Funded Projects

NOFO Title: HEAL Initiative: Development and Validation of Non-Rodent Mammalian Models of Pain (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-22-070
Summary:

Cerebral palsy (CP), the leading cause of childhood disabilities in the United States, refers to a group of neurological disorders that appear in infancy or early childhood and permanently affect body movement and muscle coordination. The experience of pain is one of the most common, poorly understood, and inadequately treated conditions in CP, impairing health and quality of life for both patients and caregivers. To understand why pain and motor dysfunction occur together, a model that accurately replicates both is needed. This project will validate an established, rabbit model of CP motor dysfunction for use in studying and developing effective treatments for CP-associated pain.

NOFO Title: HEAL Initiative: Development and Validation of Non-Rodent Mammalian Models of Pain (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-22-070
Summary:

One of the most debilitating consequences of spinal cord injury is the development of chronic neuropathic pain, which is difficult to manage with existing pain treatments. Animal models and behavioral assays that better reflect the conditions in humans are urgently needed to help in identification of novel pain treatments. This project aims to develop a new model of spinal cord injury-related neuropathic pain using pigs, because they are similar to humans in anatomy, size, metabolism, physiology, and the way their bodies process drugs.

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

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

NOFO Title: Development and Validation of Pain-Related Models and Endpoints to Facilitate Non-Addictive Analgesic Discovery
NOFO Number: NOT-NS-22-095
Summary:

Effective development of non-addictive therapies for pain requires animal models that reflect the human condition. Unfortunately, currently used models have limitations and have not always done a good job of predicting what will work in human patients. This project will refine a new way of measuring pain-related behaviors in mice that takes advantage of more natural mouse behavior and is less influenced by experimenter biases and artifacts. The research will verify that the promising results hold up in several different types of pain and that different classes of clinically used pain medications are effective. They will also make sure the data can be reproduced by an outside laboratory. If successful, this will support the use of this new read-out for future pain therapy development.

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:

Neuropathic pain is a debilitating and complex medical condition for which safe and non-addictive treatment options are urgently needed. This project aims to develop new strategies for treating neuropathic pain by controlling the activity of transmembrane protein 97 (TMEM97), also known as the sigma 2 receptor, which has been shown to relieve pain in an animal model of neuropathic pain. The research aims to develop a new molecule that increases TMEM97 activity and is safe for human use, toward obtaining approval from the U.S. Food and Drug Administration for Phase I clinical testing. 

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

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

NOFO Title: 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:

The medication monomethyl fumarate, approved for treating multiple sclerosis, has pain-relieving properties, but it also has side effects that affect the digestive tract and decrease levels of white blood cells, a problem known as leukopenia. This project will limit the availability of monomethyl fumarate to areas in the central nervous system associated with pain. Targeting the delivery of this drug to pain-related regions may improve its safety profile for treating neuropathic pain.

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:

Inhaled nitrous oxide, N₂O, is used in emergency departments in Europe to treat pain associated with sickle cell disease as well as for labor, painful fractures, and to manage serious gynecological pain. It is not a viable therapeutic option for home use for reasons such as poor dosing control, potential inhalation equipment issues, and variability in patient ventilation and lung absorption. This project seeks to optimize, characterize, and develop an oral formulation of N₂O that could be used by patients at home for unpredictable and severe episodes of pain associated sickle cell disease. Once developed, the new oral formulation of N₂O will be evaluated to determine whether it or an optimized version is ready for more clinical testing.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements. Parent Grant: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
NOFO Number: Supplement: PA-20-272; Parent NOFO: NS-21-010
Summary:

Negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have shown promise for treatment of multiple pain conditions without the serious adverse effects and safety concerns associated with opioids. This project will develop and test a novel series of highly selective mGlu5 NAMs that are structurally unrelated to earlier failed compounds and do not form toxic byproducts as with previous mGlu5 NAMs. A lead candidate is now being characterized in several studies to assess readiness for testing in Phase I clinical studies.

NOFO Title: HEAL Initiative: Planning Studies for Initial Analgesic Development [Small Molecules and Biologics] (R61 Clinical Trial Not Allowed)
NOFO Number: NS21-029
Summary:

A more thorough understanding of neuropathic pain is critical for developing new target-specific medications. Researchers know that peripheral nerve injury changes various cell processes that affect two ion channels linked with chronic pain. Preliminary studies indicate that molecular changes known as phosphorylation to the collapsin response mediator protein 2 (CRMP2), one of five intracellular phosphoproteins, promotes abnormal excitability in the brain region that contributes to neuropathic pain. This project aims to develop small molecule inhibitors of CRMP2 phosphorylation as potential therapeutics for pain.

NOFO Title: HEAL Initiative: Planning Studies for Initial Analgesic Development [Small Molecules and Biologics] (R61 Clinical Trial Not Allowed)
NOFO Number: NS21-029
Summary:

Voltage-gated sodium channels such as Nav1.7, Nav1.8, and Nav1.9 transmit pain signals in nerve fibers and are molecular targets for pain therapy. While Nav channels have been validated as pharmacological targets for the treatment of pain, available therapies are limited due to incomplete efficacy and significant side effects. Taking advantage of recent advances in structural biology and computational-based protein design, this project aims to develop antibodies to attach to Nav channels and freeze them in an inactive state. These antibodies can then be further developed as novel treatments for chronic pain.

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.

NOFO Title: HEAL Initiative: Team Research for Initial Translational Efforts in Non-addictive Analgesic Therapeutics Development (U19 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-21-015
Summary:

Opioids are widely used pain treatments, despite their relative ineffectiveness for chronic pain and their high potential for misuse and addiction. There is thus an urgent need for alternative, non-addictive pain treatments. Genetic and functional studies of human pain disorders and animal models of pain have validated Nav1.7, a voltage-gated sodium channel as an attractive target for new pain treatments. Currently available blockers of these channels can sometimes provide symptomatic relief for patients but have worrisome side effects affecting the brain and heart. This study aims to develop and validate an innovative site-directed RNA editing strategy that will offer the ability to create new versions of molecules to block Nav1.7, toward establishing a novel, non-addictive approach to treat chronic pain.