Translation from Protein to Patient

Relaxation of vascular smooth muscle is mediated by cyclic nucleotide-dependent signaling pathways. Using gene transfection and protein transduction of phosphorylated analogues of HSP20, we have recently demonstrated that the phosphorylation of HSP20 represents a point in which the cyclic nucleotide signaling pathways converge to cause relaxation [1, 2]. Vasorelaxing molecules, engineered to include phosphorylated HSP20 motifs and protein transduction domains (PTD), prevent vasospasm and intimal hyperplasia in human saphenous vein. These molecules are currently under development for clinical use.

Vein grafts represent an ideal target for this therapeutic approach in that grafts can be treated ex vivo, thus providing an optimal environment for the localization of engineered protein/peptide therapeutics. Since there is currently no universally effective agent for the treatment of vein graft spasm, the development of this proteomic treatment presents a significant therapeutic alternative (or agent). This treatment is novel in that receptors and signaling cascades are "bypassed" and the effector protein/peptide is directly introduced into the target cell. This approach represents a "post-genomic" platform for engineering biologically active protein/peptide molecules.

The steps along this pathway involve the development of an intellectual property (IP) platform that centers on composition of matter and use of the peptide analogues. The next steps involve the formation of a biotechnology start up company and licensing the technology from the University. Capitalization and the formation of a management team then leads to pre-clinical development. Pre-clinical development of the peptide involves the production of the peptides PTD-HSP20 under GMP (Good Manufacturing Practice) conditions followed by conducting acute, subacute, and genetic toxicity testing of GMP grade PTD-HSP20 under GLP (Good Laboratory Practice) conditions. This leads to the submission of an Investigational New Drug (application) of the peptide for the initiation of Phase I, II, and III clinical trials. The process is lengthy and expensive but necessary for the safe introduction of new drugs and devices into the market.

References

1. Flynn, C.R., et al., Transduction of biologically active motifs of the small heat shock- related protein, HSP20, leads to relaxation of vascular smooth muscle. Faseb J, 2003. 10: p. 1358-60.

2. Woodrum, D., et al., Phosphorylation of the heat shock-related protein, HSP20, mediates cyclic nucleotide-dependent relaxation. J Vasc Surg, 2003. 37: p. 874-81.

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