Therapeutic Application of Painless Nerve Growth Factor to Accelerate Endochondral Fracture Repair

ABSTRACT
The long-term goal of this project is to develop and validate an injectable, biodegradable nanowire delivery
platform for local and sustained release of a “painless” nerve growth factor (NGF) isoform to accelerate
fracture healing in clinical scenarios of delayed healing. Approximately 15 million fracture injuries occur
each year in the United States (US).6 An estimated 10-15% of fractures within a healthy population result in
delayed- or non-union.7,8 However, delayed healing rates increase to almost 50% in patients with vascular
damage or high co-morbidity burdens such as diabetes, increased age, smoking, and obesity.9,10 The current
standard of care for delayed healing or non-union is surgical intervention to increase stability or to promote
healing through application of bone grafts. Bone morphogenetic protein (BMP) is the only biologic with FDA
approval for use in fracture repair, with “on-label” use only within a narrow indication window. However, BMP
requires surgical implantation and is typically limited to only the most at-risk fractures due to the high cost, limited
evidence of clinical efficacy, and risk of severe off-target effects.11-14 As such, there exists an unmet clinical
need for biologics that could stimulate bone regeneration in a non-surgical delivery platform. This
application builds on strong preliminary data demonstrating that NGF accelerates fracture repair when injected
into the cartilaginous phase of long bone healing. Importantly, our preliminary data is the first to show that NGF
acts on chondrocytes to promote programs associated with endochondral ossification (EO). The goal of this
grant is to build upon these preliminary data to develop NGF into a platform suitable for clinical translation. In
the first Aim, we optimize the dose and timing of a mutant form of NGF (NGFR100W) to stimulate endochondral
fracture repair. NGFR100W is a novel “painless” NGF that efficiently binds to the TrkA receptor to provide the same
trophic effect as wild type NGF, but fails to bind to the p75NTR receptor to significantly reduce risk of
nociception.15,16 In the second Aim, we probe the mechanism by which NGF/NGFR100W stimulates fracture repair
by conditionally deleting the TrkA receptor. To date the molecular pathways stimulated by therapeutic delivery
of NGF have not been rigorously studied in long bone fracture healing. Lastly, in the third Aim, we modify our
previously developed injectable heparin coated polycaprolactone (PCL) nanowires17 for encapsulation and
sustained delivery of painless NGF. Here we also incorporate a pre-clinical model of diabetes (Lepob) established
to demonstrate delayed healing to challenge our therapy in a clinically relevant scenario of malunion. These aims
allow us to test the central hypothesis that a painless NGF therapy can improve fracture healing by acting
through TrkA signaling to stimulate chondrocyte-to-osteoblast transformation. Our interdisciplinary team
of experts in fracture healing, biomaterials, and NGF/TrkA signaling uniquely positions us to successfully
accomplish the proposed study. Importantly, our approach is grounded in creating a translationally relevant
therapeutic platform that has the potential to significantly improve patient outcomes following a fracture.

Grant Number: 3R01AR077761-04S1
NIH Institute/Center: NIH
Principal Investigator: Chelsea Bahney