An Engineered Interleukin-2/Receptor Complex for the Treatment of Chronic Migraine and Post-Traumatic Headache
Abstract
This application responds to the Fiscal Year 2022 Chronic Pain Management Research Program Focus Area: Development of novel non-opioid pharmacological solutions for the treatment of chronic pain. The research objective is to investigate whether H1222, an engineered interleukin-2/receptor complex protein, can be an effective treatment for chronic migraine and post-traumatic headache as well as the co-occurring cognitive impairment. Chronic migraine and post-traumatic headache affect a large number of U.S. military personnel and Veterans due to the stress and traumatic brain injury they encounter in the line of duty. In addition to the frequent and debilitating headache, traumatic brain injury often causes cognitive impairment, severely affecting the return to active duty or a fully functional civilian life. Despite the high prevalence, chronic migraine and post-traumatic headache are poorly understood and inadequately treated. Many patients are either not responsive to the current drugs or intolerant to their side effects. There is an urgent need to develop safer and more effective treatments. Recent work from our lab has shown that, in mouse models of chronic migraine and post-traumatic headache, daily treatment of low-dose interleukin-2 (LD-IL-2) successfully abolishes chronic headache-related behaviors as well as mild traumatic brain injury-induced memory deficit. Mechanistically, we have found that LD-IL-2 exerts therapeutic effects through expanding regulatory T cells, a special type of immune cell that suppresses the functions of various other immune cells. These results strongly suggest that enhancing the number and/or the function of regulatory T cells can alleviate the recurring headache as well the co-existing cognitive impairment in chronic migraine and post-traumatic headache patients. Many clinical studies of autoimmune diseases have shown that LD-IL-2 preferentially expands regulatory T cells and is well tolerated in patients. That said, IL-2 has to be limited at low-doses to avoid severe side effects. It also requires daily administration, which is difficult to follow. To address these issues, we have generated an engineered IL-2/receptor complex protein H1222, aiming to achieve more selective expansion of regulatory T cells with less frequent administration. Indeed, preliminary results indicate that a single injection of H1222 is sufficient to selectively and dose-dependently expand regulatory T cells in mice. Importantly, H1222 promotes faster resolution of chronic headache-related behaviors in mice with fewer and less frequent injections. Built upon these exciting findings, we propose to further characterize the properties of H1222 and to assess its efficacy in mouse models of chronic migraine and post-traumatic headache in the present study. First, we will treat mice with H1222 at a wide dose range to examine the dose-response relationships of H1222-induced regulatory T cell expansion in the blood. We will also investigate the onset, peak/plateau and recovery of H1222-induced regulatory T cell increase in tissues that are responsible for headache generation. In addition, we will determine the in vivo half-life of H1222. Secondly, we will use two mouse models to investigate whether H1222 abolishes chronic headache-related behaviors resulting from different mechanisms. This allows us to predict whether H1222 will be effective for a distinct subpopulation of patients or a broad spectrum of chronic migraine patients with various underlying causes. Lastly, we will assess H1222 in a mouse model of mild traumatic brain injury. We will ask whether H1222 alleviates acute and chronic post-traumatic headache- related behaviors; and whether H1222 abolishes injury-induced cognitive impairment. All in all, in the short term, successful completion of this study will reveal whether H1222 selectively expands regulatory T cells in vivo over a wide dose range. It will also inform us whether i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310615
Entities
People
- Yu-qing Cao
Organizations
- United States Army
- Washington University in St. Louis