R01NS122153

Cell-Directed Gene Therapy for Pain Recovery After Surgery and Inflammation - Summary

We have recently discovered macrophage ED2/CD163 gene overexpression as a novel and safe pain therapeutic target in the local peripheral immune system in a major surgery rat model. We propose to develop a cell-directed gene therapy that would correct the underlying local immunological cause of pain resulting from inflammatory processes, specifically in sub-chronic postoperative pain or inflammatory conditions.

Through unbiased genome-wide transcriptomic analyses in human primary macrophages, we identified that ED2/CD163 gene induction modulates tumor necrosis factor alpha (TNFA) and interleukin (IL)-1 beta (IL-1B). CD163 overexpression using a clinically tested nanoparticle designed to target macrophages promoted a more rapid wound healing in 3D human organotypic skin tissues and prevented sub-chronic postoperative pain behaviors and reduced local TNFA and IL-1B in rats with skin-muscle incision and retraction (SMIR) surgery.

We hypothesize that ED2/CD163 in macrophages is a safe target for the treatment of inflammatory pain with opioid sparing effects. We propose a multidimensional research plan including:

1) A sub-chronic surgical pain model, the SMIR surgery, and a knee inflammatory model, the complete Freund adjuvant (CFA)-induced knee arthritis;
2) ED2/CD163 gain and loss of function using macrophage-directed nanotechnology;
3) Novel, clinically relevant, and complex operant pain-related behaviors;
4) Cellular/molecular, tissue, and transcriptomic outcomes for mechanistic target engagement; and
5) Studies for ED2/CD163's effects on opioid requirements.

We will implement our plan through these specific aims:

1) Determine that macrophage-specific ED2/CD163 gene induction effectively promotes resolution of inflammatory pain. A mannosilated polyethyleneimine nanoparticle (MAN-PEI) designed to deliver nucleic acids specifically to macrophages will be used to conduct ED2/CD163 gain (overexpression) or loss (knock down) of function. We will assess classic behaviors (von Frey and weight bearing), and novel complex and clinically relevant functional activity and attention-related behaviors developed and validated by our team.

2) Define ED2/CD163 target engagement, i.e. ED2/CD163 as a signaling driver that dictates the dynamics of macrophage phenotype change and cellular reprogramming in inflammatory pain. TNFA and IL-1B will be measured as downstream target engagement. Also, we will use single-cell RNAseq (scRNAseq), cluster, and phenotype trajectory analysis to define how ED2/CD163 impacts gene expression programs in macrophages infiltrating the inflamed tissue.

3) Establish that macrophage ED2/CD163 gene induction results in opioid-sparing effects in surgical and inflammatory pain. We will construct dose responses of morphine in rats with SMIR or arthritis and ED2/CD163 overexpression to measure opioid-sparing effects.

Our project will establish ED2/CD163 as a cell-directed gene therapy for postsurgical pain that will reduce opioid requirements and dissect how it influences immune responses and inflammatory pain recovery. Our multidisciplinary team is uniquely equipped to successfully complete these studies.

Wake Forest University Health Sciences

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Winston Salem, North Carolina 27157 United States

Single Zip Code

Mechanisms, Models, Measurement, and Management in Pain Research (R01 Clinical Trial Optional) (PA-18-141)

Amendment Since initial award the total obligations have increased 289% from $465,287 to $1,809,441.