“Cell-Based Therapy and Tissue Engineering” short course that began in 2000. More information can be found at the center’s website: www.ncrm.us.
Random Activation of Gene Expression (RAGE)
The creation and process of RAGE was described in the 2001 Nature Biotechnology publication entitled “Creation of Genome-Wide Protein Expression Libraries Using Random Activation of Gene Expression,” led by John Harrington. RAGE is essentially a method or procedure of creating genome-wide libraries of cDNAs. In this seminal publication, the creation of RAGE libraries containing only 5 million individual clones was described as expressing all genes of interest tested, including those genes normally silent in the parent cell line, and with endogenous genes being expressed at similar frequencies and levels in libraries created from multiple different human cell lines. Various insertion vectors are utilized containing a promoter sequence, and an unpaired splice site allows the vector to be inserted via nonhomologous recombination, randomly into a eukaryotic cell’s (host) genome. The promoter sequence helps to activate expression of a gene transcript where the insertion point is upstream of a host gene, resulting in a chimeric protein made up in part of the vector-encoded sequence and a portion of the host cell protein.
One candidate protein isolated using the RAGE method that had become a lead product candidate for Athersys is a selective serotonin receptor 5HT2c agonist, called ATHX-105. The serotonin receptor 5HT2c is located in the area of the brain controlling appetite and food intake. Thus, the utility of the ATHX-105 agonist of this receptor is to reduce appetite and encourage weight loss. However, despite the completion of several phase I clinical trials for ATHX-105 demonstrating good safety tolerability, exposure levels, and regional absorption, toxicology findings in rodents and related expected risk, time, and costs of tests to resolve concerns resulted in the decision for Athersys to withdraw application for FDA IND and phase II clinical trials in 2008. The company is instead pursuing next-generation compounds with improved characteristics. Other product candidates identified using RAGE and other Athersys proprietary technologies that are in the Athersys pipeline include those for treating metabolic disorders and central nervous system disorders.
MultiStem
MultiStem is a patented stem cell product being developed by Athersys from multipotent adult progenitor cells (MAPCs) to be used in several different therapeutic areas, such as inflammatory, immune, neurological, and certain cardiovascular disorders. Examples include stroke, bone marrow transplantation, and oncology support, as well as other disease indications. As a stem cell–based product, it is considered a biologic product and as such falls under certain FDA and International Conference on Harmonization (ICH) guidelines. To meet these, Athersys is working with independent and clinical research institutions in the United States and in Europe, including Case Western Reserve University, as described above, and larger pharmaceutical companies such as Pfizer, Inc. In 2014, Athersys announced interim results from a phase II clinical trial, conducted by Pfizer, using MultiStem as a cell therapy in the treatment of ulcerative colitis. Patients were those suffering from the chronic disease who had become resistant, intolerant, or who were unresponsive to other forms of treatment. While no adverse effects were reported, there also appeared to be a lack of beneficial effects in patients at eight weeks post-treatment, but the company holds out hope for those patients receiving additional MultiStem treatments over time.
Competing Companies
With the explosion of promising findings in stem cell research, there has also been a multitude of start-up companies. Some of these competing in the stem cell market in 2014 include Fate Therapeutics, Cytori, StemCells Inc., Aastrom, ViaCyte, ReNeuron, Neuralstem, OncoMed, Orgenesis, Cellular Dynamics, Neostem, AlloOnc, Advanced Cell Technology, BioTime, Mesoblast, and Pluristem Therapeutics. However, primary competition for Athersys’s MultiStem includes products being developed by the companies Mesoblast and Pluristem Therapeutics. Osirus was another key competitor of Athersys, but it exited the stem cell arena in late 2013, selling its stem cell platform, specifically mesenchymal stem cell–based therapeutic research, to Mesoblast in 2013. Mesoblast has taken that research and is developing stem cell products for the treatment of heart failure, Crohn’s disease, orthopedics, and acute graft-versus-host disease. On the other hand, it appears that Pluristem is focusing on placenta-based cell science for their development of therapeutic products, including various inflammatory and ischemic conditions, in part using a proprietary three-dimensional cell-expansion technology.
Astra I. Chang
University of California, Davis
See Also: Adult Stem Cells: Overview; Case Western Reserve University/Cleveland Clinic; Mesenchymal Stem Cells; Stem Cell Companies: Overview.
Further Readings
Athersys Inc. “Athersys Announces Results From Phase 2 Study of MultiStem Cell Therapy for Ulcerative Colitis.” April 28, 2014. http://www.athersys.com/releasedetail.cfm?ReleaseID=842936.
Harrington, J. J., B. Sherf, S. Rundlett, et al. “Creation of Genome-Wide Protein Expression Libraries Using Random Activation of Gene Expression.” Nature Biotechnology, v.19/5 (2001).
Werner, M., T. Mayleben, and G. Van Bokkelen. “Autologous Cell Therapies: The Importance of Regulatory Oversight.” Regenerative Medicine, v.7/6 Suppl (2013).
Australia
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Australia
Australia has one of the most supportive stem cell research environments in the world, and researchers have made great strides in conducting innovative stem cell research and developing therapies for a host of diseases and conditions. In the early 1980s, Australian researchers were among the first in the world to use fertility drugs that led to live births. In 2001, the national government launched Backing Australia’s Ability, earmarking $3 billion for policy initiatives that included a new focus on stem cell research. In 2003, the government announced that it was investing $110 million over a 10-year period to establish Stem Cell Australia. That effort brought together experts from all of Australia to promote all aspects of stem cell research. In 2011, as funding for Stem Cell Australia reached the end of its cycle, the National Stem Cell Foundation of Australia was created to raise funds to continue the work begun by the government initiative.
While most Australians express support for using embryonic stem cells in research, the use of human embryonic cells remains controversial. In 2006, the government allotted an additional $22 million to establish the National Centre for Adult Stem Cell Research at the Eskitis Institute for Cell and Molecular Therapies at Griffith University in Queensland, bypassing the ethics debate. Professor Alan Mackay-Sim, an internationally recognized neurobiologist and expert on differentiating nasal stem cells, was appointed to head the facility, which focuses on developing stem cell therapies for neurological diseases and injuries.
In 2010, researchers were invited to apply for new competitive funding totaling $21 million. Local and regional stem cell organizations such as the NSW Stem Cell Network in New South Wales also contribute to the stem cell research community. Private and public foundations and biotech companies such as BresaGen Ltd, ES Cell International Pte Ltd, Norwood Abbey Ltd, and Stem Cell Sciences Pty Ltd are also engaged in various aspects of stem cell research.
Background
In the 1980s, Australian researchers began making significant discoveries in stem cell research. Teams that included Bik To and Chris Juttner of the Institute of Medical and Veterinary Science and the Royal Adelaide Hospital and a team led by Don Metcalf at WEHI /Royal Melbourne Hospital demonstrated that hematopoietic stem cells have the ability to mobilize into peripheral blood. Alan Trounson