypertrophy, contractility, cell death and heart failure. His work has been recognized with multiple awards.

About microRNAs: MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are responsible for many diseases. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets of unprecedented power.

About miRagen Therapeutics: Cardiovascular disease is the leading cause of death globally. Astonishingly, in the United States, every 37 seconds a person dies from cardiovascular disease. For survivors, life changes dramatically after an adverse heart event. Because of the significant toll that cardiovascular and muscle disease takes on patients, miRagen Therapeutics was founded in 2007 to develop innovative microRNA-based therapeutics for cardiovascular and muscle disease. Only recently discovered, miRNAs are short, single-stranded RNA molecules encoded in the genome that regulate gene expression and play a vital role in influencing cardiovascular and muscle disease. Principally funded through venture capital investments, miRagen combines world recognized leadership in cardiovascular medicine with unparalleled in-house expertise in microRNA biology and chemistry. For more information, please visit www.miragentherapeutics.com

Science, 2009.

Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, Bassel-Duby R, Sanes JR, Olson EN.

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons, denervation of target muscles, muscle atrophy, and paralysis. Understanding ALS pathogenesis may require a fuller understanding of the bidirectional signaling between motor neurons and skeletal muscle fibers at neuromuscular synapses. Here, we show that a key regulator of this signaling is miR-206, a skeletal muscle-specific microRNA that is dramatically induced in a mouse model of ALS. Mice that are genetically deficient in miR-206 form normal neuromuscular synapses during development, but deficiency of miR-206 in the ALS mouse model accelerates disease progression. miR-206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, which probably accounts for its salutary effects in ALS. miR-206 mediates these effects at least in part through histone deacetylase 4 and fibroblast growth factor signaling pathways. Thus, miR-206 slows ALS progression by sensing motor neuron injury and promoting the compensatory regeneration of neuromuscular synapses.
PMID: 20007902 [PubMed - in process]

“http://www.ncbi.nlm.nih.gov/pubmed/20007902?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1″>http://www.ncbi.nlm.nih.gov/pubmed/20007902?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1

Dev Cell., 2009.

van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ Jr, Olson EN.

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.

Myosin is the primary regulator of muscle strength and contractility. Here we show that three myosin genes, Myh6, Myh7, and Myh7b, encode related intronic microRNAs (miRNAs), which, in turn, control muscle myosin content, myofiber identity, and muscle performance. Within the adult heart, the Myh6 gene, encoding a fast myosin, coexpresses miR-208a, which regulates the expression of two slow myosins and their intronic miRNAs, Myh7/miR-208b and Myh7b/miR-499, respectively. miR-208b and miR-499 play redundant roles in the specification of muscle fiber identity by activating slow and repressing fast myofiber gene programs. The actions of these miRNAs are mediated in part by a collection of transcriptional repressors of slow myofiber genes. These findings reveal that myosin genes not only encode the major contractile proteins of muscle, but act more broadly to influence muscle function by encoding a network of intronic miRNAs that control muscle gene expression and performance.
PMID: 19922871 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/19922871?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=4
 

Genes Dev. 2009.

Xin M, Small EM, Sutherland LB, Qi X, McAnally J, Plato CF, Richardson JA, Bassel-Duby R, Olson EN.

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Vascular injury triggers dedifferentiation and cytoskeletal remodeling of smooth muscle cells (SMCs), culminating in vessel occlusion. Serum response factor (SRF) and its coactivator, myocardin, play a central role in the control of smooth muscle phenotypes by regulating the expression of cytoskeletal genes. We show that SRF and myocardin regulate a cardiovascular-specific microRNA (miRNA) cluster encoding miR-143 and miR-145. To assess the functions of these miRNAs in vivo, we systematically deleted them singly and in combination in mice. Mice lacking both miR-143 and miR-145 are viable and do not display overt abnormalities in smooth muscle differentiation, although they show a significant reduction in blood pressure due to reduced vascular tone. Remarkably, however, neointima formation in response to vascular injury is profoundly impeded in mice lacking these miRNAs, due to disarray of actin stress fibers and diminished migratory activity of SMCs. These abnormalities reflect the regulation of a cadre of modulators of SRF activity and actin dynamics by miR-143 and miR-145. Thus, miR-143 and miR-145 act as integral components of the regulatory network whereby SRF controls cytoskeletal remodeling and phenotypic switching of SMCs during vascular disease.
PMID: 19720868 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/19720868?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=9

miRagen Announces Discovery of Key microRNA Implicated in Lou Gehrig’s Disease

Findings Could Lead to Novel Therapeutic Intervention Strategies for Neuromuscular Disorders

Data published in latest issue of Science

BOULDER, Colo., December 10, 2009 – miRagen Therapeutics, Inc., a biopharmaceutical company focused on improving patients’ lives by developing innovative microRNA-based therapeutics for cardiovascular and muscle disease, today announced the publication of data demonstrating that microRNA-206 (miR-206) plays a crucial role in the progression of amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and in neuromuscular synaptic regeneration in mice. The findings, published in the December 11 issue of the journal Science, reveal miR-206 as a potential target for the development of therapeutic agents for the treatment of neuromuscular disease. The study was conducted by researchers led by Eric N. Olson, Ph.D., at the University of Texas Southwestern Medical Center. miRagen is the exclusive licensee of intellectual property (IP) rights related to this discovery, which are part of the Company’s extensive estate of enabled microRNA IP.

“This is a breakthrough with significant implications for human health,” said William S. Marshall, Ph.D., President and CEO of miRagen Therapeutics, Inc. “Currently there are no therapies available to ALS patients that will reverse or delay the onset of muscle atrophy associated with this debilitating disease. Uncovering the essential role of miR-206 in neuromuscular maintenance brings us one step closer to the day when physicians will be able to offer hope to those suffering from ALS and other neuromuscular diseases.”

“We are, quite frankly, excited by these findings,” said Dr. Olson, Chairman and Professor of Molecular Biology at the University of Texas Southwestern Medical Center and miRagen’s Chief Scientific Advisor. “One of the hallmarks of ALS and other similarly degenerative muscle diseases is the inability of the neuromuscular synapse to transmit the impulse that leads to muscle contraction. Our data show that miR-206 plays a central regulatory role in this process. We view this as an extremely promising target for therapeutic intervention.”

About microRNAs

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are responsible for many diseases. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets of unprecedented power.

About miRagen Therapeutics

Cardiovascular disease is the leading cause of death globally. Astonishingly, in the United States, every 37 seconds a person dies from cardiovascular disease. For survivors, life changes dramatically after an adverse heart event. Because of the significant toll that cardiovascular and muscle disease takes on patients, miRagen Therapeutics, Inc., was founded in 2007 to develop innovative microRNA-based therapeutics for cardiovascular and muscle disease. Only recently discovered, microRNAs are short, single-stranded RNA molecules encoded in the genome that regulate gene expression and play a vital role in influencing cardiovascular and muscle disease. Principally funded through venture capital investments, miRagen combines world recognized leadership in cardiovascular medicine with unprecedented in-house expertise in microRNA biology and chemistry. For more information, please visit www.miragentherapeutics.com

Award Highlights the Company’s Early Achievements

BOULDER, Colo., November 19, 2009 – miRagen Therapeutics, Inc., a biopharmaceutical company focused on improving patients’ lives by developing innovative microRNA-based therapeutics for cardiovascular and muscle disease, announced today it had received the Colorado BioScience Association’s 2009 Rising Star of the Year Award. The award, which recognizes a Colorado life sciences company that has demonstrated it is “one to watch,” was presented at the Association’s Annual Awards Dinner on November 10 in Denver.

“We are honored to have been recognized by the Colorado BioScience Association with this award,” said William S. Marshall, Ph.D., President and CEO of miRagen Therapeutics, Inc. “It’s particularly gratifying to have a group of industry peers acknowledge our company’s diligent efforts to produce life changing medicines.”

About microRNAs

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are responsible for many diseases. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets of unprecedented power.

About miRagen Therapeutics

Cardiovascular disease is the leading cause of death globally. Astonishingly, in the United States, every 37 seconds a person dies from cardiovascular disease. For survivors, life changes dramatically after an adverse heart event. Because of the significant toll that cardiovascular and muscle disease takes on patients, miRagen Therapeutics, Inc. was founded in 2007 to develop innovative microRNA (miRNA)-based therapeutics for cardiovascular and muscle disease. Only recently discovered, miRNAs are short, single-stranded RNA molecules encoded in the genome that regulate gene expression and play a vital role in influencing the pathways responsible for cardiovascular and muscle disease. Principally funded through venture capital investments, miRagen combines world recognized leadership in cardiovascular medicine with unprecedented in-house expertise in miRNA biology and chemistry. For more information, please visit: www.miragentherapeutics.com

BOULDER, Colo., October 15, 2009 – miRagen Therapeutics, Inc., a biopharmaceutical company focused on improving patients’ lives by developing innovative microRNA-based therapeutics for cardiovascular and muscle disease, today announced that Thomas E. Hughes, Ph.D., was elected to its Board of Directors on September 24, 2009. Dr. Hughes brings more than 20 years of drug discovery and development expertise to the company.

“For some time we had been searching for an independent Director and feel very fortunate to have attracted someone of Tom’s caliber,” said William S. Marshall, Ph.D., President and CEO of miRagen Therapeutics. “He possesses a wealth of knowledge in the development of medicines, particularly targeted to cardiovascular and metabolic disease. We are excited to be working with him and look forward to his contributions.”

“Tom adds significantly to our Board composition,” said Bruce L. Booth, D.Phil., Chairman of miRagen’s Board of Directors and Partner, Atlas Venture. “He’s a proven leader, and we anticipate his input will be extremely helpful in advancing the company.”

“microRNA-based therapeutics is an exciting field, and miRagen’s programs promise to bring meaningful relief to those suffering the effects of cardiovascular and muscle disease,” said Tom Hughes. “The company’s progress to date is impressive, and I’m thrilled to be a part of such important work.”

Throughout his career, Dr. Hughes has been involved in numerous drug discovery efforts in the metabolic and cardiovascular disease area, focusing on glucose homeostasis, lipid metabolism and the control of blood clotting. He joined Zafgen in 2008 as Chief Executive Officer following a 20-year tenure at Novartis, where he most recently served as Vice President and Global Head of the Cardiovascular and Metabolism Disease area.

In 2007, R&D Directions magazine named Dr. Hughes one of the 20 Most Notable People in R&D, and in 2009 he was named as one of the 100 most inspiring people in Pharmaceutical R&D by PharmaVoice magazine. Dr. Hughes earned his Ph.D. in Nutrition from Tufts University and received an M.S. in zoology from Virginia Polytechnic Institute & State University. He graduated with a B.A. in biology from Franklin and Marshall College.

About microRNAs

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are responsible for many diseases. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets of unprecedented power.

About miRagen Therapeutics

Cardiovascular disease is the leading cause of death globally. Astonishingly, in the United States, every 37 seconds a person dies from cardiovascular disease. For survivors, life changes dramatically after an adverse heart event. Because of the significant toll that cardiovascular and muscle disease takes on patients, miRagen Therapeutics, Inc., was founded in 2007 to develop innovative microRNA-based therapeutics for cardiovascular and muscle disease. Only recently discovered, microRNAs are short, single-stranded RNA molecules encoded in the genome that regulate gene expression and play a vital role in influencing cardiovascular and muscle disease. Principally funded through venture capital investments, miRagen combines world recognized leadership in cardiovascular medicine with unprecedented in-house expertise in microRNA biology and chemistry. For more information, please visit www.miragentherapeutics.com

BOULDER, Colo. & CAMBRIDGE, Mass., July 23, 2009 – miRagen Therapeutics, Inc., a biopharmaceutical company focused on developing innovative microRNA-based therapeutics for cardiovascular and muscle disease, and Archemix Corp., a biotechnology company focused on developing aptamer therapeutics, announced today that the two companies will collaborate on conjugated aptamer-microRNA therapies capable of intracellular delivery and subsequent microRNA targeting. miRagen and Archemix will jointly pursue research and development efforts and both companies will contribute resources under the agreement, which includes an exclusive option for miRagen to negotiate for exclusive rights to further develop and commercialize certain aptamer-microRNA therapeutics generated during the collaboration. Additional terms of the agreement were not disclosed.

“Targeting and delivery of nucleic acid drugs are challenges in the field, and aptamers are an exciting class of agents that can potentially address these issues,” said William S. Marshall, Ph.D., President and Chief Executive Officer of miRagen Therapeutics, Inc. “We are committed to building strategic relationships with innovative companies like Archemix in our efforts to translate microRNA discoveries into breakthrough therapies.”

“Combining aptamers and microRNA therapeutics has the potential to solve the intracellular delivery challenge for certain RNA-based therapeutic approaches,” said Kenneth M. Bate, President and Chief Executive Officer of Archemix. “This deal is another example of leveraging our proprietary aptamer technology to create value outside of our core expertise. Intracellular delivery has been a key challenge for RNA modalities and we are excited about the potential of bringing together our expertise in aptamers with miRagen’s expertise in microRNA therapeutics to overcome this limitation and open further potential for RNA-based therapeutics.”

About microRNAs

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are responsible for many diseases. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets of unprecedented power.

About Aptamers

Aptamers are synthetically-derived oligonucleotides, or short nucleic acid sequences, that bind to protein targets with high affinity and specificity and can be designed to have a specified duration of action. Aptamers represent an emerging class of potential therapeutic agents that Archemix believes may have broad application to treat a variety of human diseases.

About miRagen Therapeutics

Cardiovascular disease is the leading cause of death globally. Astonishingly, in the United States, every 37 seconds a person dies from cardiovascular disease. For survivors, life changes dramatically after an adverse heart event. Because of the significant toll that cardiovascular and muscle disease takes on patients, miRagen Therapeutics, Inc. was founded in 2007 to develop innovative microRNA-based therapeutics for cardiovascular and muscle disease. Only recently discovered, microRNAs are short, single-stranded RNA molecules encoded in the genome that regulate gene expression and play a vital role in influencing cardiovascular and muscle disease. Principally funded through venture capital investments, miRagen combines world recognized leadership in cardiovascular medicine with unprecedented in-house expertise in microRNA biology and chemistry. For more information, please visit www.miragentherapeutics.com

About Archemix

Archemix is a biotechnology company focused on discovering, developing and commercializing aptamer therapeutics. Using Archemix’s processes for discovering aptamers, which are protected by its broad patent portfolio, Archemix is developing aptamer product candidates for rare hematological diseases. In addition, Archemix has licensed its intellectual property to third parties to develop their own aptamer product candidates in other areas. Currently, Archemix’s licensees are evaluating five different aptamer product candidates in human clinical trials; two in Phase 2 and three in Phase 1. Archemix has additional partnerships with several pharmaceutical and biotechnology companies, including GlaxoSmithKline, Merck Serono, Pfizer, Takeda, Eli Lilly and Isis Pharmaceuticals. For more information, please visit www.archemix.com.

Media Contacts:
For miRagen:
Tammy Egan
303-531-5952 ext 107

For Archemix:
Kathryn Morris
Yates Public Relations
845-635-9828

Current Opinion in Genetics & Development, 2009.

Wang S, Olson EN.

Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390, USA.

The formation of new blood vessels through the process of angiogenesis is critical in vascular development and homeostasis. Aberrant angiogenesis leads to a variety of diseases, such as ischemia and cancer. Recent studies have revealed important roles for miRNAs in regulating endothelial cell (EC) function, especially angiogenesis. Mice with EC-specific deletion of Dicer, a key enzyme for generating miRNAs, display defective postnatal angiogenesis. Specific miRNAs (angiomiRs) have recently been shown to regulate angiogenesis in vivo. miRNA-126, an EC-restricted miRNA, regulates vascular integrity and developmental angiogenesis. miR-378, miR-296, and the miR-17-92 cluster contribute to tumor angiogenesis. Manipulating angiomiRs in the settings of pathological vascularization represents a new therapeutic approach.

PMID: 19446450 [PubMed - in process]

http://www.sciencedirect.com/

Current Opinion in Cell Biology, 2009.

Williams AH, Liu N, van Rooij E, Olson EN.

Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390, USA.

Cardiac and skeletal muscle development are controlled by evolutionarily conserved networks of transcription factors that coordinate the expression of genes involved in muscle growth, morphogenesis, differentiation, and contractility. In addition to regulating the expression of protein-coding genes, recent studies have revealed that myogenic transcription factors control the expression of a collection of microRNAs, which act through multiple mechanisms to modulate muscle development and function. In some cases, microRNAs fine-tune the expression of target mRNAs, whereas in other cases they function as ‘on-off’ switches. MicroRNA control of gene expression appears to be especially important during cardiovascular and skeletal muscle diseases, in which microRNAs participate in stress-dependent remodeling of striated muscle tissues. We review findings that point to the importance of microRNA-mediated control of gene expression during muscle development and disease, and consider the potential of microRNAs as therapeutic targets.

PMID: 19278845 [PubMed - as supplied by publisher]

http://www.sciencedirect.com