This proposal addresses Broad Challenge Area: 15: Translational Science and Specific Challenge Topic: Demonstration of """"""""proof-of-concept"""""""" for a new therapeutic approach in a neurologic disease: 15-NS-104 It is estimated that 11,000 Americans suffer spinal cord injury (SCI) every year. According to the Centers for Diseases Control and Prevention, SCI costs the nation an estimated $9.7 billion each year. Most patients survive their injury, leaving as many as 250,000 people in the United States who suffer from chronic spinal cord injury. The majority of people who survive a spinal cord injury will develop symptoms of spasticity, a pathologic exaggeration of normal spinal reflexes that develops in nerve cells below the level of injury. Spasticity is a major health problem for SCI patients. It limits their mobility and independence and can cause pain, muscle contractures, disabling muscle spasms, and bowel and bladder spasticity. Bladder spasticity is a particular problem, since it can cause urine reflux and kidney damage. The mechanisms of muscle spasticity after spinal cord injury are not well understood, but recent studies indicate that the loss of particular descending axonal pathways most likely results in the decreased activity of inhibitory interneurons, which causes overreaction of motor neurons. The primary medications used to treat spasticity either enhance neural inhibition or inhibit muscle contraction. All have significant systemic side effects and do not completely eliminate spasticity. Surgical treatments used in medically intractable cases include intrathecal baclofen, which can cause loss of residual walking ability, tolerance, withdrawal syndrome, and infectious and other complications related to indwelling catheters;and posterior rhizotomy which can cause weakness, sensory loss, urinary dysfunction, sexual dysfunction, and spinal instability. An effective local therapy that avoids systemic effects and spares residual function is an unmet need for SCI patients. A novel approach to spinal injury treatment would be to transplant inhibitory interneuron progenitor cells in segments below the injury site where they could migrate, integrate, and establish new inhibitory circuits capable of reducing spastic activity. Work in our laboratories has demonstrated that precursors of inhibitory GABAergic interneurons derived from the rodent medial ganglionic eminence (MGE), a brain region specialized to produce large numbers of inhibitory interneurons, can migrate, integrate and modulate neural circuits when grafted into the adult brain. This is a unique and robust property of MGE progenitor cells that has not been demonstrated in any other type of neural precursor cell, and our preliminary data show that MGE cells can also integrate in adult spinal cord grey matter. Our proposal will determine how these cells migrate, integrate, and function when grafted to the spinal cord grey matter (Aim 1). We will determine whether MGE progenitor cells, grafted below the level of a spinal cord injury, can provide inhibitory modulation of spinal circuits (Aim 2). Finally, we will determine if MGE cell grafts can reduce neurogenic bladder dysfunction, a measurable index of spasticity following spinal cord injury (Aim 3). If successful, our studies will lay the groundwork for a potential novel therapy for chronic spinal cord injury.

Public Health Relevance

There is an estimated 250,000 individuals who currently live with disability associated with chronic spinal cord injury. This proposal addresses a novel stem cell transplantation strategy to ameliorate bladder dysfunction and involuntary muscle spasms that accompany chronic spinal cord injury. A long-term goal of these studies is to translate this effort to the spinal cord injured patient, with a specific focus on improving bladder function and reducing muscle spasms, both of which can profoundly affect quality of life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-BDCN-T (58))
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Kleitman, Naomi
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Fandel, Thomas M; Trivedi, Alpa; Nicholas, Cory R et al. (2016) Transplanted Human Stem Cell-Derived Interneuron Precursors Mitigate Mouse Bladder Dysfunction and Central Neuropathic Pain after Spinal Cord Injury. Cell Stem Cell 19:544-557
Zhang, Haoqian; Chang, Mayland; Hansen, Christopher N et al. (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 8:206-20