PROJECT SUMMARY
The objective of this study is to develop a new long-acting injectable (LAI) delivery system that provides
tunable and sustained release of protein therapeutics, demonstrate its effectiveness in sustained local delivery
of insulin-like growth factor-1 (IGF-1) and agrin targeted to nerve and muscle tissue, and assess its functional
efficacy for treatment of peripheral nerve injury (PNI) in rat and NHP models. Current options for treating patients
with PNI offer limited functional recovery due to the deleterious effects of prolonged denervation in the target
muscle and progressive muscle atrophy. IGF-1 has shown potent trophic and anti-apoptotic effects on neural
cell types and muscle cells; though requires frequent and high doses to achieve therapeutic outcomes due to its
short half-life in vivo. However, clinical translation of such an approach is difficult due to the risks associated with
high systemic dose of IGF-1. We have recently developed a kinetically controlled assembly method for
preparation of biodegradable nanoparticles (NPs) that are capable of high loading, high bioactivity retention, and
when given locally in affected muscle tissue and nerve tissue, provide sustained release of IGF-1, and
demonstrated significantly improved functional recovery following local delivery in a rat PNI model. In addition,
motor nerve-derived glycoprotein agrin is indispensable for neuromuscular junction formation and maintenance.
Thus, we hypothesize that maintaining a sufficient concentration of agrin in target muscle for 3 months until
reinnervation can further increase the level of functional recovery. In this design-driven study, we aim to optimize
the delivery capacity of NPs and generate an off-the-shelf LAI delivery platform for both IGF-1 and agrin over 10
to 12 weeks and demonstrate the competitive advantage of this approach for functional regeneration using
translational PNI models that recapitulate the clinically observed deleterious effects and anatomical features of
PNI. We will pursue the following four aims: (1) to establish a new nanoparticle (NP)-based delivery system that
achieves tunable and sustained release profile for IGF-1 and agrin; and understand the mechanism of high
loading capacity, sustained release kinetics, and bioactivity retention; (2) to engineer NP-embedded hyaluronic
acid (HA) hydrogel microparticles (MPs) as an off-the-shelf LAI system to extend IGF-1 and agrin release
duration with preserved bioactivity and NP retention; and measure IGF-1 and agrin release kinetics and
biodistribution following in vivo delivery in rats; (3) to assess efficacy of the optimized LAI system for IGF-1/agrin
delivery in a chronic PNI rat model; and (4) to confirm efficacy, biocompatibility and safety of the optimized LAI
delivery system in a new definitive preclinical NHP PNI model. Successful completion of this study will offer an
LAI system specifically designed to transform the clinical treatment of PNI and demonstrate its translational
potential regarding scalable manufacturing and functional efficacy in clinically relevant PNI models. It will also
provide a versatile LAI platform for local and sustained delivery of a wide range of protein therapeutics.
