Information Paper on Neural Stem Cell Research Center for Neuroregenerative Medicine and Defense Centers of Excellence Initiatives

February 17, 2009

Summary: The Department of Defense has undertaken several major initiatives to facilitate the development of clinical applications of neural Stem Cell research to enhance the recovery of returning service members with injuries sustained in OIF/OEF. Two primary centers were established in 2008: the Center for Neuroscience and Regenerative Medicine and the Armed Forces Institute of Regenerative Medicine (AFIRM). In addition, TATRC continues to support initiatives in the development of neural stem cell applications relevant to injured service members.

Background: Technological advances over the past year have led to techniques and methodologies that allow for autologous stem cell development using skin cells. This technology is within the current federal parameters for stem cell research and has led to several DoD initiatives.

Center for Neuroscience and Regenerative Medicine
The Center for Neuroscience and Regenerative Medicine (CNRM) is a collaborative initiative between Uniformed Services University for the Health Sciences and the National Institute of Neurological Institute of Neurological Disorders and Stroke established in the Fall of 2008 with Congressional funding of $70 million. The primary focus of this center is regenerative medicine “from the neck up.” The Defense and Veterans Brain Injury Center has been tasked by Health Affairs as the primary DoD TBI clinical network to coordinate with the CNRM on the clinical applications of neural Stem Cells. Over 200 researchers have submitted research proposals to the Center and these are currently being reviewed for scientific merits and military relevance. The Center’s mission is to find new diagnostic tools and innovative approaches to increase neuroplasticity. Use of regenerative medicine will address brain injury at the organ, cellular, and molecular level. It is anticipated that the CNRM will collaborate with other federal agencies as well as the DoD Vision Center of Excellence and other components of the Defense Centers of Excellence to include the National Intrepid Center of Excellence for Psychological Health and TBI.
Armed Forces Institute of Regenerative Medicine
The Armed Forces Institute of Regenerative Medicine (AFIRM) was established in April of 2008. The U.S. Army Medical Research Material Command, the Office of Naval Research, the National Institutes of Health, the Air Force Office of the Surgeon General, and the Department of Veterans Affairs are funding the consortia with $85 million. In addition, $180 million are being provided from academic institutions, industry, and state and federal agencies (for a total of $250 million). The AFIRM team’s mission is to develop clinical therapies over the next five years focused on: burn repair, wound healing without scarring, craniofacial reconstruction, limb reconstruction, regeneration, or transplantation; and compartment syndrome (condition related to inflammation after surgery or injury that can lead to increased pressure, impaired blood flow, nerve damage, and muscle death). AFIRM teams (Wake Forest University Baptist Medical Center and the McGowan Institute for Regenerative Medicine at the University of Pittsburgh Medical Center; Rutgers University and the Cleveland Clinic, and the US Army Institute of Surgical Research) plan to use some placental or amniotic fluid stem cells, but most projects rely on cells taken from the patients themselves (avoiding issues of tissue rejection). Projects include hand and limb transplantation, digit regeneration, skin replacement procedures, scar reduction therapies, bone, muscle, and nerve regrowth, and optimizing skin-grafting techniques (including cell-spraying technologies).
Telemedicine and Advanced Technology Research Center
Neuro Regenerative Medicine Projects at TATRC that include neural stem cell research include [projects that cover TBI, SCI, and peripheral nerve regeneration – overlapping portfolios managed by Dr. Kenneth Curley and Eva Lai]:
1. Advanced Restoration Therapies in Spinal Cord Injury (Congressional Special Interest): Kennedy-Krieger Institute ($1.15 million FY07; pending continuation for FY08 of $849,000). This program is investigating functional electrical stimulation (FES) as a mechanism to improve functions in CNS following injury or disease. Specifically their investigations of patients with upper extremity spinal cord injuries have found neurological, physical, and functional improvements. They will be modeling FES in neural stem cell cultures, varying the frequency and durations of stimulation, in order to measure the rates of oligodendrocyte birth, proliferation, and differentiation of axonal myelination.
2. Battlefield Exercise and Combat Related Spinal Cord Injury Research: Neuroprotection and Repair after Spinal Cord Injury (Congressional Special Interest): Miami Project to Cure Paralysis (FY06: $1.095M; FY07:$1.022M; FY08 proposed funding of $2.546M). This program is investigating: A) compounds that inhibit excitotoxic cell death of neurons, and therapeutic value of inhibiting secondary injury in a cervical model of SCI (rat models); B) infusing candidate small molecules into a contusion SCI to determine effects upon locomotor behavior and tissue integrity. Examine candidates that block induced cell death. C) Complete screening of the small molecule library for agents capable of reversing microglial cell activation: D) Continue to evaluate roles of specific signaling proteins in promoting axon growth on inhibitory substrates (myelin, proteoglycans) and permissive substrates (laminin, cell adhesion molecules), using shRNAs and cDNAs.
3. Efficacy of Amnion Derived Multipotent Progenitor Cells (AMPCs) for Acute Treatment of Spinal Cord Injury (TATRC/RAD2 funded): Christopher Reeve Foundation and UC Irvine (FY07: $200,000). Testing the potential of human Amnion-derived Multipotent Progenitor cells (AMPCs) to effect recovery after spinal cord injury.
4. Acute care of blast effects and head injuries (Title: Military Neurotrauma Database and research development) (Congressional Special Interest): Shelton Foundation (FY06:$842,000). Establish a comprehensive military neurotrauma database and conduct research utilizing regenerative medicine techniques to investigate novel combinations of cell source and scaffold materials to create a cell delivery system for the treatment of traumatic brain injury. Cultured adult stem cell types examined for the ability to differentiate into neurons on composite chitosan-collagen hydrogels and electrospun composite conduits.
5. Advanced Regenerative Medicine (Sub project: A Novel Protocol to Accelerate Nerve Regeneration following Traumatic Combat Injury) (Congressional Special Interest): Pittsburgh Tissue Engineering Initiative (FY06:$1.854M; FY07:$1.223M; FY08:$1.614M). Work investigates regenerative medicine strategies for treatment of injuries commonly caused by battlefield trauma. Specifically, investigating reconstitution of functional musculotendinous tissue, regrowth of peripheral nerves, and creation of autologous skin for burn and blast injuries.
6. Northern California Institute for Research and Education (Sub project: Novel Astrocyte Signaling Therapy to Promote Neuronal Regrowth and Supress Glial Scarring During Traumatic Brain Injury) (Congressional Special Interest): Northern California Institute for Research and Education (FY05 sub project). Preliminary data indicate that HA-mediated CD44-TLRs signaling “cross-talk” in astrocytes is closely involved in neurodegeneration and CNS damage following TBI.
7. Northern California Institute for Research and Education (Sub project: Novel Neuroprotective and Regenerative Agents for Head and Spinal Cord Injury) (Congressional Special Interest): Northern California Institute for Research and Education (FY05 sub project – completed). Investigate effects of several small molecule agonists of the neurotrophen receptors TrkB and p75NTR on outcomes of traumatic brain injury. (Rat Model): Found that p75NTR ligand LM11A-31 and TrkB ligand LM 22A-4 cause a small but significant improvement in rotorod performance, and LM11A-31 significantly improves Morris Water Maze (Spatial Learning) performance following injury. LM11A-31 decreases early cell death in the hippocampus, and preliminary data suggests similar effects in the cortex. In vitro, LM11A-31 increases neural progenitor cell growth and differentiation into neurons.
8. Northern California Institute for Research and Education (Sub project: Promoting Neurogenesis by Suppressing Microglial Activation) (Congressional Special Interest) (FY06 Sub project). Studies proposed extend studies to a rat model of brain trauma. Success would identify a mechanism for facilitating neurogenesis.

Summary/Way Ahead: What is not clear at this time is if there is an integrating office to coordinate and facilitate all of the DoD stem cell research affecting the brain, spinal cord, and extremities to allow for collaboration, coordination, and translation between each of these major initiatives which involve DoD agencies, civilian federal agencies, and civilian academic institutions.