October 8, 2008
Protein Linked to Spinal Muscular Atrophy Identified
Libertyville, IL, Carlsbad, CA, Woodridge, IL October 8, 2008 - Families of Spinal Muscular Atrophy (FSMA, www.curesma.org), Invitrogen Corporation (NASDAQ:IVGN www.invitrogen.com), and deCODE chemistry & biostructures www.decodechembio.com) announced today they have identified a protein that is a potential molecular target for the treatment of Spinal Muscular Atrophy (SMA). In its most severe form, SMA often leads to death in infancy, and there is currently no treatment or cure. Research published today in the journal ACS Chemical Biology of the American Chemical Society, entitled “DcpS as a Therapeutic Target for Spinal Muscular Atrophy,” details the identification and characterization of a protein that offers a novel biological mechanism for designing new SMA therapeutics.
SMA is an inherited genetic disorder that affects approximately one in every 6,000 births in the US. The molecular basis of the disease is a deficiency in production of a specific protein – Survival Motor Neuron (SMN) protein. Motor neuron function is acutely sensitive to lowered SMN protein levels. This cellular defect is the underlying basis for the loss of control of muscles in the limbs, neck and chest in these patients. Because the genetic capability to produce SMN protein is not completely eliminated in SMA patients due to the unique presence of a back-up gene, drugs that increase SMN protein levels in motor neurons are expected to modulate the severity of the disease and have done so in SMA mouse models.
Previously, researchers at deCODE chemistry & biostructures with funding from Families of SMA had developed a class of compounds called C-5 substituted quinazolines, which increased expression of SMN protein, potentially giving clinical investigators a new class of compounds to utilize for the treatment of SMA. However, the mechanism behind this increase in SMN production was unknown.
“While the identification of compounds that increase SMN expression represents significant hope to patients with SMA, we still did not understand the mode of action of these compounds in SMA,” noted Jill Jarecki, Ph.D., Research Director at Families of SMA. “The results outlined in the paper represent a new understanding of the physiological mechanisms that can increase SMN expression and will allow us to move forward in advancing potential treatments for SMA. This discovery gets to the level of really understanding how SMN deficiency can be corrected in the cells of the body, which in turn will open up many new ways of developing therapies.”
In the present study, researchers used a lead compound from the FSMA funded program, to probe Invitrogen’s high-density ProtoArray™ protein microarray for candidate proteins binding to the test compounds. The ProtoArray allowed researchers to rapidly identify a specific human protein called DcpS (human mRNA decapping scavenger enzyme) that interacted with the FSMA compounds. Additional functional experiments preformed by the laboratory of Dr. Megerditch Kiledjian at Rutgers, The State University of New Jersey confirmed that DcpS activity is modulated by the FSMA compounds.
“The identification of DcpS as a novel drug target for SMA is but one example of how Invitrogen technologies are on the forefront of research aimed at helping to find cures for disease,” said Brian Pollok, Ph.D., Chief Scientific Officer for Invitrogen. “In 2006, we started working with FSMA to define the biomolecular mechanisms for how these compounds up-regulate SMN production, and the successful outcome of this collaboration is very gratifying. Invitrogen is committed to creating advanced technologies which progress the understanding of disease biology and support the development of new therapies.”
Lance Stewart, Ph.D. President, deCODE biostructures explained further, “This demonstrates the value of protein structures in translational research. With the identification of DcpS as a candidate molecular target, we then synthetically engineered a novel DcpS gene for protein expression and crystallization with the aid of Gene Composer (www.genecomposer.net). Purified DcpS was then entered into co-crystallization trials with the FSMA molecules, which rapidly led to the high resolution X-ray structural elucidation of how the C5-substituted quinazolines specifically inhibit DcpS.” The DcpS structural information has been made publicly available through the Protein Data Bank (www.rcsb.org/pdb, PDB IDs: 3BL7, 3BL9 and 3BLA) with the hope that this information will inspire others to build upon these research discoveries to help SMA patients.
“We have long been involved in working with FSMA to try and find a cure for this disease,” said Mark Gurney, Ph.D. Sr. Vice President of Drug Discovery and Development at deCODE, and the paper’s corresponding author. “The work carried out by ourselves in collaboration with Invitrogen, Rugters, and FSMA helps science understand the mechanisms of SMA.. While still in the discovery phase of drug development, the FSMA compounds represent novel potential treatments for SMA. We look forward to continuing our work with FSMA to move the drug candidate forward so that patients may benefit from a potential new medicine to combat SMA.”
About Families of SMA
Families of SMA is a nonprofit organization that was founded in 1984 by a small group of parents for the purpose of raising funds to advance research to find a treatment and cure for Spinal Muscular Atrophy and to support all those affected by SMA.
Families of SMA has funded and directed the leading SMA research programs over the last 25 years: including the most advanced drug discovery programs and clinical trials to develop a treatment and cure for SMA. The organization is constantly looking to innovate and provide incentives for companies and the government to get involved and invest in SMA research.
Families of SMA is a network of families, researchers and clinicians who are determined to make a difference. To date FSMA has raised and invested $43 Million towards SMA research. Support comes from generous individual donations and numerous fundraising events held by volunteer families and chapters. FSMA has 24 chapters throughout the United States and over 55,000 members and supporters. For more information visit the website www.curesma.org or call 1-800-886-1762.
About Invitrogen Corporation
Invitrogen Corporation (NASDAQ:IVGN) provides products and services that support academic and government research institutions and pharmaceutical and biotech companies worldwide in their efforts to improve the human condition. The company provides essential life science technologies for disease research, drug discovery, and commercial bioproduction. Invitrogen's own research and development efforts are focused on breakthrough innovation in all major areas of biological discovery including functional genomics, proteomics, stem cells, cell therapy and cell biology -- placing Invitrogen's products in nearly every major laboratory in the world. Founded in 1987, Invitrogen is headquartered in Carlsbad, California, and conducts business in more than 70 countries around the world. The company employs approximately 4,700 scientists and other professionals and had revenues of approximately $1.3 billion in 2007. For more information, visit www.invitrogen.com.
About deCODE chemistry & biostructures
deCODE chemistry, Inc. & deCODE biostructures, Inc. provide contract research services to pharmaceutical companies, biotechnology companies, academic institutions, and government facilities. deCODE chemistry & biostructures takes a collaborative approach to pharmaceutical research services through a seamless integration of chemistry and biology capabilities including protein production, multifaceted structural studies, lead identification, ex vivo and in vivo assays, cGMP manufacturing and regulatory capabilities which furnishes accelerated timelines for moving molecules from the concept and into the clinic. Visit deCODE chemistry & biostructures on the web at www.decodechembio.com.
deCODE gratefully acknowledges the funding from its partner FSMA, as well as the NIGMS-NCRR co-sponsored PSI-2 Specialized Center Grant U54 GM074961 which supports synthetic gene design work within the Accelerated Technologies Center for Gene to 3D Structure (www.ATCG3D.org).
October 3, 2008
October 3, 2008
REYKJAVIK, Iceland, Oct. 3 /PRNewswire-FirstCall/ -- deCODE genetics (Nasdaq: DCGN - News) today announced the filing of an investigational new drug (IND) application for DG071, the company's novel small-molecule modulator of phosphodiesterase 4 (PDE4), with the US Food and Drug Administration (FDA). The compound is being developed as a new and potentially safer means of targeting PDE4 to combat memory loss and cognitive deficits associated with Alzheimer's disease and other disorders in which neural signaling is reduced or impaired. In animal models, DG071 has been shown to significantly improve learning and long- and short-term memory at doses that offer a wide margin for safety and tolerability. The compound has the potential to eliminate the nausea that limits the utility of previous PDE4 inhibitors. deCODE plans to advance the clinical development of DG071 with a strategic partner.
"This compound has exciting therapeutic potential and reflects the exceptional capabilities of our drug discovery and structural biology groups. Our teams used protein crytallography to determine the structure of domains that regulate the enzymatic activity of PDE4, and in DG071 discovered a compound that binds to the PDE4 regulatory domain and effectively modulates the activity of the enzyme. DG071 has been shown in several animal models to potently and specifically improve cognitive function, and features a much wider safety and tolerability profile than existing PDE4 inhibitors. This is encouraging, as many of the amyloid-busting therapeutics currently entering clinical trials in Alzheimer's disease have the potential to slow or stop progression of the disease but will not reverse the destruction of neurons. Our expectation is that DG071 will allow the remaining neurons to store and retrieve memories more efficiently. DG071 could be useful in the treatment not only of Alzheimer's disease, but might also have benefit in Huntington's disease, schizophrenia, anxiety, ADHD and depression," said Dr. Kari Stefansson, CEO of deCODE.
DG071 is a novel, potent and selective PDE4D modulator discovered by deCODE's chemistry group. First and second generation PDE4 inhibitors such as rolipram, cilomilast, and roflumilast caused significant side effects, including nausea and vomiting, at the therapeutic doses in human clinical trials. Such side effects severely limit the utility of these earlier compounds. Data generated at deCODE suggest that the observed side effects were closely correlated with the binding of these molecules in the PDE4 enzymatic active site competitively with cAMP. As cAMP is of critical importance to neuronal signalling, the goal of deCODE's program has been to discover compounds that would modulate PDE4 activity via an allosteric mechanism to improve safety and tolerability.
Towards this goal, the deCODE biostructures team solved multiple novel co-crystal structures of PDE4D & PDE4B containing regulatory domains with bound ligands. Those structures allowed the deCODE chemistry team to identify a novel binding site for allosteric modulators in the PDE4 regulatory domain. Binding of an allosteric modulator at that site is non-competitive with cAMP. DG071 has been shown in animal models to improve cognitive function with benefit similar to that of cholinesterase inhibitors such as donepezil that currently are a mainstay of therapy for memory loss in early Alzheimer's disease, yet also benefiting long term memory function in animal tests where the cholinesterase inhibitors are ineffective.
deCODE has developed a broad proprietary platform for PDE4 modulators that the company is applying to discover compounds with potential utility for the treatment of over-active bladder, inflammatory and respiratory diseases.
About deCODE
deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of diagnostics and drugs for common diseases. deCODE is a global leader in gene discovery -- our population approach and resources have enabled us to isolate key genes contributing to major public health challenges from cardiovascular disease to cancer, genes that are providing us with drug targets rooted in the basic biology of disease. Through its CLIA-registered laboratory, deCODE is offering a growing range of DNA-based tests for gauging risk and empowering prevention of common diseases, including deCODE T2(TM) for type 2 diabetes; deCODE AF(TM) for atrial fibrillation and stroke; deCODE MI(TM) for heart attack; deCODE ProCa(TM) for prostate cancer; deCODE Glaucoma(TM) for a major type of glaucoma; and deCODE BreastCancer(TM) for the common forms of breast cancer. deCODE is delivering on the promise of the new genetics(SM). Visit us on the web at www.decode.com; on our diagnostics site at www.decodediagnostics.com; for our pioneering personal genome analysis service, integrating the genetic variants included in these tests and those linked to another twenty common diseases, at www.decodeme.com; and on our blog at www.decodeyou.com.
About deCODE chemistry & biostructures
deCODE chemistry, Inc. & deCODE biostructures, Inc., are wholly-owned subsidiaries of deCODE genetics providing contract research services to pharmaceutical companies, biotechnology companies, academic institutions, and government facilities. deCODE chemistry & biostructures takes a collaborative approach to pharmaceutical research services through a seamless integration of chemistry and biology capabilities including protein production, multifaceted structural studies, lead identification, ex vivo and in vivo assays, cGMP manufacturing and regulatory capabilities which furnishes accelerated timelines for moving molecules from the concept and into the clinic. Visit deCODE chemistry & biostructures on the web at www.decodechembio.com.
Any statements contained in this presentation that relate to future plans, events or performance are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to a number of risks and uncertainties that could cause actual results, and the timing of events, to differ materially from those described in the forward-looking statements. These risks and uncertainties include, among others, those relating to our ability to obtain financing and to form collaborative relationships, uncertainty regarding potential future deterioration in the market for auction rate securities which could result in additional permanent impairment charges, our ability to develop and market diagnostic products, the level of third party reimbursement for our products, risks related to preclinical and clinical development of pharmaceutical products, including the identification of compounds and the completion of clinical trials, the effect of government regulation and the regulatory approval processes, market acceptance, our ability to obtain and protect intellectual property rights for our products, dependence on collaborative relationships, the effect of competitive products, industry trends and other risks identified in deCODE's filings with the Securities and Exchange Commission, including, without limitation, the risk factors identified in our most recent Annual Report on Form 10-K and any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. deCODE undertakes no obligation to update or alter these forward-looking statements as a result of new information, future events or otherwise.
August 8, 2008
Emerald BioStructures announces the installation of new laboratory automation systems totaling $2M at its Bainbridge Island, WA laboratories. With support from the National Institute of Allergy and Infectious Diseases (www.niaid.nih.gov) funded to Seattle Structural Genomics Center for Infectious Disease (www.SSGCID.org), this capital equipment allows Emerald to efficiently determine X-ray protein crystal structures of 75 to 100 new infectious disease targets annually. Specifically, Emerald has installed the Ultimate Homelab system for X-Ray diffraction data collection from Rigaku (www.rigaku.com), which includes an FR-E+ SuperBright X-ray generator, two Saturn 944+ CCD detectors, and two ACTOR robotic sample changes with radio frequency ID tracking of crystal samples through the Crystal Miner™ database from Emerald BioSystems (www.emeraldbiosystems.com). In addition, Emerald’s cloning laboratory has automated high throughput cloning using the Freedom Evo2 liquid handling platform (www.tecan.com) and integrated intelligent construct design with Gene Composer™ software from Emerald BioSystems (www.genecomposer.net). Finally, the protein production laboratory has been upgraded with the LC90 capillary electrophoresis system for rapid, high throughput protein expression analysis from Caliper (http://www.caliper.com). Dr. Alex Burgin, Chief Operating Officer, noted that “Considering, the high costs of collecting X-ray diffraction data at synchrotron beamline facilities, and the need to increase throughput for faster gene-to-structure results, we decided to make a major investment in automation within of our core laboratories. These investments have dramatically increased our throughput to support Emerald’s SSGCID research as well as a growing number of Fragments of LifeTM projects for fragment lead discovery.”
About the Seattle Structural Genomics Center for Infectious Disease
The Seattle Structural Genomics Center for Infectious Disease (SSGCID) applies state-of-the-art structural genomics technologies to characterize targeted proteins from NIAID Category A-C pathogens and organisms causing emerging or re-emerging infectious diseases. Structures are made available to the broad scientific community with the goal that they will serve as a blueprint for structure-based drug development for infectious diseases. SSGCID, established in September of 2007, is funded by the National Institute of Allergy and Infectious Disease (NIAID) Contract HHSN266200700057C. The center is directed by Dr. Peter Myler of Seattle Biomed Research Institute and collaborative support is provided by Emerald BioStructures, along with co-investigators at the University of Washington and Pacific Northwest National Laboratories.