A Long-Acting Injectable IGF-1 Nanoparticle Delivery System To Improve Functional Recovery After Peripheral Nerve Injury in Non-Human Primates
Thomas Harris, MD1, Chenhu Qiu, MS, PhD2, William Padovano, MD3, Visakha Suresh, MD1, Pierce Perkins, MS1, Mark Poisler, BA1, Erica B Lee, MS4, Karim A Sarhane, MD, MSc2, Ahmet Höke, MD, PhD2, Kara Segna, MD4, Hai-Quan Mao, PhD2 and Sami H Tuffaha, MD3, (1)Johns Hopkins, Baltimore, MD, (2)Johns Hopkins University, Baltimore, MD, (3)Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, (4)Johns Hopkins University School of Medicine, Baltimore, MD
Introduction
Poor functional recovery remains the leading challenge in peripheral nerve injury (PNI) due to deleterious effects of prolonged denervation. Insulin-like growth factor 1 (IGF-1) has potent trophic and anti-apoptotic effects on neurons, Schwann cells and myocytes but is a small protein with a short half-life which makes clinical utility challenging. Previously, we encapsulated IGF-1 in biodegradable nanoparticles (NP) and then placed these in an injectable nanofiber fiber hydrogel composite (NHC). IGF-1 NP-NHC achieved sustained, local delivery of IGF-1 and improved functional recovery in prior chronic PNI rodent model and a non-human primate (NHP) pilot study (n=1/group). This study aimed to assess the IGF-1 NP-NHC in a larger definitive pre-clinical study using our novel NHP PNI model.
Methods
The IGF-1 NP-NHC was evaluated in 6 adult male rhesus macaques. The median nerve was transected and immediately repaired at the mid-brachium. NHPs were treated with IGF-1 NP-NHC or 0.9% sodium chloride (n=3/group). Injections were delivered every 6 weeks along the median nerve and within median nerve innervated muscle under ultrasound guidance. Flexor carpi radialis biopsies were sampled at 2-week intervals to assess release kinetics of the NP-NHC by quantifying target tissue IGF-1 levels. Motor function is being serially assessed serially using stimulated grip strength testing (SGST), to measure maximal tetanic contraction of forearm flexors, with recovery compared to baseline grip strength.
Results
The IGF-1 NP-NHC provided first-order release of IGF-1 for 6 weeks. IGF-1 treated NHPs demonstrated significantly increased grip strength 51 weeks after nerve repair (p=0.0076, Figure 1). Functional recovery using behavioral tasks to assess hand actions produced by the median nerve is ongoing. Histomorphometry of target muscle and nerve, and toxicological assessment of the NP-NHC will be performed once functional recovery plateaus.
Conclusion
The NP-NHC provides sustained, linear release of IGF-1 and SGST has demonstrated a greater increase in functional recovery in the IGF-1 treated NHPs. The NP and NHC production methods are designed for ease of scalable manufacturing and as an off-the-shelf formulation. Recombinant human IGF-1 and polymer components used in our designed NPs have been used in FDA-approved formulations and devices, which will facilitate clearance of regulatory hurdles. Completion of this definitive pre-clinical study has the potential to lead into early phase clinical trials of the IGF-1 NP-NHC.
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