Funded Projects

The need to develop non-opioid therapeutics for chronic pain is greater than ever.  One option being explored is inhibiting the activity of calpains – enzymes that have been shown to cause pain in animal models of chronic pain.  Using an artificial intelligence (AI)-driven drug discovery platform, researchers have uncovered and validated four calpain-1 inhibitors using biochemical assays.  This study by 1910 Genetics Inc. hopes to synthesize multiple analogs of its most potent discovered calpain-1 inhibitor and determine its effectiveness against calpain-2 and certain enzymes that break down proteins.  Findings that successfully significantly inhibit calpain-1 in at least one animal model of chronic pain could lead to the first oral, central nervous system penetrating selective calpain-1 inhibitor [non-opioid therapeutic] for chronic pain.

MNK-eIF4E signaling is activated in nociceptors upon exposure to pain or peripheral nerve injury, promoting cytokines and growth factors and increasing nociceptor excitability, which leads to neuropathic pain. Genetic or pharmacological inhibition of MNK signaling blocks and reverses nociceptor hyperexcitability as well as behavioral signs of neuropathic pain. A clinical phase drug for cancer shows strong specificity as an MNK inhibitor but requires optimization because MNK inhibition in the central nervous system (CNS) may lead to depression, an unacceptable side effect for a neuropathic pain drug. The research team plans a targeted medicinal chemistry and screening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatment with the goal of restricting its CNS penetration while retaining potency, specificity, and in vivo bioavailability and efficacy.

New approaches that can effectively ameliorate acute and chronic migraine pain are urgently needed. Due to its critical roles in inducing migraine pain, CGRP and its receptor complex, the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) have been targeted for migraine treatment. A new strategy for targeting the CGRP-mediated signaling pathway is needed to meet the medical need of migraine patients. The team developed a group of long-acting CGRP/RAMP1-specific peptide super-antagonists that form gels in situ in aqueous solution. Based on this exciting finding, the investigators propose to develop and identify the most potent antagonistic analog candidates (Aim 1), and characterize the pharmacokinetics of gel depots made of the selected candidates in vivo (Aim 2). This feasibility study is needed to explore the translational potential of these newly invented super-antagonists for the treatment of chronic migraine in combination with conventional migraine agents. 

We discovered a class of non-opioid modulators of the T-type Cav3.2 channel that could treat neuropathic pain. In vivo pharmacokinetic and pharmacodynamic studies and preliminary toxicological studies identified AFA-279 and other candidates, which did not produce observable side-effects and showed greater analgesic effects than other neuropathic pain medications in rodent models. The goal of this proposed project is to submit the IND application on our Cav3.2 modulator to the Food and Drug Administration (FDA). We will produce AFA-279 under Good Manufacturing Practice (GMP)–like conditions using chemical manufacturing controls for Good Laboratory Practice (GLP) nonclinical toxicity studies and GMP clinical batch future Phase 1 clinical trials, complete toxicological and safety studies to establish the safety profile of AFA-279, prepare and submit the IND application, and then initiate early clinical trials. Our ultimate goal is to deliver a safer, more effective, non-opioid Cav3.2 channel modulator to patients suffering from neuropathic pain.

The ability to de-risk lead compounds during pre-clinical development with advanced “organoid-on-a-chip” technologies shows promise. Development of microphysiological models of the peripheral nervous system is lagging. The technology described herein allows for 3D growth of high-density axonal fiber tracts, resembling peripheral nerve anatomy. The use of structural and functional analyses should mean drug-induced neural toxicity will manifest in these measurements in ways that mimic clinical neuropathology. The goals of this proposal are to establish our human model using relevant physiological measurements in tissues fabricated from human iPS cells and to validate the model system with a library of compounds, comparing against conventional cell culture models. Validating the peripheral nerve model system with drugs known to induce toxicity via a range of mechanisms will demonstrate the ability of the system to predict various classifications of neuropathy, yielding a high-content assay far more informative than traditional in vitro systems.

For patients with neuropathic pain refractory to therapy using small molecules, modulation of specific neural structures in the central or peripheral nervous system can provide effective alternative treatments. While current Food and Drug Administration–approved devices for dorsal root ganglion (DRG) stimulation are safe and effective, there have been an unfortunate number of adverse events associated with pulse generator infections and lead migration. The research team will develop a wireless, millimeter-sized nerve stimulator that can be delivered through the vasculature and stimulate the DRG to alleviate symptoms of neuropathic pain and the associated minimally invasive delivery method. This endovascular nerve stimulation (EVNS) system depends on development and integration of key novel technologies into an endovascular stent. The magnetoelectric transducers and electronic circuits will convert wireless power and data into stimulus patterns that can trigger neural activity in the DRG via miniature electrodes. After chronic demonstration of safety and functionality in large animal models, the team will prepare for regulatory discussions with the FDA. If successful, the EVNS will provide a technology platform for treating other neuropathic pain syndromes. 

Pain in the muscles and surrounding connective tissue (myofascial pain) is a significant and poorly understood health concern affecting hundreds of millions of Americans. There is a great need for tools to assess changes to myofascial tissues in individuals with chronic pain as well as to measure the effect of commonly used therapies. This project will use three imaging tools to look at differences between shoulder tissue in people with myofascial pain compared to those without pain. Using a machine learning approach, this research aims to develop a biomarker signature for myofascial pain, which will be evaluated in a randomized controlled clinical trial based on its ability to predict patient responses to myofascial pain treatments.

The opioid crisis has underscored the urgency of alleviating patients’ chronic low back pain (cLBP) with effective therapies, including evidence-based nonpharmacologic approaches. Mindfulness-based stress reduction (MBSR) is now recommended by the American College of Physicians for initial treatment of cLBP. A pragmatic clinical trial (PCT) will inform health care decision makers about whether this program can be implemented in a real-life clinical setting and measure its impact on outcomes. The OPTIMUM (Optimizing Pain Treatment In Medical settings Using Mindfulness) program will integrate and test an evidence-based mindfulness clinical pain program for patients with cLBP in the primary care provider (PCP) setting. It will be conducted with three health care system sites. Four hundred and fifty persons ? 18 years of age with cLBP will be randomized to OPTIMUM + PCP Usual Care or PCP Usual Care.

This project will use state-of-the-art technologies to analyze individual cells to characterize how human pain receptors communicate pain between the human dorsal root ganglia and the brain – including how the signals vary across diverse populations. This research will generate useful, high-quality human data about pain for further analysis and re-use by other scientific teams, toward identifying and prioritizing novel therapeutic targets for pain.

Chronic low back pain (cLBP) is recurrent and often nonresponsive to conservative treatments. Biomechanists, physical therapists, and surgeons each utilize a variety of tools and techniques to assess and interpret qualitative movement changes to understand potential mechanical and neurological sources of low back pain and as critical elements in their treatment paradigm. However, objectively characterizing and communicating this information is currently impossible, since clinically feasible (i.e., cost-effective, objective, and accurate) tools and quantitative benchmarks do not exist. This research addresses the challenge to improve cLBP outcomes through the use of unique, inexpensive, screen-printable, elastomer-based, nanocomposite, piezoresponsive sensors, which will be integrated into a SPInal Nanosensor Environment (SPINE) sense system to measure lumbar kinematics and provide an objective, quantitative platform for diagnosis, monitoring, and follow-up assessment of cLBP.

Researchers will develop a novel transcranial focused ultrasound (tFUS) device for pain treatment and establish its effectiveness for treating sickle cell disease (SCD) pain in humanized mice. The tFUS will target the specific cortical regions involved in SCD pain using a novel non-invasive electrophysiological source imaging technique. The project’s goals have several aims. Aim 1: Develop tFUS devices for pain treatment. The mouse-scale system will be designed to validate the therapeutic effect of stimulating the anticipated cortical targets. This will inform development of the simpler human-scale system, which will use models of the skull to select cost-effective transducers to reach the targets. Aim 2: Evaluate tFUS effectiveness and optimize stimulation parameters in an SCD mice model. Researchers will determine effective tFUS parameters to chronically reduce SCD pain in mice and validate this using behavioral measures. Aim 3: Use electrophysiological source imaging to target and trigger closed-loop tFUS in animal models. This aim also includes performing safety studies to prepare for human trials. The project will develop a transformative, noninvasive tFUS device to effectively and safely treat pain in SCD. 

Although digital health technologies are now widely available for both therapeutic and monitoring applications, there are wide variations in patient knowledge, attitudes, beliefs, and preferences regarding their uptake and effectiveness. There are also sociodemographic variations in willingness to participate in digital health research studies, both for chronic pain and other common disorders. However, few efforts have systematically examined patient-level predictors of digital health uptake and benefit among diverse individuals who experience chronic pain. This research will employ mixed methods to examine variations in engagement and benefit among diverse participants in a large clinical trial examining the benefits of virtual reality for treatment of chronic lower back pain.

Digital health interventions, such as virtual reality (VR) applications, have become available for the treatment and monitoring of numerous health conditions, including pain management. A current HEAL-funded study is evaluating the role of a therapeutic VR approach for chronic low back pain. However, racial and ethnic disparities exist in patient access and response to such VR applications, as well as in the incidence and reporting of pain. For example, non-Hispanic Blacks and Hispanics are more likely to report severe pain than non-Hispanic Whites, yet are less likely to have access to digital health information and interventions. To address these disparities, this project will develop a framework to advance diversity and inclusion in digital health trials and will seek to increase the proportion of non-Hispanic Black and Hispanic participants in the ongoing VR trial by tailoring recruitment materials and using novel artificial intelligence-driven cohort building tools.