Funded Projects

In the US, approximately 100,000 people, mainly of African and Hispanic background have Sickle Cell Disease (SCD). Pain is a constant companion and chronic disabling symptom for those with SCD. It is increasingly clear that adults with chronic SCD pain also experience periods of acute worsening of their pain. The evaluation of nonpharmacological therapies that reduce chronic pain and the need for opioid medication among individuals with SCD is critically needed to address lack of adequate pain control to prevent periods of acute deterioration and high opioid use with negative sequelae. The investigators will conduct a hybrid type 1 effectiveness-implementation trial to assess the effectiveness of acupuncture and guided relaxation in patients with SCD while observing and gathering information on implementation in three health systems. The study will utilize a 3-arm, 3-site pragmatic randomized controlled SMART trial design that evaluates adaptive interventions, in which selection of interventions responds to patients? characteristics and evolving clinical status. The investigators will use the Consolidated Framework for Implementation Research to plan, execute, and evaluate implementation processes.

Medication-based treatment for opioid use disorder OUD aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, however there is a clear need to increase the armamentarium of therapeutics for OUD. The ?non-classical? NOcicePtin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) and is a promising target based on the evidence for its function in the regulation of the rewarding and motivational effects of opioids and alcohol. This study plans to assess the ability of the novel and selective NOPr antagonist BTRX-246040 to block oxycodone intake without abuse liability, and to suppress oxycodone withdrawal and relapse-like behaviors in rats. The study will also determine Drug Metabolism and Pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. If successful, these preclinical studies will be followed by a Phase 1 clinical trial in non-treatment seeking OUD participants. These investigations will advance the prospects of validating a novel medication for OUD.

Opioid use disorder (OUD) is a significant public health problem in the United States. Particularly troubling is the rapid evolution of an opioid epidemic within the past decade, characterized by a surge in unintentional overdose deaths involving synthetic opioids, such as fentanyl. The current standard of care for opioid overdose is reversal with opioid antagonist naloxone. Naloxone is effective at reversing overdose from prescription opioids and heroin, but less effective when combating fentanyl, due to fentanyl?s high potency. Therapeutic monoclonal antibodies (mAbs) against fentanyl could overcome this problem by specifically preventing the drug from entering the central nervous system, averting overdose and attenuating opioid-induced respiratory depression. This study will develop and design of laboratory protocols needed to establish a Good Manufacturing Practice (GMP) process, quality assurance protocol, and stability profile for a new human mAb against fentanyl. Subsequent production of current GMP material will enable Good Laboratory Practice (GLP) toxicology studies in rats and dogs and eventually a Phase I/IIa clinical trial. This material will also be used in final opioid-induced respiratory depression studies in mice and non-human primates to confirm therapeutic efficacy of final drug product. If successful, these activities will enable filing for an investigational new drug application for this mAb candidate with the FDA.

High rates of relapse and overdose deaths pose significant challenges to the treatment of Opioid Use Disorder (OUD). Anti-opioid immunotherapies (i.e., vaccines and monoclonal antibodies) have great potential to reduce long-term opioid use and overdose, with minimal risk of side effects, when used in conjunction with pharmacological treatments and/or behavioral therapies. The ability of an anti-opioid vaccine to induce antibodies that render an opioid less effective, or less rewarding, and protect from accidental overdose could provide an important therapeutic option for patients undergoing treatment for OUD. The goal of this collaborative study is to design, develop, and evaluate vaccines for use in the treatment of opioid use disorder

The opioid epidemic in the United States is associated with alarming rates of overdose and overdose deaths. Medication Assisted Treatment (MAT), in combination with psychosocial intervention, is the most effective treatment for OUD; however, many individuals are unable to access treatment, are not sufficiently retained in treatment, or experience barriers that prohibit their participation in treatment. A multipronged approach is needed that includes 1) development of integrated networks of care, both formal and informal, to better address the needs of individuals with OUDs and 2) measures of the efficacy of these integrated networks for addressing the needs of individuals with OUD. This project will build a learning collaborative to address gaps in knowledge about the delivery, sustainability, and assessment of recovery service for individuals on MAT. The collaborative will foster collaboration and communication between stakeholders and with the larger community of research and providers interested in improving the delivery of OUD recovery support services. This community-academic partnership will address the lack of evidence regarding effective recovery support services.

One novel approach to address the opioid crisis is predicting the likelihood of retention in treatment for opioid use disorder (OUD) by assessing someone?s risk of early departure from treatment. Current methods rely on providers intuition to identify when an individual is at risk of leaving treatment early in order to intervene. This intervention, when it happens, often comes too late. Mobile health (mHealth) and Machine Learning (ML) predictive analytics offer a new opportunity to personalize OUD treatment, improve retention in OUD care, and mitigate the risk of relapse and overdose episodes. Project Motivate will combine physiological and behavioral data from disparate sources in order to predict when an individual is at risk of early departure from OUD treatment. If successful, results of the study will save lives, and lower medical costs, municipal emergency response costs, recidivism, workplace accidents, lost workplace productivity and costs to families.

This project will establish a rapid research pipeline for linking plant-derived compounds to nociception (pain) and to G Protein-Coupled Receptors (GPCRs) and ion channels in the druggable human genome. As more than 80% of these membrane proteins are conserved in the C. elegans nematodes, the study will screen for compounds and genes affecting nociception as well as to identify novel ligand-receptor pairs using this model organism. The study will test which understudied GPCRs and ion channels are involved in nociception as well as attraction or repulsion behaviors. This research has the potential to reveal novel ligand-receptor pairs that could serve as new entry points for improved or alternative pain treatments.

Opioids and other addictive substances have powerful rewarding properties that drive the development of addiction. They also have aversive properties that motivate their avoidance and protect against addiction. This project will explore the role of Type 2 Taste Receptor proteins (Tas2Rs or T2Rs) in regulating the aversive properties of opioids, potentially establishing an entirely new class of receptors that can be targeted for the development of novel addiction therapeutics.

There is an urgent unmet need for more efficacious analgesics that act via a non-opioid pathway. Mitogen Activated Protein Kinase-interacting kinase 2 (MNK2) is an enzyme that has been implicated in pain signaling, and there is compelling evidence that inhibiting MNK2 has significant pain-reducing effects with few side-effects. Since MNK2 selective inhibitors have not yet been identified, selective inhibition of MNK2 with a small molecule has not been possible. The development of such compounds will enable studies that will illuminate key differences between MNK2 and MNK1. More importantly, from a therapeutic standpoint, highly selective MNK2 inhibitors may prove to have enhanced efficacy and a more favorable side-effect profile than molecules that inhibit both MNK2 and MNK1. This project will support the design and synthesis of at least one MNK2 inhibitor, with >100-fold selectivity over MNK1, that may be developed into a lead compound for treating neuropathic pain.

G-protein coupled receptor 3 (GPR3) is an orphan receptor present in the central nervous system (CNS) that plays important role in many normal physiological functions and is involved in a variety of pathological conditions. Although the brain chemical that activates this receptor has not been identified, work with GPR3 knockout mice has identified GPR3 as a novel drug target for several Central Nervous System (CNS) mediated diseases including neuropathic pain. However, despite the emerging behavioral implications of the GPR3 system, little is known about how GPR3 affects behavior due to the lack of potent and selective chemical probes that allow scientists to examine functioning of the receptor. Recently, two cannabinoid chemicals present in the cannabis plant were discovered as affecting GPR3. This study will modify the chemical structure of these compounds to increase their potency and selectivity so that they may be used as pharmacological tools to investigate the role of GPR3 in modulating pain. In addition, this project focuses on identifying new compounds that show promise for development into therapeutics for the treatment of pain.

Chronic orofacial pain during Temporomandibular Disorders (TMD) and oral cancer is a significant health problem with scarce non-opioid treatment options. This study aims to validate critical regulators of the balance between protective immunity and immunopathology during chronic inflammatory diseases?tumor necrosis factor alpha superfamily members, LIGHT (TNFSF14) and lymphotoxin-beta (LT?) and their receptors, LT?R and Herpes Virus Entry Mediator (HVEM)?as novel therapeutic targets. The study also seeks to determine whether inhibition of LIGHT and LT? signaling prevents the development and inhibits maintenance of chronic TMD and oral cancer pain via peripheral mechanisms involving plasticity of immune, muscle and tumor cells as well as sensory neurons. The study will define the contribution of LIGHT and LT? signaling to TMD-induced excitability of trigeminal sensory neurons innervating the masseter muscle and joint. New validated therapeutic targets for prevention and treatment of orofacial pain that can be peripherally targeted would reduce side effects of current pain medicates related to drug dependence or tolerance.

This project aims to develop and clinically validate a 64-channel spinal cord stimulation therapy for treating chronic neuropathic pain of the lower extremities, groin, and lower back. With an increased channel count and the ability to precisely target medial and lateral structures of the spinal cord, the system will treat chronic pain with greater efficacy and reduced side effects. This project will pursue a safe, effective, and non-addictive treatment for neuropathic pain through the testing of enhanced HD64 active leads to be manufactured under GMP regulations. The leads will then undergo electrical, mechanical, biocompatibility, and sterilization testing before being tested in a 10-subject early feasibility study.