Enhanced paracellular transport of insulin can be achieved via transient induction of myosin light chain phosphorylation

Oral delivery of proteins such as peptide therapeutics remains a major challenge for the pharmaceutical industry. Recently we reported the enhanced transport of oral insulin across rat intestine in vivo using peptides that that were rationally designed to induce myosin light chain (MLC) phosphorylation. These permeable inhibitors of MLC phosphatase (PIP peptides) transiently open intestinal tight junctions that exist between adjunct epithelial cells. In doing so, PIP peptides can be used to dynamically enhance solute uptake through the paracellular route, proving a promising new, mechanism-based approach for enhancing peptide therapeutic absorption following oral administration.

Presently, the medical field and pharmaceutical industry are facing a diabetes epidemic on a global scale with most patients poorly controlling their blood sugar levels, leading to devastating morbidity issues and ultimately advanced mortality. Better management of blood sugar is of paramount concern to limit this ever-increasing burden on health care systems. Oral delivery of insulin, and more recently incretin molecules such as GLP-1 secreted by intestinal epithelial cells in response to food intake, could provide a simpler needle-free method of treating diabetes, with the possibility of an enhanced clinical benefit. Orally administered insulin absorbed across the intestinal mucosa and would be delivered to the liver by the portal circulation, just as insulin is normally delivered to the liver by the pancreas of a non-diabetic human. Thus, successful oral administration of insulin and GLP-1 are now considered more than just a strategy to improve patient compliance and comfort, but essential to effectively combat the diabetes epidemic. PIP peptides will likely lead to exciting opportunities for oral delivery of therapeutic agents such as insulin and GLP-1, and to transformative treatments for diabetic patients.

These peptides act by a defined mechanism of action, without causing any intestinal damage, by direct actions on the epithelium after topical application. Clinical utilization of agents enhancing paracellular permeability without first understanding their mechanisms of permeabilization is challenging both because of potential safety issues and translation to humans from pre-clinical models. PIP peptides overcome previous challenges to clinical development strategies for oral insulin and GLP-1 dosage forms because they act transiently and locally following topical application, and do not appear to affect other tissues prior to their metabolism and elimination from the body.  Most importantly, PIP peptides work through a defined and endogenous pathway, do not appear to incite cell damage or an extensive co-uptake of bacterial components (like lipopolysaccharides) present in the intestinal lumen.

Our initial studies using a simple administration into the intestine of rats have shown 3-4% bioavailability for insulin. We believe that formulation efforts to enhance the stability of the peptides therapeutic to be delivered could increase this level of bioavailability significantly. While our initial studies have used insulin to demonstrate the feasibility of PIP peptides, we are interested in exploring a spectrum of therapeutic peptides for oral delivery. Although only insulin has been tested to date we would expect the PIP peptides to be capable of delivering other peptides and small proteins orally. We are seeking industrial partners for this technology and are keen to validate the PIP peptides in a large animal study.