Funded Projects

NOFO Title: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-21-010
Summary:

Patients with severe, intractable chronic pain primarily receive treatment with opioids, and non-opioid treatment options are urgently needed. These patients may be candidates for treatment using other types of pain medications administered via intrathecal injection—that is, injection directly into the fluid-filled space between the membranes surrounding the brain and spinal cord. Intrathecal injection requires much lower medication doses than systemic administration. Centrexion Therapeutics Corporation seeks to develop CNTX-3100, a highly selective and highly potent novel small molecule that activates the nociception receptor (NOPr), for intrathecal administration using a pump approved by the U.S. Food and Drug Administration. In animal studies, such NOPr agonists had powerful analgesic effects when delivered directly to the spinal cord by intrathecal administration. CNTX-3100 has ideal properties for intrathecal delivery and in animal studies provided pain relief and a safety profile that was superior to intrathecally administered morphine. This project will scale up the drug, develop a formulation that ensures a stable product for intrathecal delivery, and conduct preclinical toxicity studies to prepare for a Phase 1 clinical trial.

NOFO Title: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-19-010
Summary:

Pain signals originate predominantly in a subset of peripheral sensory neurons that harbor a distinct subset of voltage-gated sodium (NaV) channels; however, current NaV channel blockers, such as local anesthetics, are non-selective and also block NaV channels vital for function of the heart, muscle, and central nervous system. Genetic studies have identified human NaV1.7, NaV1.8, and NaV1.9 channel subtypes as key players in pain signaling and as major contributors to action potential generation in peripheral neurons. ProTx-II is a highly potent and moderately selective peptide toxin that inhibits human NaV1.7 activation. This study will optimize ProTx-II selectivity, potency, and stability by exploiting the new structures of ProTx-II—human NaV1.7 channel complexes, advances in rational peptide optimization, and rigorous potency and efficacy screens to generate high-affinity, selective inhibitors of human NaV1.7, NaV1.8, and NaV1.9 channels that can define a new class of biologics to treat pain.

NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

There is an urgent need for new non-opioid therapeutic agents that treat the pain associated with Osteoarthritis (OA) ? a chronic, progressive disease that leads to pain in weightbearing joints, pain during movement, and pain at rest. This project will refine techniques for targeting several proteins expressed in sensory neurons associated with OA pain, with the goal of testing the potential of these proteins to serve as targets for development of effective, non-opioid painkillers.

NOFO Title: HEAL Initiative: Planning Studies for Initial Analgesic Development [Small Molecules and Biologics] (R61 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-21-029
Summary:

Natural products, which are substances found in nature and made by living organisms, have been used in the past as good sources for developing new medications. Natural products isolated from marine bacteria that attach to the pain-signaling protein sigma-2 receptor (also known as transmembrane protein 97 [TMEM97]), may serve as a starting point to create new, non-opioid pain medications. This project will use chemistry and biology approaches to refine such natural products as a treatment for neuropathic pain.

NOFO Title: HEAL Initiative: Translational Development of Diagnostic and Therapeutic Devices (R18 Clinical Trial Not Allowed)
NOFO Number: RFA-EB-22-002
Summary:

People with sickle cell disease often experience episodes of severe pain (vaso-occlusive crisis) that are caused by the abnormal red blood cells and frequently result in opioid use. Tools that can identify and measure the degree of such a crisis early on could allow clinicians to pre-emptively disrupt this process. This project aims to develop a rapid, automated screening technology for evaluating red blood cells that allows assessment of patients at risk of pain crisis right in their health care provider’s office.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: PAR-20-092
Summary:

Osteoarthritis is a degenerative joint disease marked by progressively worsening chronic joint pain that affects function and quality of life. Non-opioid, alternative medications are needed for people with this condition. Joint inflammation, damage, and pain involve signaling through the interleukin-6/glycoprotein 130 pathway. This project will test blocking this pathway in rodents with a new molecule with improved drug-like properties, toward developing an oral medication for osteoarthritis. 

NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041
Summary:

Multidisciplinary chronic pain treatments show incomplete recovery at the population level because of significant heterogeneity on the individual level in the high impact chronic pain population. Subgroups of individuals either completely respond, do not change, or even worsen following pain management. Therefore, diagnostic biomarker signatures are needed to differentiate high impact chronic pain from low impact chronic pain. This study aims to develop prognostic biomarkers to predict the disease trajectory for individuals with musculoskeletal high-impact chronic pain. These biomarker signatures will integrate central nervous system (CNS), multi-?omic?, sensory, functional, psychosocial, and demographic domains into detection algorithms. Biomarker signatures from the proposed research are intended to facilitate risk and treatment stratification for clinical trial design and to facilitate treatment decisions in clinical practice for patients with musculoskeletal chronic pain.

NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO Number: NOT-NS-18-073
Summary:

Spinal cord injury (SCI) impairs sensory transmission leading to chronic, debilitating neuropathic pain. While our understanding of the molecular basis underlying the development of chronic pain has improved, the available therapeutics provide limited relief. In the lab, we have shown the timing of exercise is critical to meaningful sensory recovery. Early administration of a sustained locomotor exercise program in spinal cord–injured rats prevents the development of neuropathic pain, while delaying similar locomotor training until pain was established was ineffective at ameliorating it. The time elapsed since the injury occurred also indicates the degree of inflammation in the dorsal horn. We have previously shown that chronic SCI and the development of neuropathic pain correspond with robust increases in microglial activation and the levels of pro-inflammatory cytokines. This proposal seeks to lengthen the therapeutic window where rehabilitative exercise can successfully suppress neuropathic pain by pharmacologically reducing inflammation in dorsal root ganglia.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

TWIK-related spinal cord K+ (TRESK) channel is abundantly expressed in all primary afferent neurons (PANs) in trigeminal ganglion (TG) and dorsal root ganglion (DRG), mediating background K+ currents and controlling the excitability of PANs. TRESK mutations cause migraine headache but not body pain in humans, suggesting that TG neurons are more vulnerable to TRESK dysfunctions. TRESK knock out (KO) mice exhibit more robust behavioral responses than wild-type controls in mouse models of trigeminal pain, especially headache. We will investigate the mechanisms through which TRESK dysfunction differentially affects TG and DRG neurons. Based on our preliminary finding that changes of endogenous TRESK activity correlate with changes of the excitability of TG neurons during estrous cycles in female mice, we will examine whether estrogen increases migraine susceptibility in women through inhibition of TRESK activity in TG neurons. We will test the hypothesis that frequent migraine attacks reduce TG TRESK currents.

NOFO Title: Mechanisms, Models, Measurement, & Management in Pain Research (R01)
NOFO Number: PA-13-118
Summary:

Chronic pain diminishes the quality of life for millions of patients, and new drugs that have better efficacy and/or fewer side effects are needed. A promising target is the sphingosine-1-phosphate (S1P) receptor system, which mediates central nervous system (CNS) neuromodulatory functions. FTY720-phosphate, the active metabolite of FTY720 (FTY), acts as an agonist at four of the five S1P receptors (S1P1, 3, 4, 5). We propose that the S1P1 receptor is a target for treatment of neuropathic pain. We will test whether S1P1 receptors mediate anti-hyperalgesic effects in a mouse neuropathic pain model. The specific aims are to: 1) determine the role of S1P1Rs in alleviation of neuropathic pain by S1PR ligands; 2) determine the role of FTY-induced S1PR adaptation in FTY-mediated reversal of neuropathic pain; and 3) determine the role of S1P and S1P1 receptors in spinal glia in CCI-induced neuropathic pain and its reversal by FTY.

NOFO Title: HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: NS22-034
Summary:

Interstitial cystitis/bladder pain syndrome is a debilitating disease affecting many women. Opioid-based pain management is a common feature of current treatment approaches but is associated with the risk of addiction. The causes of this disorder remain unknown, and no effective treatments are available. This project will provide new insights using genetic, medication-based and other approaches in a mouse model, along with single-cell gene expression studies conducted with cells from mice and human patients who have this condition. The analyses will help provide targeted, safe, and effective treatment approaches for individuals with interstitial cystitis/bladder pain syndrome.

NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041
Summary:

Up to 5 percent of adolescents suffer from high-impact chronic musculoskeletal (MSK) pain, and only about 50 percent with chronic MSK pain who present for treatment recover. Current treatments for chronic MSK pain are suboptimal and have been tied to the opioid crisis. Discovery of robust markers of the recovery versus persistence of pain and disability is essential to develop more resourceful and patient-specific treatment strategies, requiring measurements across multiple dimensions in the same patient cohort in combination with a suitable computational analysis pipeline. Preliminary data has implicated novel candidates for neuroimaging, immune, quantitative sensory, and psychological markers for discovery. In addition, a standardized specimen collection, processing, storage, and distribution system is in place, along with expertise in machine learning approaches to extract reliable and prognostic bio-signatures from a large and complex data set. This project will facilitate risk stratification and a resourceful selection of patients who are likely to respond to current multidisciplinary pain treatment approaches.

NOFO Title: Emergency Awards: HEAL Initiative-Early-Stage Discovery of New Pain and Opioid Use Disorder Targets Within the Understudied Druggable Proteome (R21 Clinical Trial Not Allowed)
NOFO Number: RFA-TR-22-011
Summary:

There is an urgent need to find new ways to treat chronic pain through better targeting of underlying biological processes. Research shows that flexible synapses within the amygdala brain region play a role in the progression of pain from acute to chronic, but the details are not fully understood. The receptor glutamate delta 1 helps to form and maintain synapses in the amygdala in inflammatory and neuropathic pain. This project will study how the shape and characteristics of glutamate delta 1 affect pain conditions that involve the amygdala, toward informing future development of pain medications.