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.
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.
This Development Candidate Feasibility Award (DCF) application proposes to evaluate transplantation of human embryonic stem cell-derived inhibitory neuron precursor cells as a treatment for bladder spasticity and neuropathic pain associated with chronic 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 spinal inhibitory mechanisms that are essential for normal bladder and sensory functions. The applicant has demonstrated that murine inhibitory nerve cells integrate into the adult spinal cord and improve symptoms in an animal model of chronic spinal cord injury, and has also recently developed methods to create human inhibitory interneurons from human embryonic stem cells. This proposal will capitalize on these recent developments and determine whether human embryonic stem cell-derived inhibitory nerve cells can be successfully transplanted into the grey matter of the injured spinal cord in a mouse model of spinal cord injury and reduce neurogenic bladder dysfunction and neuropathic pain.
Objective and Milestones
- Reviewers expressed serious concerns about the overall approach, since cell transplants are planned for sites remote from the normal location of inhibitory neurons, and reviewers felt that it was unlikely that appropriate integration into the host neurocircuitry would occur.
- Since the goal of the work is to develop a treatment for pain and spasticity associated with SCI, it was unclear why much of the initial effort (Milestones 1 - 3) was focused on studies with uninjured spinal cord.
- Other aspects of the objectives and scientific approach appeared both sound and clinically relevant.
- Reviewers found the milestones straightforward but inadequately described.
- The success criteria for moving forward in each of the study components were unclear.
Rational and Significance
- Improved approaches for managing bladder spasticity and dysfunction and chronic central neuropathic pain would be a significant contribution, since these symptoms are among the top quality-of-life complaints of patients with SCI.
- The selection of inhibitory neurons for this approach is logical, as a loss of spinal inhibition has been suggested as a potential underlying mechanism driving both chronic pain and spasticity following SCI.
- Reviewers expressed concern that the timing of potential treatments and their assessment was not adequately addressed, as neuropathic pain following SCI can be delayed for months after the initial injury.
Research Project Feasibility and Design
- The proposal is supported by very good preliminary data.
- Reviewers considered the proposal section describing neuropathic pain to be inadequately developed.
- Reviewers expressed concern that planned electrophysiological studies would be carried out only with control (non-SCI) animals.
- It is unclear whether the stringency of lineage markers and purity of differentiated neuronal populations would be adequate for moving the project toward clinical application.
- The applicant did not address how one would determine whether this approach is better than transplantation of any other cell type currently being studied for treatment of SCI.
- There was no information about how long transplanted cells survive or addressing the relevance of the proposed mechanism.
- Reviewers expressed concern that the proposed cell populations may not have sufficient purity for clinical application.
- The inclusion of preliminary data to demonstrate even partial return of bladder function would have substantially strengthened the proposal.
Qualification of the PI (Co-PI, and Partner PI) and Research Team
- The PI and Co-PI are productive leaders in their respective fields.
- The team has all of the necessary expertise to successfully carry out the proposed experiments. Both PI and Co-PI have exemplary track records with respect to publications and funding, and there is a clear commitment of appropriate effort by as well as the means to readily communicate.
- The assembled team is of very high quality.
Collaborations, Assets, Resources and Environment
- The institution, resources, and environment appear appropriate for the proposed work.
Responsiveness to the RFA
- The application is responsive to the RFA
- The project employs human induced pluripotent stem cells, and a specific disease target has been identified.
- A motion was made to move this application into Tier 1 (Recommended for Funding). The programmatic reasons provided were that spinal cord injury is an important area in need of therapies and underrepresented in the CIRM portfolio. Reviewers reiterated the proposal’s scientific strengths and weaknesses. The motion failed.