Funded Projects

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Project # Project Title Research Focus Area Research Program Administering IC Institution(s) Investigator(s) Location(s) Year Awarded
3R01AR064251-07S1
Osteoarthritis Progression And Sensory Pathway Alterations Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NIAMS RUSH UNIVERSITY MEDICAL CENTER MALFAIT, ANNE-MARIE Chicago, IL 2020
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.
1R01CA249939-01
Identification of Novel Targets for the Treatment of Chemotherapy-Induced Painful Peripheral Neuropathy Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF MARYLAND BALTIMORE MELEMEDJIAN, OHANNES KEVORK Baltimore, MD 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN accounts for significant dose reductions and/or discontinuation of these life-saving treatments. Unfortunately CIPN can also persist in cancer-survivors, adversely affecting their quality of life. CIPN is not well-managed with existing pain therapeutics. Recent preliminary findings suggest that the transcription factor hypoxia-inducible factor alpha (HIF1A) is the target for the chemotherapeutic bortezomib, a proteasome inhibitor. This project will test the hypothesis that bortezomib chemotherapy-induced expression of HIF1A, PDHK1 and LDHA constitute an altered metabolic state known as aerobic glycolysis (AG) that leads to the initiation and maintenance of peripheral neuropathy and pain using a novel tumor-bearing animal model of CIPN. This project aims to validate HIF1A as a therapeutic target for the prevention of CIPN, as well as validate PDHK1 and LDHA as non-opioid therapeutic targets for chronic or established CIPN in animal models.
3U44NS115692-01S1
Development and Optimization of MNK Inhibitors for the Treatment of Neuropathic Pain Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS 4E THERAPEUTICS INC. SAHN, JAMES JEFFREY Austin, TX 2020
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 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.
1R01AR077890-01
Validation of Novel Target for OA Treatment Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF ILLINOIS AT CHICAGO SAMPEN, HEE-JEONG IM; LASCELLES, DUNCAN Chicago, IL 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of pain and disability. Current challenges of managing OA are that there is no OA disease-modifying drug available, there are few effective treatment strategies, and there is an over-reliance on the use of opioids to manage OA-related joint pain. This project aims to validate vascular endothelial growth factor receptors 1 and 2 (VEGFR 1 receptor = Flt1) and (VEGFR 2 receptor = Flk1) as novel therapeutic targets for OA. This is based on a hypothesis that blocking these two specific receptors of VEGF will inhibit cartilage tissue degeneration and alleviate pain symptoms. This study will test the role of VEGFR-1 and -2 in multiple OA animal models using multiple available VEGF inhibitor molecules. The findings from these studies will develop a rationale for future clinical trials to target VEGFR-1 and -2 for OA patients and develop a novel non-addictive treatment for both joint pain and OA pathology.
3R01NS113257-01S1
Isolation of GPR160 for biochemical analysis of the activation mechanism and development of a high throughput screening assay to identify small molecule inhibitors Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS SAINT LOUIS UNIVERSITY SALVEMINI, DANIELA Saint Louis, MO 2020
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:

Neuropathic pain conditions are difficult to treat, and novel non-narcotic analgesics are desperately needed. The G protein-coupled receptor 160 (GPR160) has emerged as a novel target for analgesic development, as GPR160 in the spinal cord may play a role in the transition from acute to chronic pain. Cocaine- and Amphetamine-Regulated transcript peptide (CARTp) was identified as a ligand for GPR160. Blocking endogenous CARTp signaling in the spinal cord attenuates neuropathic pain, whereas intrathecal injection of CARTp evokes painful hypersensitivity in rodents through GPR160-dependent extracellular signal-regulated kinase (ERK) and cyclic AMP response element-binding pathways (CREB). This project will isolate and biochemically characterize GPR160 and establish methods for biochemical characterization of GPR160 interaction with CARTp activator. Researchers will miniaturize and optimize biochemical assay and scale up protein production for future high throughput biochemical screening to identify potent inhibitors of GPR160 activation. These studies are critical for defining the molecular mechanism of CARTp/GPR160 interactions and initiating large-scale screens for new inhibitors to develop novel therapeutics.
1R01NS118504-01
Targeting GPCRs in Amygdalar and Cortical Neural Ensembles to Treat Pain Aversion Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIV OF NORTH CAROLINA CHAPEL HILL SCHERRER, GREGORY Chapel Hill, NC 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

There is a distinct neural ensemble in the brain that encodes the negative affective valence of pain. This project will identify novel targets to treat pain by determining the molecular identity of these BLA nociceptive cells via in situ hybridization and single cell RNAsequencing (scRNA-seq). Resolving the molecular identity of these ACC nociceptive cells will also reveal new targets to treat pain affect. To achieve these results the project will catalog candidate Gi/o-GPCR targets in BLA and ACC, test their utility to treat pain, and verify these new targets have no effect in the brain?s reward and breathing circuitry. The experiments in this project will also evaluate each target for abuse potential and effects on breathing by using behavioral assays for reward processing and whole-body plethysmography, respectively. To evaluate whether our results in rodents are likely to translate clinically, there will be an analysis of expression patterns of these drug targets in human tissue using in situ hybridization.
3R01AT010773-02S1
Minor Cannabinoids and Terpenes: Preclinical Evaluation as Analgesics Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NCCIH RESEARCH TRIANGLE INSTITUTE WILEY, JENNY L. Research Triangle Park, NC 2020
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:

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.
1R01NS116694-01
Validation of Spinal Neurotensin Receptor 2 as an Analgesic Target Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF ARIZONA PATWARDHAN, AMOL M Tuscon, AZ 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

Epidural/spinal administration of analgesics such as opioids, ziconotide and local anesthetics have profound efficacy in some of the most intractable pain conditions such as severe neuropathic pain after failed back surgery, cancer pain and post-operative pain after major abdominal/thoracic surgeries. Contulakin G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin and was shown to be safe in humans in preliminary studies. A small pilot study demonstrated CGX?s analgesic effect in some patients with spinal cord injury-associated pain. Preliminary findings from mechanistic studies in rodents identified neurotensin receptor 2 (NTSR2) as the mediator for analgesic effects of CGX. This project aims to validate spinal NTSR2 as an analgesic target utilizing three species (rat, mice and human), and two pain models (neuropathic pain and post-surgical pain). The project will utilize pharmacological and gene editing tools such as CRISPR-Cas9 and will include assessment of both sensory and affective measures of pain. A two-site parallel confirmation study is designed based on multisite clinical trials to further authenticate spinal NTSR2 as an analgesic target. Successful completion of this project could lead to the development of a non-opioid spinal analgesic that has high translational potential.
3R01NS111929-01A1S1
Anatomic, Physiologic and Transcriptomic Mechanisms of Neuropathic Pain in Human DRG Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF TX MD ANDERSON CAN CTR DOUGHERTY, PATRICK M Houston, TX 2020
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:

Using neural tissues from pain patients, this project will investigate mechanisms of neuronal and/or immune dysfunction driving chronic pain. The researchers will use spatial transcriptomics on human dorsal root ganglion (DRG) and spinal cord tissues to examine the cellular expression profile for these targets using the 10X Genomics Visium technology. The use of tissues from control surgical patients and organ donors as well as surgical patients with neuropathic pain will enable validation of expression of these targets in human tissue as well as indication of their potential involvement in neuropathic pain. This collaborative effort will use DRGs removed from pain-phenotyped patients during neurological surgery, as well as lumbar DRGs and spinal cord from organ donors. This study will map the spatial transcriptomes at approximately single cell resolution in the human DRG and spinal cord.
1R01NS116759-01
Validating ASCT2 for the Treatment of Chronic Postsurgical Pain Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF MARYLAND BALTIMORE MELEMEDJIAN, OHANNES KEVORK Baltimore, MD 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

Pain associated with surgery is experienced by millions of patients every year. Although post-surgical pain usually resolves as the surgical site heals, up to half of the patients develop chronic pain after surgery. Opioids remain the mainstay treatment for post-surgical pain which are fraught with serious side-effects and abuse liabilities. The endogenous mechanism that leads to the resolution of post-surgical pain remain unclear, specifically the effects of surgery on the metabolism of sensory neurons and how those changes influence the resolution of post-surgical pain are not known. Preliminary findings suggest that surgical trauma suppresses pyruvate oxidation while increased glutamine catabolism was associated with the resolution of post-surgical pain. This project will test the hypothesis that tissue incision and surgery disrupt the expression of the glutamine transporter ASCT2, which then prevents the resolution of post-incisional pain and aims to validate ASCT2 as a therapeutic target. This project will also employ pharmacological, genetic and animal pain model studies test a novel RNA expression-based strategy to enhance ASCT2 expression in DRG sensory neurons and alleviate postoperative pain in animal model systems. Successful completion of this project would validate ASCT2 as a novel endogenous non-opioid and non-addictive mechanism-based target for the resolution of postoperative pain.
3R01DE029187-01S2
LIGHT and Lymphotoxin targeting for the treatment of chronic orofacial pain conditions Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF TEXAS HLTH SCIENCE CENTER AKOPIAN, ARMEN N; RUPAREL, SHIVANI B; TUMANOV, ALEXEI V San Antonio, TX 2020
NOFO Title: Notice of Special Interest to Encourage Eligible NIH HEAL Initiative Awardees to Apply for PA-18-906 Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed)
NOFO Number: NOT-NS-20-023
Summary:

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.
1RF1AG068997-01
Subchondral Bone Cavities in Osteoarthritis Pain Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS JOHNS HOPKINS UNIVERSITY CAO, XU; GUAN, YUN Baltimore, MD 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

A key marker of inflammation in Osteoarthritis (OA) is accompanied by significantly increased sensory innervation within the diseased joint. This study aims to validate the hypothesis that defective bone resorbing cells are responsible for the enlarged bone cavity, giving rise to the inflammatory marker causing further increases in levels sensory innervation and resulting in increased OA pain perception.
3UH3NS113661-02S1
Deep Brain Stimulation of the Subgenual Cingulate Cortex for the Treatment of Medically Refractory Chronic Low Back Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS UNIVERSITY OF CALIFORNIA LOS ANGELES BARI, AUSAF; POURATIAN, NADER Los Angeles, CA 2020
NOFO Title: Notice of Special Interest to Encourage Eligible NIH HEAL Initiative Awardees to Apply for PA-18-906 Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed)
NOFO Number: NOT-NS-20-023
Summary:

A current obstacle to developing more effective therapies for chronic low back pain is the lack of clinical trials assessing the feasibility and potential effectiveness of promising new targets for neuromodulation. This project will explore the feasibility of using deep brain stimulation of a new brain target for treating chronic low back pain. The study will also explore imaging biomarkers in patients with chronic low back pain that can be used to predict whether someone is a candidate or may respond to deep brain stimulation therapy, to guide programming and patient selection for this therapy in the future.
1R01DE029074-01A1
Novel Target Identification for Treatment of Chronic Overlapping Pain Using Multimodal Brain Imaging Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF MARYLAND BALTIMORE TRAUB, RICHARD J; MELEMEDJIAN, OHANNES KEVORK Baltimore, MD 2020
NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

As many as 64% of patients with Temporomandibular Joint Disorders (TMJDs) report symptoms consistent with Irritable Bowel Syndrome (IBS). However the underlying connection between these comorbid conditions is unclear and treatment options are poor. As such, pain management for these Chronic Overlapping Pain Conditions (COPCs) is a challenge for physicians and patients. This project will determine whether the convergence of pain from different peripheral tissues and perceived stress occurs in the brain and elicits a change in central neural processing of painful stimuli. This project will identify and validate specific lipids, enzymes and metabolic pathways that change expression in the brain during the transition from acute to chronic overlapping pain that can be therapeutically targeted to treat COPCs. Multi-disciplinary approaches will be used to combine brain imaging, visualization of spatial distribution of molecules, genetics, pharmacological and behavioral research techniques.
3U44NS115111-02S1
High-Resolution, Spinal Cord Stimulation for Non-Opioid Treatment of Neuropathic Pain Preclinical and Translational Research in Pain Management NINDS MICRO-LEADS, INC. MCLAUGHLIN, BRYAN L Somerville, MA 2020
NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA18-591
Summary:

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.
1UG3NS115108-01A1
Home-based transcutaneous electrical acustimulation for abdominal pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS JOHNS HOPKINS UNIVERSITY CHEN, JIANDE Baltimore, MD 2020
NOFO Title: HEAL Initiative: Translational Devices to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-19-016
Summary:

Currently, there are no adequate therapies for abdominal pain in patients with Irritable Bowel Syndrome (IBS), a gastrointestinal disorder affecting 14-20% of the US population. More than 40% of IBS patients regularly use opioid narcotics. An alternative treatment for IBS that has been shown to be an effective pain management strategy is electroacupuncture. However its drawbacks include infrequent administration, unclear mechanistic understanding, and lack of methodology optimization. This study will use a noninvasive method of transcutaneous electrical acustimulation (TEA) by replacing needles with surface electrodes and testing acupoints that target peripheral nerves. Based on prior mechanistic and clinical studies, two stimulation parameters and effective acupoints will be tested. In the UG3 phase, the TEA device and a cell phone app will be optimized for use in IBS abdominal pain, and an acute clinical study will determine the best stimulation locations and parameters. During the UH3 phase, an early feasibility clinical study will be performed in 160 IBS patients in treating abdominal pain. Participants will self-administer the therapy at home/work and will be randomized across four treatment groups to determine the therapeutic potential of the TEA system.
1UH3NS115647-01A1
A Double-Blind, Randomized, Controlled Trial of Epidural Conus Medullaris Stimulation to Alleviate Pain and Augment Rehabilitation in Patients with Subacute Thoracic Spinal Cord Injury (SCI) Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS DUKE UNIVERSITY LAD, SHIVANAND P Durham, NC 2020
NOFO Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
NOFO Number: RFA-NS-19-018
Summary:

Pain is a major problem for spinal cord injury (SCI) patients that tends to persist and even worsen with time. No treatments are currently available to consistently relieve pain in SCI patients. This study will investigate the feasibility of Epidural Electrical Stimulation (EES) using the Abbott Proclaim? SCS system with two electrodes to treat neuropathic pain in patients with thoracic spinal cord injury. In this double-blind, prospective, randomized clinical trial, patients with subacute, traumatic, complete thoracic SCIs with American Spinal Injury Association (ASIA) Impairment Scale A will be randomized to receive either ?EES on? (treatment intervention) or ?EES off? (control intervention) of the target regions for pain control (lead overlying the spinal cord anatomy corresponding with their pain distribution) and neurorestoration (lead overlying the conus medullaris) as an adjunct to physical therapy. This study will help determine whether EES can help patients with SCI neuropathic pain and have more widespread clinical applicability.
1U18EB030607-01
Non-invasive Nonpharmaceutical Treatment for Neck Pain: Development of Cervical Spine-specific MR-guided Focused Ultrasound System Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS UNIVERSITY OF UTAH RIEKE, VIOLA Salt Lake City, UT 2020
NOFO Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
NOFO Number: RFA-EB-18-003
Summary:

Neck pain is the fourth leading cause of disability and also a significant cause of cervicogenic headaches. Many of the currently available neck pain treatments are invasive with associated risks and complications, particularly because of the complex anatomy. Magnetic resonance guided focused ultrasound, a novel, completely noninvasive technique, can precisely target spinal facet joints to help ameliorate neck pain, potentially transforming the current practices. The goal of this study is to develop a cervical spine-specific device and demonstrate its safety and efficacy on targeting cervical sensory fibers and the third occipital nerve. The results of these studies will provide an understanding on how to best use this technology for chronic neck pain as well as a basis for translation into human use.
1R61NS113258-01A1
Multi-Omic Biomarkers for Neuropathic Pain Secondary to Chemotherapy Preclinical and Translational Research in Pain Management Discovery and Validation of Biomarkers, Endpoints, and Signatures for Pain Conditions NINDS CLEVELAND CLINIC LERNER COM-CWRU ROTROFF, DANIEL; FOSS, JOSEPH F; JOHNSON, KENWARD B; Cleveland, OH 2020
NOFO Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
NOFO Number: RFA-NS-18-041
Summary:

Taxanes are among the most effective chemotherapeutic agents and are frequently used in the treatment of early stage and metastatic breast cancer. However, they are known to produce a pain condition known as Chemotherapy-Induced Peripheral Neuropathic Pain (CIPNP). CIPNP is one of the primary reasons a patient receives a limited dose of taxane. No diagnostic tool exists to identify patients that will develop CIPNP in response to taxane therapy. Biomarker signatures associated with taxane-induced neuropathic pain will be developed to: 1) identify patients at risk for developing debilitating taxane neuropathic pain before chemotherapy is initiated; and 2) to identify patients already on treatment who are at risk of developing neuropathic pain and need dosing adjustments to prevent CIPNP symptoms. This biomarker signature will be used to detect CIPNP-susceptible patients early and personalize their taxane therapy to minimize CIPNP while optimizing the therapeutic taxane dosing.
1R61NS118651-01A1
Prognostic Biomarkers for High-Impact Chronic Pain: Development and Validation Preclinical and Translational Research in Pain Management Discovery and Validation of Biomarkers, Endpoints, and Signatures for Pain Conditions NINDS STANFORD UNIVERSITY MACKEY, SEAN C Redwood City, CA 2020
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.
1R34NS126032-01
Stem cell-loaded microgels to treat discogenic low back pain Preclinical and Translational Research in Pain Management Development and Optimization of Non-Addictive Therapies to Treat Pain NINDS CEDARS-SINAI MEDICAL CENTER SHEYN, DMITRIY Los Angeles, CA 2021
NOFO Title: HEAL Initiative: Planning Studies for Initial Analgesic Development Initial Translational Efforts [Small Molecules and Biologics] (R34 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-21-016
Summary:

Pain caused by the degeneration of discs between vertebrae in the spine makes up a significant proportion of all chronic low back pain conditions. Although opioids are prescribed as treatments for this chronic condition, they often do not provide effective pain management, and currently there are no treatments that target the underlying disc disease. Notochordal cells mature into the cells that make up discs between vertebrae. Preliminary studies have shown that notochordal cells can be made from induced pluripotent stem cells, offering a potential replacement for diseased cells between discs. This study aims to develop a novel treatment for painful disc degeneration using a microgel/microtissue embedded with human notochordal cells made in the lab from induced pluripotent stem cells.
1R34NS126036-01
Synthesis of peripherally active CB1 agonists as analgesics Preclinical and Translational Research in Pain Management Development and Optimization of Non-Addictive Therapies to Treat Pain NINDS ST. LOUIS COLLEGE OF PHARMACY MAJUMDAR, SUSRUTA (contact); DROR, RON ; GEREAU, ROBERT W St. Louis, MO 2021
NOFO Title: HEAL Initiative: Planning Studies for Initial Analgesic Development Initial Translational Efforts [Small Molecules and Biologics] (R34 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-21-016
Summary:

Current medications for chronic pain are largely ineffective and rely heavily on opioids, one contributor to the nation’s opioid crisis. The endocannabinoid system that consists of cannabinoid receptors (CB1R and CB2R) and their endogenous ligands is a natural pathway in the human body and has emerged as an alternative target for developing new pain medications with few side effects. Current molecules that bind to CB1R in the brain and spinal cord have psychoactive side effects, limiting their therapeutic use for treating chronic pain. This study aims to develop new molecules to bind to CB1R tightly and selectively, are metabolically stable, and are also unable to enter the brain.
1UG3NS123965-01
Novel, non-opioid, non-addictive intrathecal therapy for the treatment of chronic pain Preclinical and Translational Research in Pain Management Development and Optimization of Non-Addictive Therapies to Treat Pain NINDS CENTREXION THERAPEUTICS CORPORATION CAMPBELL, JAMES N Boston, MA 2021
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.
1UG3NS123964-01
Disease Modifying Analgesia with CA8 Gene Therapy Preclinical and Translational Research in Pain Management Development and Optimization of Non-Addictive Therapies to Treat Pain NINDS UNIVERSITY OF MIAMI SCHOOL OF MEDICINE LEVITT, ROY C Coral Gables, FL 2021
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:

Efforts to identify non-opioid analgesics for treatment of chronic pain have identified a protein, carbonic anhydrase-8 (CA8), in pain-sensing nerve cells in the spinal cord (dorsal root ganglion cells) whose expression regulates analgesic responses. Gene therapy delivering CA8 to dorsal root ganglion cells through clinically relevant routes of administration functions as a “local anesthetic” that induces long-lasting pain relief in animal models of chronic pain. This project will further develop CA8 gene therapy with the goal of treating chronic knee osteoarthritis pain. It will assess several gene therapy constructs to determine the doses needed, safety, efficacy, and specificity to nerve cells for each construct. It will then select the safest and most effective construct that can be administered via the least invasive route for further development. The project will include all steps necessary to identify one candidate gene therapy construct that will be suitable to begin clinical trials in patients with chronic knee osteoarthritis pain.
1UG3NS123958-01
Development of a CCKBR-targeting scFv as Therapy for Chronic Pain Patients Preclinical and Translational Research in Pain Management Development and Optimization of Non-Addictive Therapies to Treat Pain NINDS UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR WESTLUND-HIGH, KARIN N (contact); ALLES, SASCHA R Albuquerque, NM 2021
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:

Cholecystokinin B receptor (CCKBR) is a molecule found in the brain that helps regulate anxiety and depression but also influences the development of tolerance to opioids. CCKBR levels are also increased in models of nerve injury-induced (neuropathic) pain. Therefore, targeting CCKBR may offer a new approach to treating neuropathic pain and the associated anxiety and depression. Researchers have developed mouse antibodies that can inactivate CCKBR. However, to be usable in humans without causing an immune response, these antibodies need to be modified to include more human sequences. This project will use a fragment of the CCKBR antibody, modify it with the addition of human antibody sequences, and then select the clones that bind most strongly and specifically to human CCKBR. These will then be tested in cell and animal models of neuropathic pain to identify the most promising candidates for further evaluation in humans.