Restoration of Neuromuscular Function Following Critical Nerve Gap Injuries

1 Abstract – More than 500,000 surgical procedures are performed annually in the United States to address 2 peripheral nerve injuries at a cost of more than $1.1B. Fewer than 50% of patients report satisfactory functional 3 recovery following nerve injury repair procedures, likely due to slow axonal regrowth and difficulty in bridging 4 across the sites of injury due to inflammation, scarring, and axonal misdirection. Poor recovery from nerve injuries 5 leads to significant impacts on patient quality of life. For example, motor and/or sensory impairment from nerve 6 injuries can prevent patients from performing basic daily activities, can be accompanied by chronic pain, and 7 result in severe psychosocial impacts. Injuries to proximal segments and gaps > 1 cm are challenging and have 8 inconsistent outcomes, while gaps larger than 3 cm seldom achieve any meaningful recovery. A number of 9 products used for nerve gap injury repair such as conduits and allografts exist; however, none has shown 10 compelling clinical improvements in functional outcomes, particularly when compared to the “gold standard” 11 autograft. Renerva has developed Peripheral Nerve Matrix (PNM), a tissue-based hydrogel derived from porcine 12 nerve that can be used as a nerve conduit filler for the purpose of improving functional outcomes following the 13 repair of challenging gap injuries. PNM has been shown to modulate key early events in the nerve regeneration 14 process including macrophage recruitment, macrophage polarization towards a pro-regenerative/angiogenic 15 phenotype, and Schwann cell recruitment. In a sub-critical (0.8 cm) rodent nerve gap injury model, silicone 16 conduits filled with PNM were shown to increase axon extension (10x empty conduit control) and improve 17 functional recovery (compound motor action potential; 2x control), which was equivalent to the improvements 18 obtained using control autografts. While promising, PNM has yet to be tested in critical nerve gap defect models, 19 and additional optimization of the PNM formulation could yield results exceeding the performance of nerve 20 autografts. In this Phase I project, Renerva will optimize the PNM formulation (gel concentration and residual 21 chondroitin sulfate content) and mechanical properties (rheologic and compressive modulus) with the goal to 22 exceed the performance of the gold-standard nerve autograft in a rat critical nerve gap injury model (1.5 cm). An 23 established suite of longitudinal motor and sensory endpoints will be employed over a period of 12 weeks to 24 assess in vivo recovery. Electrophysiologic function as well as multiple histologic and immuno-labeling endpoints 25 will be performed at termination. Renerva will further test the shelf stability of the optimized PNM formulation via 26 in vitro and in vivo studies. The proposed objectives address critical requirements for regulatory and future clinical 27 use of PNM, and will critically de-risk PNM to enable Phase II of this project. Phase II will determine the optimized 28 PNM's ability to promote recovery in clinically relevant large gap injuries (>3 cm) in a large animal model and 29 support the completion of the safety tests required for commercializing the optimized PNM product. This project 30 will advance the field and allow clinicians to offer an effective product for critical size nerve gap injuries.