Targeting STAT3 Signaling to Promote Recovery from Neuropathic Pain
Abstract
Injury to nerves often results in chronic, debilitating pain that is not managed effectively by currently used medications. It is becoming increasingly apparent that cells of the immune system (namely macrophages) are important mediators of the pain that follows nerve injury. However, currently available drugs for nerve injury pain are not designed to target macrophages; these cells, therefore, represent a new area to explore for development of novel pain-killing drugs. Based on how macrophage-targeting drugs work, we predict that such drugs are far less likely to have effects on the brain or become addictive, like opioids. Of the focus areas designated in this grant mechanism, we are addressing two—the first is development of non-opioid therapies for the treatment of chronic pain and the second is development of mechanistically justified therapies to prevent chronic pain. Inflammation at sites of nerve injury that does not resolve is thought to be due (at least in part) to macrophages and other immune cells entering the injured tissue from the bloodstream. They are attracted there by inflammatory signals from the damaged tissue and are able to enter more readily because of the increased leakiness of the barrier separating the blood vessels from the nerve tissue. Once present in the nerve, these macrophages produce reactive oxygen species, a known promoter of chronic pain. Crucially, many of these processes are mediated by a protein within macrophages and other cells referred to as STAT3. We developed a drug (TTI-101) that targets STAT3 and reduces inflammation, a roadblock to pain relief and recovery. This represents a significant departure from the types of pain-relieving drugs and drug candidates that have come before, since it addresses one of the root causes of nerve injury pain becoming chronic. Our preliminary data support the hypothesis that TTI-101 will bring about both short-term and long-term relief of nerve injury pain, which, if further supported by the studies outlined in this proposal, would have a dramatic positive effect on patient quality of life, something that currently eludes as many as three out of every four patients with this chronic pain. While we will first be testing this new drug in animal models of nerve injury pain caused by surgery, our earlier observations strongly suggest that the biological mechanisms underlying different types of nerve injury pain overlap. This suggests to us that patients suffering from nerve pain due to other common causes, such as diabetes or cancer chemotherapy, may also benefit from treatment with TTI-101. We predict that the risk to patients of taking TTI-101 will be low, since the drug is well-tolerated in multiple animal species, and it targets a biological process that is only active at sites of injury and inflammation. Furthermore, once we have extensively validated TTI-101 in rodents with nerve injury, we will run a limited number of experiments in squirrel monkeys. If successful, this will provide the best possible evidence that TTI-101 will one day be effective in pain relief in patients. Upon successful completion of this study, we will be well-positioned to begin the process of clinical trials of TTI-101 in patients experiencing nerve injury pain. In addition, our studies also will shed new light on the importance of resolving inflammation at sites of nerve injury, and how and why this relates to ongoing pain. Ultimately, our hope is that a drug such as TTI-101 can be used to leverage the patients’ own immune system to begin the process of healing damaged nerves and bring about substantial and durable pain relief.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210685
Entities
People
- Andrew J Shepherd
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army