Nonviral Gene and Reprogramming-Based Cell Therapies for Peripheral Nerve Injury
Abstract
This project will address the topic of Peripheral Neuropathy, focusing on the area of encouragement of regenerative medicine-based solutions for peripheral nerve injury, such as gene therapy. Traumatic nerve injuries in the military typically result from high-velocity gunshot wounds or blast injuries that compromise multiple tissues. Although warfare has historically led to a large number of nerve injuries, the standard care for this condition has evolved very little throughout conflicts and continues to be a significant challenge for military surgeons. Moreover, the treatment of traumatic nerve injuries is often delayed in order to address additional complications from the injury, including hemorrhages, tissue necrosis and infections, among others. This, in turn, can result in severe long-term consequences, as the injured nerve and denervated muscle tissue continue to progressively deteriorate. The complications from peripheral nerve injuries are further compounded by lifelong chronic disabilities. Nerve injuries could result in pain, weakness, loss of sensation, and loss of independence, and as such have a significant impact in unit readiness and return-to-duty rates. Therefore, there is a clear need for the development of novel approaches that can be used to treat traumatic nerve injuries more promptly, and with simple-to-implement and versatile methodologies compatible with intervention across all levels of military medical care. This application is focused on developing game-changing nanotechnologies that could be used to deliver simple to implement solutions, compatible with implementation at all levels of military medical care (e.g., from the battlefield to major military centers in the U.S.), for peripheral nerve injuries in the military. The proposed research will seek to develop novel nanotechnologies to repair or protect mangled nerves or muscle through a one-time intervention, lasting only a few milliseconds. The goal is to potentiate endogenous reparative mechanisms based on the novel concept of tissue nanotransfection (TNT)-driven reprogramming, which can either replace the current standard of care for nerve injuries in the military or delay progressive nerve damage until proper surgical intervention. TNT is a technology developed by the Principal Investigator, Gallego-Perez, which can be used to deliver therapeutic genes into tissues in a fast (e.g., it only takes a one-time intervention lasting ~100 milliseconds), benign (e.g., it does not cause tissue damage or deleterious side effects), and effective manner (e.g., superior performance to status quo gene delivery methodologies). The proposed studies will be conducted in preclinical animal models of nerve injury, and will be subdivided into 4 aims, as follows: Aim 1: Develop optimized TNT strategies to generate new blood vessels to support the repair of nerve injury: Blood vessels are important for the repair and regeneration of mangled nerve tissue. At the completion of these studies, we expect to have developed novel strategies to drive the formation of new blood vessels that can help injured nerve repair faster and more effectively. Aim 2: Develop optimized TNT approaches to generate neurons in denervated skeletal muscle as a protective strategy: Nerve signals are important for the health of muscle tissue. Nerve injury can sometimes remove those nerve signals, which results in muscle atrophy. At the completion of these studies, we expect to have developed novel strategies to drive the formation of neurons in muscle tissue that can help to maintain muscle health until the nerve signals can be permanently restored. Aim 3: Develop optimized TNT approaches to achieve localized immunoprotection in cellular nerve allografts: Large nerve defects could be repaired better with donor nerve graft tissue that still contains cells. However, since those cells, which are key to the success of the graft, can be rejected by the patient’s immune system, the p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210392
Entities
People
- Daniel Gallego-Perez
Organizations
- Ohio State University
- United States Army