Grants We Funded

Abstract

Impact Statement: This proposal addresses peripheral nerve injury, a clinical area with critical need for scientific advancements. Using living tissue engineered nerve grafts (TENGs) combined with a safe and effective adeno-associated virus (AAV) gene therapy approach, we propose a novel strategy for peripheral nerve regeneration. Control of when and where the nerve growth factors are present along the nerve graft is the key impact for this study. We hope to improve on strategies for bridging long nerve gaps, and to use these AAV-TENGs as a platform to study different nerve growth factors and their effect in nerve regeneration.

Project Summary: Full functional recovery after nerve injuries to the arm and leg is not readily achieved. When injured, the proximal nerve end has to travel down and reconnect to the distal nerve end and muscle. The long nerve gap distance and the slow axonal regrowth rate of approximately 1 mm per day make this nerve regeneration difficult. Oftentimes, the regrowth after repair does not occur in sufficient time. This leads to irreversible muscle atrophy and permanent functional damage. The gold standard treatment to address this problem is to take a less essential sensory nerve from another part of the body and to use it to connect the injured nerve ends (autograft). Several limitations to this approach include numbness at the body site from where the autograft is taken, overall insufficient number and length of autografts available, and increased operative time. For this grant application, we propose to develop novel living tissue engineered nerve grafts (TENGs) that produce growth factors, which can accelerate an injured nerve to regrow towards the target nerve and muscle. TENGs have been well-established in our laboratory and have been shown to be as good as autografts in small animal when used to bridge a 1 cm nerve gap. We hope to further enhance the TENGs for longer nerve gaps by infecting them with adeno-associated virus (AAV) that encode for nerve growth factors. AAVs are safe and effective vehicles for gene therapy and are already used in clinical trials for many diseases. While the production of these nerve growth factors are likely to be beneficial, uncontrolled production will lead to bad outcome. Hence, we plan to use AAVs that become activated only in the presence of doxycycline, an antibiotic that is widely used. This will enable us to control the growth factor production from the AAV-TENGs on and off. In addition, we will be designing the AAV-TENGs by infecting only one end of the TENG, so that the growth factors are produced from one end of the TENG that is closer to the target but not the other end. This will accelerate the regrowth rate by enticing and directing the growing nerves towards the target instead of allowing the growing nerves become distracted by ubiquitous presence of growth factors (“candy-store effect”). These studies will be done at a benchtop for this proposal. Our long term goal is to move this technology to small and then large animal models, and eventually to human clinical trials to improve nerve generation after injury.

Biography
I am a fellowship-trained Orthopaedic Hand surgeon with a PhD background in Bioengineering from University of Pittsburgh and UPMC. During my PhD training, I worked on tissue engineering approaches for cartilage regeneration. I became an Assistant Professor at University of Pennsylvania (UPenn) and a staff physician at Corporal Michael J. Crescenz VA Medical Center (CMC-VAMC) in Philadelphia in September 2020, with the goal of becoming a clinician-scientist. I have a strong passion to perform translational basic science research in my clinical area of Hand Surgery, with specific focus on peripheral nerve regeneration and recalcitrant bone healing. Through my patient interactions at UPenn and CMC-VAMC, including my experiences taking level-1 hand trauma call at Penn Medicine system, I see first-hand the clinical areas that desperately need further scientific advancements. In the future, I hope to become an established investigator with my own laboratory to perform translational benchtop research that I can ultimately bring back to my patients.