Developing A Platform Technology For β-Cell-Targeted Drug Delivery

PROJECT SUMMARY
Type 1 diabetes is characterized by the loss of β-cell mass and decreased insulin production capacity. Thus,
developing a pharmacologic method for stimulating the expansion of β-cell mass has substantial potential
therapeutic value. Recently, our group and others have successfully developed highly potent small-molecule
inducers of human β-cell proliferation; however, the growth-promoting activity of these molecules is non-
selective. Consequently, the potential for inducing off-target cellular proliferation is a primary barrier to the safe
use of these regenerative compounds in humans. Herein, a novel, generalizable prodrug strategy for the
selective delivery of regerative therapeutics to the β-cell will be developed. The strategy leverages a unique
biologic activity of the β-cell to convert latent prodrugs into bioactive daughter compounds. Building on prior
success, progress will be furthered by incorporating relevant advances made in the broader field of targeted drug
delivery into this new prodrug strategy; including the incorporation of molecular linkers used in antibody- and
small molecule-drug conjugates that ensure compounds are fully latent prior to bioactivation and are unscarred
following bioactivation. Additionally, the cellular mechanisms of prodrug activation will be elucidated. This work
will deliver a robust, milestone-based data package for β-cell targeted drug delivery that includes a deep
understanding of prodrug bioactivation, structure-activity relationship data, pharmacokinetic characterization,
cell-type-specific activity and in vivo efficacy with a human islet-based preclinical model. The replicative activity
of target (β-cells) and off-target tissues will be assessed following short-term and long-term compound exposure;
studies critical to demonstrating the sustained specificity and efficacy of this β-cell targeted therapeutic delivery
strategy. These studies have the potential to deliver safe, potentially transformative, first-in-class lead
compounds for regenerative treatment of diabetes. Critically, the developed technology may be used for β-cell-
targeted delivery of nearly any therapeutic.

Grant Number: 5U01DK136965-03
NIH Institute/Center: NIH
Principal Investigator: Justin Annes