RAGE provides a unique solution for drug development or other research applications in the post-genomic environment, since it can be used to produce human cell lines expressing virtually any protein encoded in the human genome, without requiring the cloning and isolation of individual genes. RAGE is used to randomly activate genes, including those that are expressed rarely or expressed at very low levels, solving one of the major problems in genomics research. RAGE enhances productivity and shortens the drug discovery process by enabling researchers to directly link biological function with expression of a specific protein. As opposed to taking the approach of systematically searching one by one through thousands of genes to ultimately find a protein with an interesting or medically relevant characteristic, RAGE allows for genome-wide, simultaneous analysis and the rapid association of proteins with their biological function.
Since RAGE activated genes are tagged, Athersys scientists can rapidly conduct functional genomics studies on a genome-wide basis to identify and isolate those genes that express proteins of biological significance, such as genes that make cells resistant to chemotherapeutic drugs, are involved in apoptosis, play a role in inflammation, control cell growth and tissue formation, affect tumor formation or tumor biology, and affect immune cell function. RAGE also facilitates the validation of therapeutic antibody targets that may be used to create therapeutic antibodies to treat disease. By greatly compressing the process of protein and antibody target validation, RAGE delivers on the promise of genomics.
Once an appropriate assay system has been established, Athersys scientists create a RAGE library in which each member of the library, or cell, contains a single randomly activated gene. The randomly activated gene is expressed along with the normal complement of genes typically expressed in the host cell type. Collectively, the RAGE library may contain millions of independent members, representing essentially the entire genome expressed in a single cell type. The RAGE library is then analyzed with the assay designed to detect a particular biological characteristic of interest. Since genes activated by the RAGE technology are tagged, this enables the rapid and efficient isolation and identification of specific genes that cause the phenotype of interest.
The pharmaceutical industry faces a growing problem in the drug development process: how to obtain access to validated drug targets in order to develop new therapies without infringing on patents that restrict the use of cloned and isolated gene sequences encoding the target. Athersys' RAGE technology provides a comprehensive solution to this obstacle to drug development. RAGE can be used to express validated protein drug targets from virtually every gene in the human genome without having to clone cDNA molecules. As a result, RAGE may be used to create cell lines that express certain validated drug targets in a manner that is independent of conventional approaches, overcoming a significant hurdle in the drug development process.
Since the RAGE approach results in the activation of virtually every gene within the genome, RAGE can be used to generate cells expressing many validated biological targets, including: ion channels, G-protein coupled receptors, kinases, phosphatases, hormone receptors and cytokine receptors. Cell lines that express these targets may then be used for high-throughput drug screening projects at pharmaceutical companies. In this way, RAGE enables the development of novel pharmaceutical products, directed against specific biological targets, which hold the promise of new, safer, more effective treatments for patients.
Athersys has provided validated drug targets to companies such as Bristol-Myers-Squibb and Pfizer for drug discovery projects. The company has also applied RAGE to its own internal drug discovery programs.
As a compliment to the RAGE technology, Athersys has another proprietary, genetic technology that leads to rapid identification of gene function, directly linking the gene to its role in the cell's biology and accelerating the functional validation of human genes. The GECKO technology can:
- Rapidly create genome-wide knock-out libraries for use in cell-based screening systems
- Directly associate biological function with gene and protein structure
- Efficiently knock-out protein expression without requiring advance knowledge of gene sequence
Following the same principles established in traditional genetic screens, GECKO libraries are utilized to reveal cellular phenotypes that are relevant to human disease. The GECKO technology is unique for multiple reasons. First, it can be used in cell culture to knock-out gene function of each expressed gene, reducing the discovery time of a genetic screen to a fraction of what it would be if conducted in whole animals. Second, the gene knock-outs produced by GECKO are more robust than other available approaches, such as siRNA, antisense and ribozymes. Third, the GECKO technology facilitates rapid identification of known and novel genes in the context of their cellular functions. These characteristics make the GECKO technology a powerful approach for identifying gene function during the discovery of novel targets for therapeutic intervention.
Athersys has performed extensive validation studies using the GECKO technology in which GECKO libraries have been created and screened for a number of disease-related phenotypes, such as inflammation and resistance to known inducers of apoptotic cell death. Each screen performed has uncovered genes already known to play roles in the pathways being examined, fulfilling one of the validation criteria. More importantly, however, many of the genes identified in the GECKO screens have been shown to be involved in specific biological or disease pathways for the first time, supporting the claim that novel drug targets will emerge from use of the GECKO technology. As additional GECKO libraries are created and screened, Athersys anticipates this technology will add to the growth of its drug candidate pipeline.