Chronic pain is a complex disorder affects both physical and mental functioning and could compromise quality of life. Treatment for chronic pain is far from satisfactory because of the aversive effects associated with opioid medications. It is known that the development and maintenance of pain are mediated in the central nerves system; however, the pathophysiological causes contributing to pain remain to be determined. Neuroepigenetic mechanisms have been linked to the development and maintenance of pain through preclinical models of inflammatory and neuropathic pain. One family of epigenetic enzymes, known as histone deacetylases (HDACs), are being considered as therapeutic targets due to the analgesic responses achieved through HDAC inhibitors. Inhibition of HDACs leads to symptom amelioration in experimental models of pain. However, there is limited evidence about HDAC density concerning human pain across the entire brain. We have recently achieved a significant research goal by resolving a PET imaging agent, [11C]Martinostat, that selectively binds to a subset of HDAC enzymes. Our imaging studies to date, including more than 40 healthy human volunteers, have identified key features that make [11C]Martinostat a rare and promising HDAC probe including robust brain uptake and high specific binding. We are extremely excited to take a large step forward to develop [11C]Martinostat PET as a quantitative image biomarker for pain detection and diagnosis, with an ultimate goal of using [11C]Martinostat PET to monitor treatment responses. In this application, we propose a series of initial proof-of-concept clinical validation studies to evaluate if [11C]Martinostat PET is a sensitive biomarker to detect the typical (axial) chronic low back pain (cLBP). When successful, we will further explore the validity of using [11C]Martinostat PET to differentiate subtypes of pain by comparing [11C]Martinostat PET binding between axial cLBP with cLBP patients with radiculopathy. In addition, we plan to conduct a longitudinal study in sub-acute LBP patients (sLBP) to investigate whether there is unique imaging signature that differentiate patients who have convert to cLBP vs. those who recover from low back pain. We believe the research outlined in the proposal takes a robust and systematic approach to develop and validate [11C]Martinostat PET as a quantitative image biomarker for low back pain in patients. PET/MR imaging in humans with [11C]Martinostat will deliver answers to fundamental questions about chromatin modifying enzymes in the living human brain in a way that has not been possible until now. Importantly, using [11C]Martinostat to understand the alternation of HDAC expression in chronic pain patients will enable validation of an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism/target engagement in developing novel analgesics.
Histone deacetylase (HDAC) enzymes are key components regulating gene expression in response to life experience and have recently been associated with the development and maintenance of pain. We propose to evaluate HDAC availability in the brain of lower back pain patients and determine if HDAC availability is biomarker capable of differentiating subtypes of low back pain and monitoring progression of pain.
