|
|
| Line 394: |
Line 394: |
| | <h1>Hepatitis C</h1> | | <h1>Hepatitis C</h1> |
| | <p>We designed a device for the therapy of hepatitis C, composed of microencapsulated mammalian cells that include a genetic bistable toggle switch with a positive feedback loop, where in one state the cells produce interferon alpha (IFN-α) as the antiviral effector and in the second state they produce hepatocyte growth factor (HGF) to promote liver regeneration.</p> | | <p>We designed a device for the therapy of hepatitis C, composed of microencapsulated mammalian cells that include a genetic bistable toggle switch with a positive feedback loop, where in one state the cells produce interferon alpha (IFN-α) as the antiviral effector and in the second state they produce hepatocyte growth factor (HGF) to promote liver regeneration.</p> |
| - | <ul style="padding-left:30px">
| + | |
| - | <li>The therapy of hepatitis C by the local production of interferon alpha followed by the production of hepatocyte growth factor, providing a regeneration step.</li>
| + | |
| - | <li>The therapy of ischaemic heart disease with anakinra as an antiinflammatory agent, while vascular endothelial growth factor and platelet-derived growth factor, produced in stoichiometric amounts enhance angiogenesis and tissue oxigenation. </li>
| + | |
| - | </ul>
| + | |
| - | <br/>
| + | |
| - | <img src="https://static.igem.org/mediawiki/2012/b/b3/Svn12_implementation_overview_fig1.png"></img>
| + | |
| - | <p><b>Figure 1. The proposed therapeutic implementations of our synthetic biology device.</b></p>
| + | |
| - | <h3>Important advantages, considerations and limitations of the therapeutic implementation of the synthetic cellular devices based on cell microencapsulation</h3>
| + | |
| - | <h4>Advantages</h4>
| + | |
| - | <ul style="padding-left:30px">
| + | |
| - | <li>The ability to produce several protein therapeutics at the same time or <b>in a defined temporal sequence.</b></li>
| + | |
| - | <ul style="padding-left:60px">
| + | |
| - | <li>Two therapeutics under the control of different operators can be timed to expression at different stages of the disease or its therapy.</li>
| + | |
| - | <li>Introduction of the p2a (or t2a) amino acid sequence in frame between two or more protein coding sequences allows concurrent stoichiometric production of these proteins (Szymczak et al., 2004; see stimulation of angiogenesis in the therapy of ishaemia for an example, Banfi et al., 2012). </li>
| + | |
| - | </ul>
| + | |
| - | <li>The ability to <b>switch between several therapeutic regimens.</b></li>
| + | |
| - | <li>Therapeutic action can be <b>localized within the affected tissue.</b></li>
| + | |
| - | <li>Engineered therapeutic cells can mimic stem cells, which secrete many growth factors (e.g. the antiinflammatory and antifibrotic effect of mesenhymal stem cells in lung injury was attributed to secretion of anakinra (Ortiz et al., 2007).</li>
| + | |
| - | <li>Continuous production of a therapeutic protein, <b>avoiding peaks and dips in drug concentration, reducing the side effects.</b></li>
| + | |
| - | </ul>
| + | |
| - | <h4>Limitations</h4>
| + | |
| - | <ul style="padding-left:30px">
| + | |
| - | <li>The efficient exchange of nutrients is limited by the size of the microcapsules therefore posing limitations to the maximal ammount of encapsulated cells.</li>
| + | |
| - | <li>The amount of protein production is limited by the number of microcapsules, the number of encapsulated cells per one microcapsule and the maximum productivity of each cell.</li>
| + | |
| - | <li>The choice of therapeutics is mainly limited to proteins, such as hormones, growth factors, enzymes, cytokines or antibodies.</li>
| + | |
| - | <li>Productivity of microencapsulated cells may vary with time.</li>
| + | |
| - | </ul>
| + | |
| - | <h4>Other considerations for specific therapies</h4>
| + | |
| - | <ul style="padding-left:30px">
| + | |
| - | <li>The site of microcapsule implantation.</li>
| + | |
| - | <ul style="padding-left:60px">
| + | |
| - | <li>Does the therapeutic protein readily crosses microcapsules and penetrates into the diseased tissue?</li>
| + | |
| - | <li>Is implantation safe and <b>anatomically feasible?</b></li>
| + | |
| - | <li>would it be too invasive to implant microcapsules?</li>
| + | |
| - | </ul>
| + | |
| - | <li>How many cells are required to produce sufficient therapeutic amounts of the biological drug? We estimate that therapeutic production by encapsulated cells can probably reach up to a few tens of µg per day. This suggests most perspective therapeutics would be hormones, enzymes, cytokines and other proteins that act as regulators or are catalytic, while neutralizers such as antibodies are appropriate only for highly localized production.</li>
| + | |
| - | <li>Microencapsulated synthetic cellular devices are expected to be best suited for therapy of acute disorders with duration of the therapy up to a few weeks or months rather than for chronic diseases. </li>
| + | |
| - | </ul>
| + | |
| | <h2 style="color:grey;">References</h2> | | <h2 style="color:grey;">References</h2> |
| | <p style="color:grey;"> | | <p style="color:grey;"> |
| Line 444: |
Line 407: |
| | <hr> | | <hr> |
| | <b> | | <b> |
| - | Next: <a href="https://2012.igem.org/Team:Slovenia/ImplementationHepatitisC">Hepatitis C >></a> | + | Next: <a href="https://2012.igem.org/Team:Slovenia/ImplementationIschaemicHeartDisease">Ischaemic heart disease >></a> |
| | </b> | | </b> |
| | | | |
Hepatitis C
We designed a device for the therapy of hepatitis C, composed of microencapsulated mammalian cells that include a genetic bistable toggle switch with a positive feedback loop, where in one state the cells produce interferon alpha (IFN-α) as the antiviral effector and in the second state they produce hepatocyte growth factor (HGF) to promote liver regeneration.
References
Banfi, A., von Degenfeld, G., Gianni-Barrera, R., Reginato, S., Merchant, M.J., McDonald, D.M., and Blau, H.M. (2012) Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB. FASEB J. 26, 2486-2497.
Ortiz, L.A., Dutreil, M., Fattman, C., Pandey, A.C., Torres, G., Go, K., and Phinney, D.G. (2007) Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc. Natl. Acad. Sci. U S A 104, 11002-11007.
Szymczak, A.L., Workman, C.J., Wang, Y., Vignali, K.M., Dilioglou, S., Vanin, E.F., Vignali D.A. (2004) Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nat. Biotechnol. 22, 589-94.
Next: Ischaemic heart disease >>
"
