Developing Novel Strategies for CNS Repair and Protection
We are actively exploring a broad range of treatment strategies for the protection and repair of the central nervous system in spinal cord injury, multiple sclerosis, and stroke. These strategies include cell transplantation approaches, as well as delivery of cell products, antibodies, small molecules, and biomaterials. Using our expertise in cell isolation, transplantation, behavioral recovery assessment, and quantitative morphological analysis of tissues, are rigorously analyzing the therapeutic potentials and risks of different treatment approaches. Many of these studies are being carried out in collaborations around the world. Our emphasis has been on preclinical studies designed to provide the kinds of information necessary for assessing the feasibility of producing clinically significant improvements in patient function and for choosing the appropriate treatment parameters for clinical trials if the data suggests they are warranted.
Cell-Based Repair of the Injured Nervous System
Our cell-based repair program is exploring the potential of transplanted cells, including adult derived myelin forming cells, adult stem cells, and induced pluripotent stem cells to restore signal conduction in demyelinated axons, facilitate axon regeneration, and/or reduce neuronal loss. We are investigating transplantation of myelin-forming cells into the site of injury as an approach to induce remyelination of demyelinated axons and thereby restore impulse conduction. We are also exploring the use of human mesenchymal stem cells, derived from the adult bone marrow, as an approach to repair of the injured brain and spinal cord. For example, we have shown that these autologous cells—administered intravenously—can limit the damage to brain or spinal cord tissue in animal models of stroke or contusive spinal cord injury. Of ongoing interest, we are evaluating the relative therapeutic effectiveness of different cell types with similar overall properties and to identify parameters most important for transplant success.
Exosomes: A New Class of Therapeutic Agents for CNS Repair
Exosomes, small, virus-sized particles containing protein, lipids and RNAs released by cells, can influence the function of other cells. These recently characterized particles are produced by all cell types and are believed to play important roles in cell-cell communication in both health and disease. Our recent work suggests that exosomes produced by mesenchymal stem cells may be responsible for the therapeutic effects in CNS injury. Exosomes are far more stable and easy to store compared to cells. They are less likely to induce immune rejection, and amenable to large-scale production. Exosomes therefore represent a more practical alternative to some cell based therapies. In collaboration with researches in the laboratory of Philip Askenase (Dept. of Immunology, Yale), we are also exploring the effects of exosomes in inflammation, and the RNA species which may be responsible for their efficacy.
Focus on CNS Vasculature
We and others have recently highlighted the importance of the blood-brain and blood-spinal-cord barrier integrity in protecting the CNS from damage. Our studies in a rat model of MS showed that transient disruption of the blood spinal cord barrier alone is sufficient to induce a demyelinating lesion as the site of disruption in animals which had been immune sensitized, but which had been previously free of lesions. This observation suggested that increasing the stability of the blood-brain and blood-spinal cord barriers could represent a novel target for preventing the progression of MS. Similarly, our investigations into the mechanisms of therapeutic efficacy of intravenous MSCs for promoting recovery after contusive spinal cord injury showed that the rapid improvement in functional recovery correlated closely with a rapid restoration of BSCB integrity, implying that the ongoing vascular leakage after CNS trauma contributes significantly to poor outcomes.
Anti-Nogo Antibodies -- Inhibiting the Inhibitors
Although axons can regenerate after peripheral nerve injury, the environment of the central nervous system is not conducive to long distance axon growth. This poor regeneration is due in large part to the presence of molecules such as NOGO, which inhibit regeneration. In collaboration with the Strittmatter laboratory (Dept. of Neurology, Yale), we are engaged in a randomized blinded study of the long-term effects of function blocking anti-NOGO antibodies on long distance regeneration of severed spinal cord axons, as well as evaluating potential negative side effects of such treatments.
Targeting Serotonin to Improve Motor Control After Spinal Cord Injury
Fibers descending from the brain through the raphe spinal tract make synaptic connections with motor neurons in the spinal cord, which allow individuals to control the movement of their arms or legs. Cells of the raphe spinal tract use the neurotransmitter serotonin to control the motor neurons. We have shown that raphe spinal tract axons which are spared after a spinal cord injury can sprout many new connections (synaptic terminals) over a period of several months after injury and that the appearance of these new synaptic terminals correlates with improved control over the limb. Furthermore, drugs which affect the serotonin system can reversibly affect limb control. These data suggest that medications, which enhance communication at serotonergic terminals, may improve muscle control for individuals with incomplete spinal cord injuries.
Collaborating on Clinical Trials
Our preclinical studies have played an important role in establishing the safety profile of human bone marrow mesenchymal stem cells for treatment of stroke and spinal cord injury. We maintain a close relationship with colleagues in Sapporo, Japan (Drs. Osamu Honmou and Masanori Sasaki) who are conducting Phase I Clinical trials of autologous human bone marrow mesenchymal stem cells for the treatment of stroke and spinal cord injury. Collaboration between our two groups has been important for continuously assessing safety risks and refining treatment protocols.