FY2025 PRMRP Awarded Projects

Pathology-Activated Drugs to Treat Oxidative Stress Underlying Peripheral Neuropathy

Principal Investigator: GRACE, PETER
Institution Receiving Award: M.D, Anderson Cancer Center, University of Texas
Program: PRMRP
Proposal Number: 
Funding Mechanism: I
Award Amount:  $3,466,088.00

Abstract:

TOPIC AREA: This proposal is submitted to the Peripheral Neuropathy Topic Area and Strategic Goal of Treatment: Develop and evaluate novel pharmacological or nonpharmacological treatments or intervention strategies, which may include repurposing of existing drugs within the Neuroscience and Behavioral Health Portfolio Category. This project is relevant, as we propose to complete preclinical development of a new small molecule, engaging a novel target, to treat neuropathic pain among Service Members and Veterans.

OBJECTIVES AND RATIONALE: Chronic pain affects Service Members and Veterans at more than twice the rate seen in the general public, largely due to frequent traumatic injuries. Nearly half of all Service Members experience trauma during combat, which can lead to persistent pain. Veterans are also diagnosed with type 2 diabetes at double the civilian rate, with chronic neuropathy as a common complication. Current treatments for this pain are often ineffective and carry significant risks, particularly with opioid medications, which have contributed to a national crisis. There is a pressing need for effective, non-opioid pain relief solutions for Service Members, Veterans, and the broader community. Most available therapies target only a single pathway, while neuropathic pain arises from multiple, overlapping biological mechanisms. A promising advance would be a treatment that addresses several of these mechanisms at once. The 1,2-dicarbonyl prodrug developed in this project is designed to meet this need. Its active component, monomethyl fumarate (MMF), has both antioxidant and anti-inflammatory properties—key factors in neuropathic pain that are not effectively addressed by current drugs. While MMF is non-sedating, non-opioid, and non-addictive, its use can be limited by side effects when distributed throughout the body. The innovation here lies in the design of compounds that release MMF only at sites where it is needed. By chemically modifying MMF to react with molecules that are abundant at sites of nerve injury, the treatment is activated locally, reducing systemic side effects and improving safety. This targeted approach has been validated in published studies, and a lead compound has been identified. The objective of this application is to identify and characterize a lead and backup 1,2-dicarbonyl MMF-releasing compound, and to complete IND-enabling studies for the lead 1,2-dicarbonyl MMF-releasing compound. This will be completed across three independent aims: 1) Optimize the lead and identify a backup 1,2-dicarbonyl MMF-releasing compound; 2) Evaluate the effectiveness of these compounds in male and female mouse models of neuropathic pain (including trauma and diabetic neuropathy), with validation in human nerve cells; 3) Conduct comprehensive safety and toxicity studies to support regulatory approval for clinical trials.

BENEFICIARIES AND OUTCOMES: The research is expected to help Service Members, Veterans, and their families by advancing a new, well-tolerated, non-addictive therapy which treats the drivers of neuropathic pain. Our precision therapy has beneficial applications in addressing the urgent need for non-addictive and effective pain relief to improve quality of life and enable return to duty. We expect increased efficacy over standards of care, as MMF treats the multi-mechanism problem of neuropathic pain through simultaneous resolution of oxidative stress and neuroinflammation. Any side-effects of the 1,2-dicarbonyl MMF-releasing compound will be identified during completion of the proposed work. Successful completion of this project will have major impact in positioning us to advance a first-in-class, locally-activated therapeutic into clinical trials, offering new hope for Service Members and Veterans suffering from neuropathic pain.