Funded Projects

Project # Project Title Sort descending Research Focus Area Research Program Administering IC(s) Institution(s) Investigator(s) Location(s) Year Awarded
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
FOA Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
FOA 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.

1R43DE029369-01
A Novel Opioid-Free Targeted Pain Control Method for Acute Post-Operative Localized Pain Related to Oral Surgical Procedures Preclinical and Translational Research in Pain Management Small Business Research and Development NIDCR LAUNCHPAD MEDICAL, LLC JADIA, RAHUL; KAY, GEORGE Boston, MA 2019
FOA Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
FOA Number: PA-18-574
Summary:

There is a compelling need to develop a front line, non-opioid-based acute pain management strategy for outpatient oral surgical procedures. LaunchPad Medical has developed Tetranite® (TN), a novel bone regenerative mineral-organic self-setting adhesive biomaterial. TN has been extensively studied in vivo in a canine jaw model and shown to be effective and well-tolerated. In this project, researchers will demonstrate that drug-loaded TN can be a novel route to providing localized and time release pain medication following wisdom tooth extraction by determining the release profile of various pain medications from TN at different concentrations. The ability to release pain therapeutics in a controlled fashion and directly at the site of injury offers improved pain control following oral surgical procedures without exposing the patient to opioids. This novel approach to pain management can be extended to more invasive orthopedic procedures such as joint replacement, spinal fusions or reconstructive trauma surgery. In Phase II the team will conduct an in vivo study to assess efficacy of medicated TN to address post-operative pain following wisdom tooth odontectomy, optimize incorporation and release of medications in TN formulations, develop cGMP manufacturing process for the compounded product, and ultimately conduct clinical trials for bone void filler using medicated TN.

1R44AR074820-01A1
A phenotypic screen for osteoarthritic pain therapeutics using all-optical electrophysiology Preclinical and Translational Research in Pain Management Small Business Research and Development NIAMS QUELL TX, INC. LIU, PIN; MCMANUS, OWEN B Cambridge, MA 2019
FOA Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
FOA Number: PA-18-574
Summary:

 Quell Therapeutics uses the Optopatch platform for making all-optical electrophysiology measurements in neurons at a throughput sufficient for phenotypic screening. Using engineered optogenetic proteins, blue and red light can be used to stimulate and record neuronal activity, respectively. Custom microscopes enable electrophysiology recordings from 100’s of individual neurons in parallel with high sensitivity and temporal resolution, a capability currently not available with any other platform screening technology. Here, researchers combine the Optopatch platform with an in vitro model of chronic pain, where dorsal root ganglion (DRG) sensory neurons are bathed in a mixture of inflammatory mediators found in the joints of osteoarthritis patients. The neurons treated with the inflammatory mixture become hyperexcitable, mimicking the anticipated cellular pain response. Investigators calculate the functional phenotype of arthritis pain, which captures the difference in action potential shape and firing rate in response to diverse stimuli. The team will screen for small molecule compounds that reverse the pain phenotype while minimizing perturbation of neuronal behavior orthogonal to the pain phenotype, the in vitro “side effects.” The highest ranking compounds will be chemically optimized and their pharmacokinetic, drug metabolism, and in vivo efficacy will be characterized. The goal is to advance therapeutic discovery for pain, which may ultimately help relieve the US opioid crisis.

1R44NS115196-01
A single dose long-acting non-addictive polymer conjugate formulation of buprenorphine that provides immediate and prolonged analgesia for post-operative pain Preclinical and Translational Research in Pain Management Small Business Research and Development NINDS SERINA THERAPEUTICS, INC. VIEGAS, TACEY XAVIER; MOREADITH, RANDALL W Huntsville, AL 2019
FOA Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
FOA Number: PA-18-574
Summary:

SER-227 is a long-acting polymer pro-drug of buprenorphine that is being developed to treat post- operative pain following major surgeries such as bunionectomy, abdominoplasty, thoracotomy and knee and hip surgery. The ultimate goal is to demonstrate that SER-227 can be manufactured and tested preclinically to show that it is safe for use in a Phase I clinical study. Aims include 1.SER-227 chemistry and process optimization to generate a technical package, 2. SER-227 manufactured under current Good Manufacturing Practices, 3. Evaluated in formal toxicology studies in rodent and non-rodent animals so that justifications can be made to support a ‘first-in-man’ study, and 4. Submission of an Investigational New Drug application (IND) along with a Phase I clinical  protocol in normal volunteers to measure the safety, tolerability and pharmacokinetics of  buprenorphine that is released from SER-227. 

3R01NS102432-02S1
AIBP and regulation of neuropathic pain Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS Univ. of Calif., U.C. San Diego Miller, Yury La Jolla, CA 2018
FOA Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
FOA Number: NOT-NS-18-073
Summary:

Persistent pain states arising from inflammatory conditions, such as in arthritis, diabetes, HIV, and chemotherapy, exhibit a common feature in the release of damage-associated molecular pattern molecules, which can activate toll-like receptor-4 (TLR4). Previous studies suggest that TLR4 is critical in mediating the transition from acute to persistent pain. TLR4 as well as other inflammatory receptors localize to lipid raft microdomains on the plasma membrane. We have found that the secreted apoA-I binding protein (AIBP) accelerates cholesterol removal, disrupts lipid rafts, prevents TLR4 dimerization, and inhibits microglia inflammatory responses. We propose that AIBP targets cholesterol removal to lipid rafts harboring activated TLR4. The aims of this proposal are to: 1) determine whether AIBP targets lipid rafts harboring activated TLR4; 2) test whether AIBP reduces glial activation and neuroinflammation in mouse models of neuropathic pain; and 3) identify the origin and function of endogenous AIBP in the spinal cord.

3R01NS102432-02S1
AIBP AND REGULATION OF NEUROPATHIC PAIN Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS UNIVERSITY OF CALIFORNIA, SAN DIEGO MILLER, YURY; YAKSH, TONY L. LA JOLLA, CA 2019
FOA Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
FOA Number: PA-18-591
Summary:

Persistent pain states arising from inflammatory conditions, such as in arthritis, diabetes, HIV, and chemotherapy, exhibit a common feature in the release of damage-associated molecular pattern molecules, which can activate toll-like receptor-4 (TLR4). Previous studies suggest that TLR4 is critical in mediating the transition from acute to persistent pain. TLR4 as well as other inflammatory receptors localize to lipid raft microdomains on the plasma membrane. We have found that the secreted apoA-I binding protein (AIBP) accelerates cholesterol removal, disrupts lipid rafts, prevents TLR4 dimerization, and inhibits microglia inflammatory responses. We propose that AIBP targets cholesterol removal to lipid rafts harboring activated TLR4. The aims of this proposal are to: 1) determine whether AIBP targets lipid rafts harboring activated TLR4; 2) test whether AIBP reduces glial activation and neuroinflammation in mouse models of neuropathic pain; and 3) identify the origin and function of endogenous AIBP in the spinal cord.

1R44NS113740-01
An Instrument to Assess the Functional Impact of Chronic Pain Preclinical and Translational Research in Pain Management Small Business Research and Development NINDS BARRON ASSOCIATES, INC. CLARK, BRIAN R Charlottesville, VA 2019
FOA Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
FOA Number: PA-18-574
Summary:

The proposed Fast Track SBIR effort will develop and validate the reliable, low-cost KnowPain instrument. KnowPain will objectively and quantitatively assess the functional impact of chronic pain using measures derived from six degrees-of-freedom motion, heart rate, skin surface temperature, and skin conductivity collected via a specially designed, ergonomic wrist-worn biometric sensing instrument. The new assessment instrument will apply advanced psychometric methods to both physiologic and kinematic data to provide precise scores for functional impairment due to chronic pain. The assessment results will be presented to the clinician in an easy-to-understand report and will include longitudinal results, confidence estimates, and normative data to enable comparisons both within and between patients. The system will include provision to interface with electronic medical records. Accurate functional assessment is a crucial component in the effective treatment of chronic pain. The proposed approach will supplement existing methods for assessing patient function by providing novel and highly complementary information for a more complete (and often unobserved) picture of the impact of chronic pain on patient function. KnowPain measures will provide important data on the practical consequences of pain and on treatment efficacy. 

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
FOA 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
FOA 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.

3R44TR001326-03S1
Automation and validation of human on a chip systems for drug discovery Preclinical and Translational Research in Pain Management Small Business Research and Development NCATS HESPEROS, LLC SHULER, MICHAEL L; HICKMAN, JAMES J Orlando, FL 2019
FOA Title: PHS 2017-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44])
FOA Number: PA-17-302
Summary:

Hesperos uses microphysiological systems in combination with functional readouts to establish systems capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. The team constructed physiological systems that represent cardiac, muscle and liver function, and demonstrated a multi-organ functional cardiac/liver module for toxicity studies as well as metabolic activity evaluations. In addition, the team demonstrated multi-organ toxicity in a 4-organ system composed of neuronal, cardiac, liver and muscle components. While much is known about the cells and neural circuitry regulating pain modulation there is limited knowledge regarding the precise mechanism by which peripheral and spinal level antinociceptive drugs function, and no available human-based model reproducing this part of the pain pathway. The ascending pain modulatory pathways provide a well characterized neural architecture for investigating pain regulatory physiology. In this project, the research team propose a human-on-a-chip neuron tri-culture system composed of nociceptive neurons, GABAergic interneurons and glutamatergic dorsal projection neurons (DPN) integrated with a MEMS construct. Using this model, investigators will interrogate pain signaling physiology at three levels, 1) at the site of origin by targeting nociceptive neurons with pain modulating compounds including noxious stimuli and inflammatory mediators, 2) at the inhibitory GABAergic interneuron, and 3) at the ascending spinal level by targeting glutamatergic DPNs. These circuits will be integrated utilizing expertise in patterning neurons as well as integration with BioMEMs devices. This system provides scientists with a better understanding of ascending pain pathway physiology and enable clinicians to consider alternative indications for treating pain at peripheral and spinal levels. 

1R01NS117340-01
B Lymphocyte-Mediated Autoimmunity in Pain After Trauma Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS PALO ALTO VETERANS INSTIT FOR RESEARCH CLARK, DAVID J Palo Alto, CA 2020
FOA Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
FOA Number: RFA-NS-18-043
Summary:

A major recent advancement for the field of pain research is the recognition of immune system dysregulation as a contributor to the most serious adverse consequences of pain from injury. Accumulating data from clinical and laboratory studies place the activation of B lymphocytes at the center of much of this work, particularly with respect to chronic pain and disability-related outcomes. Validation of this B cell hypothesis could lead directly to trials testing the efficacy of novel or existing immunomodulating agents on posttraumatic pain. To achieve these goals a well-validated core mouse model of limb fracture will be employed with additional studies to be conducted in incisional and nerve injury models to broaden the assessment of B cell mediated effects on pain. Age and sex will be included as variables to enhance rigor.

3R01LM010685-09S1
BEYOND PHEWAS: RECOGNITION OF PHENOTYPE PATTERNS FOR DISCOVERY AND TRANSLATION - ADMINISTRATIVE SUPPLEMENT Preclinical and Translational Research in Pain Management NLM VANDERBILT UNIVERSITY MEDICAL CENTER Denny, Joshua C. NASHVILLE, TN 2018
FOA Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
FOA Number: PA-18-591
Summary:

Genomic medicine offers hope for improved diagnostic methods and for more effective, patient-specific therapies. Genome-wide associated studies (GWAS) elucidate genetic markers that improve clinical understanding of risks and mechanisms for many diseases and conditions and that may ultimately guide diagnosis and therapy on a patient-specific basis. Previous phenome-wide association studies (PheWAS) established a systematic and efficient approach to identifying novel disease-variant associations and discovering pleiotropy using electronic health records (EHRs). This proposal will develop novel methods to identify associations based on patterns of phenotypes using a phenotype risk score (PheRS) methodology to systematically search for the influence of Mendelian disease variants on common disease. By doing so, it also creates a way to assess pathogenicity for rare variants and will identify patients at highest risk of having undiagnosed Mendelian disease. The project is enabled by large DNA biobanks coupled to de-identified copies of EHR.

1R61NS113315-01
Biomarker Signature to Predict the Persistence of Post-Traumatic Headache Preclinical and Translational Research in Pain Management Discovery and Validation of Biomarkers, Endpoints, and Signatures for Pain Conditions NINDS MAYO CLINIC ARIZONA CHONG, CATHERINE DANIELA Scottsdale, AZ 2019
FOA Title: Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain (R61/R33 Clinical Trial Optional)
FOA Number: RFA-NS-18-041
Summary:

There is currently no recognized way of accurately predicting who will recover from post-traumatic headache (PTH) during the acute phase following concussion and who will go on to develop persistent post-traumatic headache (PPTH), a condition that is difficult to treat effectively. Clinical experience suggests that early treatment is most effective, before headache patterns become persistent, but treating all patients with PTH would expose some patients to unnecessary treatment. Clinicians lack the information needed to make informed treatment decisions. Therefore, the study goals are to develop a prognostic biomarker signature for PPTH using clinical data and structural and functional brain neuroimaging and to assess the predictive accuracy of an ensemble biomarker signature for the early identification of patients at high risk for PPTH. This study can be translated into clinical practice and integrated into PTH clinical trials for early identification of those individuals who are at high risk for PPTH.

5R01NS104295-03
Cellular and Molecular Role of CXCR4 signaling in Painful Diabetic Neuropathy Preclinical and Translational Research in Pain Management Discovery and Validation of Novel Targets for Safe and Effective Treatment of Pain NINDS Northwestern University MENICHELLA, DANIELA M Evanston, IL 2019
FOA Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
FOA Number: NOT-NS-18-073
Summary:

Neuropathic pain is a debilitating affliction present in 26% of diabetic patients, with substantial impact on the quality of life. Despite this significant impact and prevalence, current therapies for painful diabetic neuropathy (PDN) are only partially effective, and the molecular mechanisms underlying neuropathic pain in diabetes are not well understood. Our long-term goal is to elucidate the molecular mechanisms responsible for PDN in order to provide targets for the development of therapeutic agents. Our objective is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration. Our aims will determine: 1) the ion-channel current profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN; 2) the gene expression profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN; and 3) the specific features of nociceptor mitochondrial dysfunction produced by CXCR4/SDF-1 signaling in PDN.

1UG3NS115637-01
Clinical Translation of Ultrasonic Ketamine Uncaging for Non-Opioid Therapy of Chronic Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS STANFORD UNIVERSITY AIRAN, RAAG D; WILLIAMS, NOLAN R Stanford, CA 2019
FOA Title: HEAL Initiative: Translational Devices to Treat Pain (UG3/UH3 Clinical Trial Optional)
FOA Number: RFA-NS-19-016
Summary:

The research team has developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. This project will clinically translate ultrasonic ketamine uncaging for chronic pain therapy. In the UG3 phase, the research team will scale our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. In the UH3 phase, they will complete a first-in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. This project aims to yield a novel, noninvasive, non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

3R01NS094461-04S2
Clustering of individual and diverse ion channels together into complexes, and their functional coupling, mediated by A-kinase anchoring protein 79/150 in neurons 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 SCI CTR SAN ANTONIO SHAPIRO, MARK S San Antonio, TX 2018
FOA Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
FOA Number: NOT-NS-18-073
Summary:

Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of cellular signals. Many ion channels are clustered either with the receptors that modulate them or with other ion channels whose activities are linked. Often, the clustering is mediated by scaffolding proteins, such as AKAP79/150. We will probe complexes containing AKAP79/150 and three different channels critical to nervous function: KCNQ/Kv7, TRPV1, and CaV1.2. We will use"super-resolution" STORM imaging of primary sensory neurons and heterologously expressed tissue-culture cells, in which individual complexes can be visualized at 10–20 nm resolution with visible light. We hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which we will examine by patch-clamp electrophysiology of the neurons. Since all three of these channels bind to AKAP79/150, we hypothesize that they co-assemble into complexes in neurons and that they are dynamically regulated by other cellular signals.

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
FOA 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)
FOA 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.

1UH3NS113661-01
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 Los Angeles, CA 2019
FOA Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
FOA Number: RFA-NS-19-018
Summary:

This study aims to address critical gaps and unmet therapeutic needs of chronic low back pain (CLBP) patients using a next-generation deep brain stimulation (DBS) device with directional steering capability to engage networks known to mediate the affective component of CLBP. Researchers will utilize patient-specific probabilistic tractography to target the subgenual cingulate cortex (SCC) to engage the major fiber pathways mediating the affective component of chronic pain. The objective is to conduct an exploratory first-in-human clinical trial of SCC DBS for treatment of medically refractory CLBP. The research team aims to: (1) assess the preliminary efficacy of DBS of SCC in treatment of medically refractory CLBP; (2) demonstrate the safety and feasibility of SCC DBS for CLBP; and (3) develop diffusion tensor imaging–based blueprints of response to SCC DBS for CLBP.

1R43NS115294-01
Developing EXP-1801 as an imaging agent to quantify pain and analgesia Preclinical and Translational Research in Pain Management Small Business Research and Development NINDS EXPESICOR, INC. NORWOOD, BRAXTON Kalispell, MT 2019
FOA Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
FOA Number: PA-18-574
Summary:

The use of a pain imaging technology would allow for objective efficacy data (both pre-clinically and in clinical trials), and reduce costs by enabling smaller sample sizes due to more homogeneous populations; i.e. with a particular “pain signal,” and more accurate measurement of analgesic effects. This research team recently invented a novel positron emission tomography (PET) imaging agent as a tool to address these issues in pain care and therapy development. Although the ability of PET to detect pathological changes for (early) disease detection is widely used in cancer and neurological diseases, it has not yet been used for pain indications. The goals of this project are: 1) to change the evaluation of (experimental) pain therapies, and 2) the standard of care in pain assessment through molecular imaging. The proposed study is designed to determine the feasibility of our imaging agent to objectively measure pain in rodents. This will set the stage for a Phase II study that further develops this agent into a tool for quantifying pain/analgesia.

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
FOA 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
FOA 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.

1U44NS115692-01
Development and Optimization of MNK Inhibitors for the Treatment of Neuropathic Pain Preclinical and Translational Research in Pain Management Optimizing Non-Addictive Therapies to Treat Pain NINDS 4E THERAPEUTICS INC. SAHN, JAMES JEFFREY Austin, TX 2019
FOA Title: HEAL Initiative: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain - (U44 Clinical Trial Not Allowed)
FOA Number: RFA-NS-19-020
Summary:

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.

1R43AR074369-01
Development of a fixed-dose combination therapy for the treatment of chronic musculoskeletal pain Preclinical and Translational Research in Pain Management Small Business Research and Development NIAMS NEUROCYCLE THERAPEUTICS, INC. TOCZKO, MATTHEW ALEXANDER Sheridan, WY 2019
FOA Title: PHS 2017-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44])
FOA Number: PA-17-302
Summary:

Non-steroidal anti-inflammatory drugs (NSAIDs) are a first line pharmacologic pain therapy for chronic musculoskeletal pain, and rheumatoid arthritis (RA) and moderate to severe osteoarthritis (OA) specifically. However, insufficient pain relief by NSAID monotherapy has encouraged the use of combination therapy. Combinations of NSAIDs plus weak opioids are widely used although objective evidence for efficacy is limited and they have many adverse events.  A growing body of evidence suggests that ?2/?3 subtype-selective positive allosteric modulators (PAM) of the ?- aminobutyric acid A receptor (GABAAR) may effectively restore central pain regulatory mechanisms thus providing effective relief of chronic pain with reduced prevalence and severity of side-effects.  Based on these promising preliminary studies and considerable supporting literature data, the research team will test the hypothesis that combination dosing of TPA-023B with an NSAID will work synergistically to suppress the acute and chronic pain components of chronic musculoskeletal pain. 

1R43NS110117-01
Development of a novel anti-migraine therapeutics Preclinical and Translational Research in Pain Management Small Business Research and Development NINDS ADEPTHERA, LLC HSU, SHEAU-YU TEDDY Palo Alto, CA 2019
FOA Title: PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)
FOA Number: PA-18-574
Summary:

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. 

1U18EB029351-01
Development of an MRgFUS system for precision-targeted neuromodulation of pain circuits with simultaneous functional MRI Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB VANDERBILT UNIVERSITY MEDICAL CENTER CASKEY, CHARLES F; CHEN, LI MIN; GRISSOM, WILLIAM A Nashville, Tennessee 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

This project aims to develop a next-generation noninvasive neuromodulation system for non-addictive pain treatments. The research team will build an integrated system that uses magnetic resonance image-guided focused ultrasound (MRgFUS) stimulation to target pain regions and circuits in the brain with high precision. The system will use MR imaging to locate three pain targets commonly used in clinical pain treatments, to stimulate those targets with ultrasound, and to monitor responses of nociceptive pain circuits using a functional MRI readout. Three collaborating laboratories will tackle the goals of this project: (Aim 1) Develop focused ultrasound technology for neuromodulation in humans, compatible with the high magnetic fields in an MRI scanner. (Aim 2) Develop MRI technology to find neuromodulation targets, compatible with focused ultrasound transducers. (Aim 3) Validate the complete MRgFUS neuromodulation system in brain pain regions in nonhuman primates. By the end of the project, the research team will have a fully developed and validated MRgFUS system that is ready for pilot clinical trials in pain management.

1U18EB029353-01
Development of a Wireless Endovascular Nerve Stimulator for Treatment of Refractory Neuropathic Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB BAYLOR COLLEGE OF MEDICINE KAN, PETER TZE MAN; ROBINSON, JACOB T; SHETH, SUNIL Houston, TX 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

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. 

1UG3NS115718-01
Development of MRGPRX1 positive allosteric modulators as non-addictive therapies for neuropathic pain Preclinical and Translational Research in Pain Management Optimizing Non-Addictive Therapies to Treat Pain NINDS JOHNS HOPKINS UNIVERSITY TSUKAMOTO, TAKASHI Baltimore, NC 2019
FOA Title: Optimization of Non-addictive Therapies [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Not Allowed)
FOA Number: RFA-NS-19-010
Summary:

Although opioid-based analgesics have been proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical dependence, tolerance, and respiratory depression. Cumulative evidence suggests that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited side effects due to its restricted expression in nociceptors within the peripheral nervous system; however, direct activation of MRGPRX1 at peripheral terminals is expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without activating peripheral MRGPRX1. An intrathecal injection of a prototype MRGPRX1 PAM, ML382, effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. The goal of this study is to develop a CNS-penetrant small-molecule MRGPRX1 PAM that can be given orally to treat neuropathic pain conditions.