Ischaemic heart disease

We designed a device for the therapy of myocardial ischaemia, composed of microencapsulated mammalian cells that include a genetic bistable toggle switch with a positive feedback loop, where in one state the cells produce anakinra as the anti-inflammatory effector and in the second state they produce a stoichiometric amount of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor B (PDGF-BB) to promote angiogenesis in the damaged tissue.

A pharmacokinetic model demonstrated that implantation of the device into the injured heart tissue results in a high level of anakinra concentration within the affected tissue, while the systemic level of anakinra is very low, preventing systemic immunosupression.

We demonstrated that the production level of anakinra by engineered cells is sufficient for the therapeutic implementation of microencapsulated cells for this indication.

Figure 1. Regulated release of therapeutic proteins into the dammaged tissue.

References

Feld, J.J. and Hoofnagle, H. (2005) Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 436, 967-72.

Loignon M, Perret S, Kelly J, Boulais D, Cass B, Bisson L, Afkhamizarreh F, Durocher Y. (2008) Stable high volumetric production of glycosylated human recombinant IFNalpha2b in HEK293 cells. BMC Biotechnol. 8, 65.

Nakamura, T., Sakai, K., Nakamura, T. and Matsumoto, K. (2011) Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol. Hepatol. 26, 188-202.

Oyagi, S., Hirose, M., Kojima, M., Okuyama, M., Kawase, M., Nakamura, T., Ohgushi, H. and Yagi, K. (2006) Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol. 44, 742-8.

Pawlotsky, J.M. (2004) Pathophysiology of hepatitis C virus infection and related liver disease. Trends in Microbiology. 12, 96-102.

Ueki, T., Kaneda, Y., Tsutsui, H., Nakanishi, K., Sawa, Y., Morishita, R., Matsumoto, K., Nakamura, T., Takahashi, H., Okamoto, E. and Fujimoto, J. (1999) Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat. Medicine 5, 226-30.