STTR Phase I: Developing a novel drug delivery system to enable an oral peptide based drug for kidney stones

The broader impact/commercial potential of this STTR project is to develop a novel drug delivery system composed of peptide-loaded hydrogel nanoparticles for targeted and sustained therapeutic peptide release to the intestine. The gastrointestinal system and gut microbiome have emerged as critical drivers of human health, offering new opportunities to treat diseases such as food allergies, fungal infections, inflammatory bowel disease, and hyperoxaluria. However, a new class of drug systems are required to target the local biology of these diseases. The first indication pursued is hyperoxaluria and associated recurrent kidney stones and kidney diseases. With over ~27M calcium oxalate kidney stone (KS) patients in the U.S. (affecting 1 in 5 men and 1 in 11 women) and even higher global incidence, KS is a healthcare epidemic with no effective medication. Recent discoveries at the University of Chicago revealed the opportunity to treat hyperoxaluria through novel peptides that require local action in the intestine. Thus, a unique peptide-loaded hydrogel nanoparticle drug delivery system can enable a first-in-class therapeutic for the millions of patients with hyperoxaluria. More importantly, this drug system opens the door for additional orally administered, locally delivered, peptide therapeutics for other difficult gastrointestinal conditions, creating substantial healthcare and economic gains. This STTR project is developing an innovative drug delivery system consisting of peptide-loaded hydrogel nanoparticles (PLHN) as a vehicle to deliver novel peptides to the intestinal epithelium, ultimately enabling a first-in-class oral pill to prevent and treat hyperoxaluria and related kidney stones (KS). Once delivered, the nanoparticles will adhere to the intestinal mucosa and slowly release the peptides, stimulating intestinal oxalate secretion, thereby lowering plasma and urine oxalate and hence preventing KS formation. Such delivery will enable peptides to immediately act on the intestinal epithelium to induce oxalate secretion, before being degraded by proteolytic enzymes, mimicking the behavior of a gut bacteria, from which peptides were derived. Research objectives are: 1. Develop PLHN for sustained and localized delivery of peptides to the intestinal epithelium. Peptide release kinetics will be quantified to ensure a 4-week release duration. 2. Show that the PLHN, given rectally as enemas and orally by gavage, will deliver the peptides to the intestinal epithelium in a localized/sustained manner, and that they will significantly reduce plasma and urine oxalate levels in hyperoxalemic and hyperoxaluric mice. Showing dosing once every 3 days similarly reduces urine and plasma oxalate levels compared to twice daily dosing will demonstrate sustained releasability. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.