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Creating a Gene Therapy For Chronic Pain and Spinal Cord Disorders

by Michael J. Iadarola, Ph.D. Chief, Neuronal Gene Expression Unit , NIDCR

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by Michael J. Iadarola, Ph.D. Chief, Neuronal Gene Expression Unit , NIDCR

This research demonstrates a new treatment strategy for chronic pain. It is currently in transition from the lab bench to the patient bedside, as we prepare for a first clinical trial in human subjects. What follows is a personal account of how the research evolved and where it can go in the future. The "paracrine paradigm" we developed is applicable in a general fashion to therapy for chronic neurological disorders.

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Photograph of Alan Finegold (left) and Michael IadarolaImage Added
Alan Finegold (left) and Michael Iadarola

Pain: Study It or Treat It?

This work began in the summer of 1993 with a small program in therapeutics"small because I was able to carve out only limited time over two summers with an HHMI high school student, Susan Lee (who has since gone on to Harvard Medical School in Boston). I had always been a basic bench scientist, and my lab had been studying synaptic-induced gene regulation in the spinal cord in models of persistent peripheral inflammation. I had discovered that persistent pain up-regulates the opioid peptide dynorphin in the dorsal spinal cord, the first synaptic processing station for pain"first observing this with a radioimmunoassay for dynorphin peptide and later measuring the corresponding mRNA increases, performing studies to localize the spinal neurons involved, and eventually examining seven base pairs of enhancer sequence in the promoter.

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The transition to translational research was sparked through our weekly laboratory meetings. What was then the Neurobiology and Anesthesiology Branch contained both basic and clinical research groups, and the clinical group sometimes presented patients with chronic pain problems. This was my first exposure to patients with chronic neuropathic pain disorders, and it was a real eye-opener. Chronic neuropathic pain is notoriously difficult to control with currently available drugs and procedures, and the subjects we were seeing exemplified this clinical state of the art. Often, what had begun as relatively minor nerve damage after a traumatic injury progressed to a severe chronic pain disorder. Patients experienced high levels of spontaneous pain and mechanical allodynia (pain from a normally nonpainful stimulus). Just brushing the skin in the neuropathic zone was enough to cause them excruciating pain. This exposure stimulated us to begin exploring new treatments for pain, in addition to studying the molecular neurobiology of pain.

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