Gene Therapy for Prevention of Phantom Limb Pain Following Extremity Injuries
Abstract
A high percent of combat-related traumatic injuries involve the extremities. While limb salvage is possible in cases where damage is moderate, severe extremity injuries often occur as a result of high-impact blasts involving multiple tissue levels. In such cases, partial or complete amputation may be considered a best option in order to reduce long-term disability and avoid serious complications such as ischemia and infection. There are now over 1,500 amputees resulting from injuries sustained in recent conflicts. A common consequence of limb amputation, by some estimates affecting 60-90% of amputees, is the emergence of pain seeming to originate from the missing limb, called “phantom limb pain” (PLP). PLP has been described using descriptors such as crushing, burning, stabbing, and agonizing, leading to further disability and limiting participation in rehabilitation and withdrawal from daily activities. Unfortunately, pain medications, including opioids, are only modestly effective at best and are often fraught with unacceptable side effects, possibly including tolerance and addiction. Mechanisms underlying PLP are poorly understood, but appear to involve both peripheral and central nervous system reorganization of pain signaling. Thus, early post-operative pain intervention, at or near the time of amputation, is likely to be most effective in controlling aberrant pain signaling and development of PLP. The overall goal of this proposal is to develop strategies for post-operative PLP management following orthopaedic trauma (fiscal year 2017 Peer Reviewed Orthopaedic Research Program Focus Area). Recent work in our laboratory and others has been devoted to designing gene therapy strategies to intervene in alleviating neurological disorders. Using this approach, genes for therapeutic molecules such as analgesic peptides are inserted into selected pain processing regions of the nervous system where they are locally synthesized to dampen pain signals. Key advantages of this approach for the treatment of chronic pain are the ability to provide a sustained source of pain-reducing molecules directly at the centers of pain processing where they are needed, as well as avoiding the off-target side effects of systemically administered medications. For this proposal, we have selected two promising analgesic peptides that are under development in our laboratory and have shown good pain-reducing effects in other pain models. One of these, Serinehistogranin, blocks abnormal hyperexcitability in spinal cord pain processing regions, and the other adds a natural opioid peptide, endomorphin-1. The genes will be delivered using adeno-associated viral vectors, which are currently considered clinical candidates due to their safety and stability. PLP after amputation has been observed to mimic the pain that was felt in the limb before it was amputated. Combat-related extremity injuries are usually complex, involving several potential sources of injury-induced pain, particularly peripheral nerve compression/crush and limb inflammation. Thus, the first aim of the study will be to establish relevant parameters in the rat model for evaluation of gene therapy treatments. This will be done using a peripheral nerve constriction injury and/or hind limb inflammatory injection as pre-amputation pain exposure. A complete sciatic nerve transection will be used to model amputation, resulting in pain-related autotomy behaviors that can be quantified. Administration of a fluorescent reporter gene at various time points and injection routes will be used to select the most feasible and robust parameters to achieve targeted gene expression in the spinal cord. Aim 2 will assess the ability of our engineered analgesic peptides to alleviate pain-related behavior in the rat PLP model. Clinically relevant post-injury and treatment scenarios will be evaluated for pain management using the gene therapy strategy. Available pain medications wil
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810494
Entities
People
- Jacqueline Sagen
Organizations
- United States Army
- University of Miami