Translating GLP Compatible Immunomodulatory and Pro-regenerative Particles To Promote The Function Of Islets Following Transplantation In Humans.

Islet transplantation into the liver of someone with Type 1 diabetes stabilises blood glucose control but rarely results in insulin independence, as most islets are destroyed post-transplant from inflammation and immune-mediated mechanisms.

We have developed microparticles (MPs) from the polymer poly(DL-lactic-co-glycolic acid): a biodegradable material used in pharmaceutical formulations in which drugs can be loaded and their release controlled.

The polymer has a galactose (Gal) moiety attached to it and targets the liver via the liver-specific asialoglycoprotein receptor (ASGPR).

We have determined the safe and effective dose of specific anti-inflammatory and pro-regenerative drugs which significantly improves glycaemic control in a diabetic mouse model transplanted with islets via the portal vein. Importantly, the effective dose of drugs is a fraction of the systemic dose required.

Our objectives are to : 1.

Develop a range of Gal-MPs packaged individually with anti-inflammatory/immunomodulatory and pro-regenerative drugs (Drug-Gal-MPs) to target the liver with appropriate release kinetics; 2.

Demonstrate efficacy/safety/mechanism of action of islets co-transplanted with these Drug-Gal-MPs including Drug-MPs in combination; 3. Understand regulatory landscape. We will assess the: 1. Release kinetics of other Drug-Gal-MPs already developed; 2. Biodistribution /pharmacokinetics of Drug-Gal-MPs; 3.

Short-term effects of Gal-MPs on liver; 4. Long-term metabolic effects of Gal-MPs.

We will develop the most efficacious Drug-Gal-MPs to GLP-grade, test in small and large animal models with islets including ex-vivo in human liver.

We will explore the Drug-Gal-MPs with hESC islets through our collaborators and work with Catapult to understand the regulatory landscape to develop the Drug-Gal-MPs for clinical use.