Invited Speaker

Transglutaminase and Linkage of Active Agents To Tissues
Philippe Djian
France

Transglutaminase catalyzes the formation of intermolecular isopeptide cross-links between glutamine and lysine residues of polypeptides. We had proposed that the neuronal aggregates characteristic of the diseases of polyglutamine expansion, such as Huntington disease, resulted from crosslinking by transglutaminase. As a model for polyglutamine-induced diseases, we have shown that a polyglutamine conferred excellent substrate properties on any peptide, as long as the peptides were rendered sufficiently soluble by the flanking residues. Lengthening the polyglutamine increased not only the reactivity of the peptide, but also the reactivity of each glutamine residue. Under optimal conditions, virtually all the Q residues acted as amine acceptors. We then thought to use the exceptional qualities of polyQ and polyK as substrates of transglutaminase in order to develop and commercially exploit a novel drug delivery technology platform that has wide applicability within not only the pharmaceutical and OTC (topical and systemic) markets, but also the human protection and cosmeceutical markets. The technology permits prolonged, durable attachment of active agents or agent-loaded reservoir devices to the top layer (stratum corneum) of external body surfaces, specifically, squamous epithelial tissue such as skin, cornea, nails, hair, mouth, vagina and the esophagus. We will present evidence on how transglutaminase in cunjunction with synthetic substrates allows the conjugation of active agents to body surfaces in order to achieve sustained topical presence and prolonged activity. We will also discuss the potential use of transglutainase in nanosphere technology in order to permit the controlled release of therapeutics over time and, as a result, achieve extended activity, reduced dosing and the potential for increased compliance, often on select areas of the body that are not possible today. On the long term transglutaminase could enable the systemic delivery (e.g., transdermally, transmucosally) of therapeutics in new therapeutic areas, without the use of intrusive devices and without being confined to patch-sized surface areas.