Funded Projects

NOFO Title: HEAL Initiative: Translational Devices to Treat Pain (U44 Clinical Trial Optional)
NOFO Number: RFA-NS-19-017
Summary:

The research team will develop HD64—a high-resolution, 64-channel spinal cord stimulation therapy to provide more pain relief for those suffering from chronic neuropathic pain and opioid dependence. HD64 provides an ultra-thin conformal blanket of stimulation contacts across the width of the spinal cord and enables more precise targeting of the lateral structures of the spinal cord to enhance pain relief. A cadaveric pilot run followed by a non-significant risk intraoperative study will be performed to inform the design parameters of HD64 arrays. The study will evaluate activation of medial and lateral spinal targets. At the end of Phase 1, the clinical feasibility of HD64 surgical leads will be established. In Phase 2, researchers will develop an external active lead pulse generator and charger. They will perform an early feasibility study human trial using active HD64 and mechanical and electrical design verification testing and chronic safety studies in large animals.

NOFO Title: Administrative Supplements for Validation of Novel Non-Addictive Pain Targets (Clinical Trials Not Allowed)
NOFO 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.

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:

Mismanagement of orofacial chronic pain, such as temporomandibular joint and muscle disorders (TMJD) and oral cancer, substantially contributes to opioid overuse; overdose-related deaths; and cardiovascular, renal, and neurological complications at epidemic proportions. The current paradigm implies that orofacial conditions could trigger maladaptation of the immune system and plasticity supporting persistent inflammation, which influences the development and maintenance of orofacial chronic pain. LIGHT (TNFSF14) and Lymphotoxin-beta (LT?), members of the tumor necrosis factor superfamily, provide a balance between protective immunity and immunopathology during chronic inflammatory diseases. This project will test the hypothesis that targeting LIGHT and LT? signaling could prevent the development and inhibit the maintenance of chronic pain produced by TMJD and oral cancer, via peripheral mechanisms involving plasticity of immune, stromal, and tumor cells, as well as sensory neurons. The proposed research is significant as it advances our understanding of mechanisms regulating the development and maintenance of orofacial pain and offers new therapeutic targets and an immunotherapeutic approach for preventing and blocking chronic pain during TMJD and oral cancer.

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

Spinal cord injury (SCI) impairs sensory transmission and leads to chronic, debilitating neuropathic pain. While our understanding of the development of chronic pain has improved, the available therapeutics provide limited relief. We will examine the peripheral immune and inflammatory response. Secondary inflammation in response to SCI is a series of temporally ordered events: an acute, transient upregulation of chemokines, followed by the recruitment of monocytes/macrophages and generation of an inflammatory environment at the lesion site in the spinal cord, but also surrounding primary nociceptors in the dorsal root ganglia (DRG). These events precede neuropathic pain development. Previous work indicates that after SCI, macrophage presence in the DRG correlates with neuropathic pain. We propose to study: 1) whether the phenotype of macrophages that infiltrate the DRG is different than those that persist chronically after SCI and 2) how manipulation of macrophage phenotype affects nociceptor activity and pain development.

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

The clinical utility of opioids for pain treatment is limited by its risk for developing opioid usage disorders (OUD). These untoward effects impose a severe burden on society and present difficult therapeutic challenges for clinicians. We propose to extend our cerebral organoid MPS to facilitate the investigation of neuronal response to opioids and identify cellular and molecular signatures in patients vulnerable to OUD. We have assembled a team with complementary expertise in clinical characterization of OUD, cerebral organoid MPS modeling, single cell RNA-seq technology, and functional characterization of neurons in a mesolimbic reward system to test the hypothesis that midbrain MPS is a clinically relevant pre-clinical model for study of opioid usage disorder.

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:

An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. Researchers have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, researchers anticipate that their compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions.

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: Limited Competition: International Cooperative Biodiversity Groups (U19)
NOFO Number: RFA-TW-13-001
Summary:

An International Cooperative Biodiversity Group with an interdisciplinary leadership team of physicians, pharmacologists, evolutionary biologists, and chemists will discover and develop therapeutic agents produced by Brazilian symbiotic bacteria. The team will target three therapeutic areas: 1) infectious fungal pathogens, 2) Chagas disease and leishmaniasis, and 3) cancers of the blood. All three areas represent major threats to human health that need to be addressed with new therapeutic agents. Internationally, invasive fungal diseases kill more people than malaria or TB, while Chagas disease imposes a special burden on Brazil, killing as many Brazilians as TB. Leishmaniasis has now passed Chagas disease in the Brazilian population. Despite major improvements in cancer chemotherapy, cancer is projected to result in 8 million deaths internationally this year (13% of all deaths, WHO) and an estimated 13 million per year by 2030.

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

Debilitating neuropathic pain occurs in 40 percent to 70 percent of people who suffer from spinal cord injury (SCI). There are no distinguishing characteristics to identify who will develop neuropathic pain. The objective of this research is to develop a biomarker signature prognostic of SCI-induced neuropathic pain (NP). The aims of the project are to (1) identify autoantibodies in plasma samples from acute SCI patients to CNS autoantigens and determine the relationship between autoantibodies levels to the development of NP, (2) identify the autoantibody combination with maximal prognostic accuracy for the development of NP at six months after SCI, and (3) develop and optimize an assay to simultaneously measure several autoantibodies and independently validate the prognostic efficacy for NP using plasma samples collected prospectively. Establishing a panel will refine the prognostic value of these autoantibodies as biomarkers to detect who are vulnerable to NP and may be used to for development of nonaddictive pain therapeutics.

NOFO Title: Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System (U44 Clinical Trial Optional)
NOFO Number: PAR-18-541
Summary:

We propose to develop a safe and effective nonopioid analgesic to treat neuropathic pain that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Development of systemic NaV1.7 inhibitors has been complicated by the challenge of achieving selectivity over other NaV isoforms expressed throughout the body. We have discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.

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:

Identification of new targets and mechanisms underlying chronic neuropathic pain is essential for the discovery of novel treatments and preventative tactics for better neuropathic pain management. A recent exploration of next-generation RNA sequencing identified a large, native, full-length long noncoding RNA (lncRNA) in mouse and human dorsal root ganglion (DRG). It was named as nerve injury-specific lncRNA (NIS-lncRNA), since its expression was found increased in injured DRGs, in response to peripheral nerve injury, but not in response to inflammation. Preliminary findings revealed that blocking the nerve injury-induced increases in DRG NIS-lncRNA levels ameliorated neuropathic pain. This project will validate NIS-lncRNA as a therapeutic target in animal models of neuropathic pain and in cell-based functional assays utilizing human DRG neurons. Completion of this proposal will advance neuropathic pain management and might provide a novel, non-opioid pain therapeutic target.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO 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.

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

Many chronic pain conditions are dependent upon activity of the sympathetic nervous system. Sympathetic blockade is used clinically in chronic pain conditions, but the clinical and preclinical evidence for this practice is incomplete. We propose that certain pathological pain conditions require intact sympathetic innervation of the sensory nervous system at the level of the dorsal root ganglion (DRG) and that release of sympathetic transmitters enhances local inflammation and leads to pain. Our preliminary data show large, rapid, and long-lasting reduction of pain behaviors and inflammatory responses following a"microsympathectomy" (mSYMPX) in both neuropathic and inflammatory pain models. Our aims are to: 1) characterize the effects of mSYMPX on pain and on local inflammation in the DRG; 2) explore the molecular mechanisms for sympathetic regulation of inflammatory responses in the DRG; and 3) assess the functional role of sympathetic transmitters in the sympathetically mediated inflammatory responses in the DRG.