Tetragenetics Inc, an early stage biotechnology company in Cambridge, MA, has developed a powerful cross-cutting technology for the overexpression of eukaryotic membrane and secreted proteins using Tetrahymena thermophila, an important model organism with a unique features particularly well suited to the production of these important classes of proteins. The company's proprietary SionXTM technology, for example, has enabled expression of properly folded and functional human ion channel at levels 50-100 fold higher than has previously been possible with mammalian CHO or HEK cells, the current gold standard for the production of these otherwise difficult to produce proteins. These data have garnered considerable attention within the biotech and large pharma arenas, and while the platform has numerous applications in basic research, transfer of the technology to the broader academic community has challenges as well. From a technical standpoint, Tetrahymena is complex in terms of its genetics and not amenable to the kinds of out-of-the box (kit-type) solutions available for more conventional systems. At the same time, much of the technology for cell line development and expression optimization is proprietary and demands relatively high upfront licensing fees for commercial use that are beyond what academic researchers can afford. To address this issue and to make the Tetrahymena platform accessible to the entire biomedical research community, Tetragenetics Inc proposes to join forces with the NIH (ORIP)-funded Tetrahymena Stock Center at Cornell University to provide overexpressing cell lines and/or starting material for protein purification to not-for-profit academic and government research laboratories at reasonable costs. The Stock Center has a well developed infrastructure for ordering, storing and disseminating strains, while Tetragenetics has the state-of-the-art vectors, cell lines and growth conditions that make this system so powerful. The proposal describes how this public-private partnership will work to bring the technology to the not-for-profit research community. Additionally, the proposal delineates plans to expand the capabilities of the current platform by developing new tools for heterologous gene expression including new vectors allowing 'plug and play' options for construct design (particularly with respect to epitope tag placement); new promoters for driving inducible gene expression; and new cell lines that will permit identification of positive transformants without direct drug selection. These improvements will expand the flexibility of the platform for both academic and commercial use. Finally, Tetragenetics will explore use of the SionXTM platform for expression of historically challenging G-protein coupled receptors in collaboration with Heptares Therapeutics, a British company that has pioneered the development of stabilized GPCRs for structure-based drug design. The proposed studies are intended to remove a major stumbling block to the study of broad families of proteins that are critically important in normal functionin of the nervous, respiratory, endocrine, and urinary and immune systems.

Public Health Relevance

The proposed project seeks to put a new and powerful technology for the production of genetically engineered proteins into the hands of basic scientists in academic and government laboratories through the establishment of a public private partnership between Tetragenetics Inc, an early stage biotechnology company in Cambridge, MA, and the NIH-funded Tetrahymena Stock Center at Cornell University in Ithaca, NY. The underlying technology platform will permit in-depth studies on proteins that were previously inaccessible with the long- term goal of developing new and improved drugs for diseases ranging from neuropathic pain to cancer and autoimmunity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-IMST-J (15))
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Maas, Stefan
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Tetragenetics, Inc.
United States
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