Human ES cell-derived MGE inhibitory interneuron transplantation for spinal cord injury

Human ES cell-derived MGE inhibitory interneuron transplantation for spinal cord injury

Funding Type: 
Early Translational III
Grant Number: 
TR3-05606
Approved funds: 
$1,623,251
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Active
Public Abstract: 
Transplantation of neuronal precursors into the central nervous system offers great promise for the treatment of neurological disorders including spinal cord injury (SCI). Among the most significant consequences of SCI are bladder spasticity and neuropathic pain, both of which likely result from a reduction in those spinal inhibitory mechanisms that are essential for normal bladder and sensory functions. Our preliminary data show that embryonic inhibitory neuron precursor cells integrate in the adult nervous system and increase inhibitory network activity. Therefore inhibitory nerve cell transplants could be a powerful way to establish new inhibitory circuits in the injured spinal cord that will reduce bladder spasticity and attenuate central neuropathic pain. We already have proof-of-principle data that murine inhibitory nerve cells integrate in the adult spinal cord and improve symptoms in an animal model of chronic spinal cord injury. We have also recently developed methods to create human inhibitory interneurons from embryonic stem cells. This proposal will capitalize on these recent developments and determine whether our human embryonic stem cell-derived inhibitory cells can be successfully transplanted into the grey matter of the injured spinal cord and reduce neurogenic bladder dysfunction and neuropathic pain, two major causes of suffering in chronic SCI patients. If successful, our studies will lay the groundwork for a potential novel therapy for chronic SCI.
Statement of Benefit to California: 
There are an estimated 260,000 individuals in the United States who currently live with disability associated with chronic spinal cord injury (SCI). Symptoms of chronic SCI include bladder dyssynergia reflected by incontinence coincident with asynchronous contraction of internal and external sphincters, and central neuropathic pain, both of which severely impede activities of daily living, reduce quality of life, and contribute to the very high medical costs of caring for the Californians who suffer from chronic spinal cord injury. The Geron trial for SCI, as well as other cell-based approaches, aim to treat acute SCI. This proposal considers a different potentially complementary cell-transplantation strategy that is directed to more chronic SCI with the goal of improving bladder function and reducing pain. We propose to use cell grafts of inhibitory interneurons that we have derived from human stem cells in order to provide a novel treatment. If successful, we will have defined a therapeutic option that targets the most prevalent population of spinal cord injured patients. As the country's most populous state, California has the largest number of patients with chronic SCI, approximately 12,000. The estimated economic cost to California in lost productivity and medical expenses amounts to $400,000,000 annually. The potential savings in medical care costs, and improvement in quality of life will therfore have a disproportional benefit to the state of California.
Progress Report: 

Year 1

From the past six months of work, we report considerable progress toward our aims of investigating the safety and efficacy of human inhibitory nerve precursor (MGE) cell transplantation for the treatment of spinal cord injury-induced bladder spasticity and neuropathic pain. Our first aim details the injection of human MGE cells into the uninjured rodent spinal cord and investigation of cell fate and potential adverse side effects from their transplantation. During the reporting period, we completed histological analyses for the two-month time point post-injection, and we found that the human MGE cells, derived from human embryonic stem cells (hESCs), appropriately matured into forebrain-type inhibitory interneurons in the rodent spinal cord. Also, we initiated histological examination of animals six months post-injection and detected robust human cell survival, dispersal into the spinal cord grey matter, and neuronal maturation, but no evidence of tumor formation. In addition, we completed behavioral analyses of animals injected with hESC-derived MGE cells at two and six months post-injection. Thus far, we have not observed any adverse side effects when human MGE cells are transplanted into the uninjured animal as determined by measures of body weight, locomotion, bladder function, and pain sensitivity.

© 2013 California Institute for Regenerative Medicine