Precision Medicine to Manage Pain and Improve Rehabilitation
Abstract
BACKGROUND: Persistent pain is prevalent in the US military and general population and costs about $650 billion annually, making it a top priority to address with new therapeutics. All current local anesthetics are short-acting and disabling due to the complete loss of all sensation (including desirable protective sensory functions) and motor function. In the absence of suitable alternatives, an epidemic of opioid overuse, abuse, and life-threatening complications has occurred. LONG-TERM GOALS: Develop a safe and effective long acting local anesthetic (LALA) which, when administered in customary ways to peripheral nerves will produce profound analgesia without loss of motor function, non-pain sensory functions, or systemic toxicity. OBJECTIVES: Using precision medicine, we will develop, quality control, and test the functions of a proprietary biotherapeutic which, when delivered using customary routes of administration, will produce intense long-lasting local analgesia without loss of other desirable protective sensory functions, motor functions, or toxicity. RATIONALE: We have demonstrated in prior preclinical studies that our prototype biotherapeutic can produce profound analgesia in mice equivalent to greater than 250mg of oral morphine in 60kg adult. While this local anesthetic is not an opioid, the analgesia produced is equivalent to a dose of morphine that far exceeds the recommended maximum daily oral intact of morphine. However, our analgesic biotherapeutic technology does not cause loss of motor or desirable sensory functions. In this AIMM Proposal (W81XWH-18-DMRDP-AIMM) we will develop and test a novel proprietary LALA that is designed to selectively target with precision medicine-only pain sensing fibers using a Food and Drug Administration (FDA)-approved form of gene therapy. OBJECTIVE: 1: PRODUCE ND VALIDATE (QUALITY CONTROL) THESE GENE THERAPY REAGENTS. RATIONALE: In this project we will create novel gene therapy reagents using precision medicine to target selectively a subset of pain sensing fibers in well-controlled experiments. Why target a specific subset of pain sensing fibers? The gene we are targeting is expressed exclusively in pain sensing fibers. Humans with heritable mutations in this target gene demonstrate complete insensitivity to pain, without a loss of motor function or many other desirable sensory functions. Thus, after exposure to our biotherapeutic we expect to quiet (make less responsive to painful stimuli, without nerve destruction) this subset of sensory nerves to produce profound analgesia. In these experiments, we will focus on the design, construction and production of our precision medicine biotherapeutics. We will then quality control these novel biotherapeutics to ensure that they are potent and highly purified so they may be released from our manufacturing process. EXPECTED OUTCOMES: High potency, non-toxic biotherapeutics that act to quiet pain-sensing fibers, where pain is located. This is the first go/no-go decision point before further safety and efficacy testing in suitable cell lines. If these gene therapy reagents fail quality control testing, we will troubleshoot and/or rework them until they pass. Timeline: 6 months OBJECTIVE 2: DEMONSTRATE SPECIFICITY AND EFFICACY OF THESE GENE THERAPY REAGENTS. RATIONALE: These studies represent the next critical validation step after the design, construction, production, purification, and quality control of our novel potent biotherapeutics. We will ensure the integrity and functions related to the target analgesic pathway of these novel biotherapeutics in suitable cell cultures. EXPECTED OUTCOMES: We will show in these nonclinical experiments that these biotherapeutics inhibit cellular functions previously determined to produce analgesia. We will also demonstrate that our biotherapeutics, when delivered by gene therapy, will function selectively in the targeted pain sensing fibers. This is the second go/no-go decis
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910525
Entities
People
- Roy Levitt
Organizations
- United States Army
- University of Miami