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NIH Symposium: Challenges & Promise of Cell-Based Therapies
May 6, 2008
Natcher Conference Center
NIH Main Campus, Bethesda, Maryland

Session 1: Neurological Disorders

Moderator: Ronald McKay, Ph.D.; National Institute of Neurological Disorders and Stroke, NIH

Preclinical Development of Remyelination and Motor Neuron Replacement Strategies in the Central Nervous System
Douglas Kerr, M.D., Ph.D., Transverse Myelitis Center, The Johns Hopkins University

Dr. Kerr began by discussing ES cell-derived motor neurons as a model of spinal muscular atrophy (SMA). He noted that the differentiation process from ES cells is stochastic and difficult to control. Nonetheless, the application of factors such as retinoic acid and sonic hedgehog to ES cells can influence neuralization, caudalization, and ventralization, and differentiation of ES cells into active spinal motor neurons can occur within seven days in culture (Wichterle H, Cell 2002;110:385-397; Harper JM, PNAS 2004;101:7123-7128). The addition of a depolarizing factor such as potassium chloride causes SMA (or survival motor neuron [SMN] protein-deficient) motor neurons to undergo a profound, cell type-specific degeneration. In essence, any stimulus that triggers depolarization causes these cells to degenerate. This process is characterized by the failure of mitochondria to migrate into the axon; SMN-deficient motor neurons thus have a reduced mitochondrial density. However, pretreatment with nicotinamide adenine dinucleotide (NAD) causes redistribution of mitochondria into motor neurons that are deficient in SMN protein. Furthermore, the compound restores axonal length and protects against axonal degeneration in these neurons.

Dr. Kerr then discussed in vivo transplantation of ES cell-derived motor neurons in paralyzed rats. Neuroadapted sindbus virus induces motor neuron injury in rats by promoting loss of motor axons in the spinal cord of infected animals. Could this damaged motor circuit be reconstituted using ES cells? Although transplanted motor neurons survive, they fail to form neuromuscular junctions. However, six months after a transplantation paradigm that includes growth factors and GDNF, electrically-active neurons are observed, along with modest physical recovery. Thus, transplanted motor neurons can reach muscle given the correct set of cues. Once there, they can form synapses with muscle, and these connections are electrically active. With this approach, rats recover up to 40% of hind-limb grip strength. However, it must be noted that this approach represents a focal therapy for a multifocal disorder. The strategy is currently being investigated in large mammal studies using human ES cells. Ricin is injected to promote focal weakness, and motor neurons are derived from human ES cells produced under FDA-compliant Good Laboratory Practice (GLP) conditions. The clinical population for initial studies is mammals with type 1 SMA, which is universally fatal without life support.

Finally, Dr. Kerr described potential use of glial-restricted precursors (GRPs), which can become astrocyte and oligodendrocyte progenitors, for treating demyelinating disorders. The naturally restricted fate of these cells offers enhanced efficacy and control of treatment with fewer side effects. Moreover, the cells are easily isolated and are relatively safe. Human GRPs can migrate well during short periods following transplantation and can express myelin basic protein. To deliver these cells in a multifocal way, very late antigen 4 (VLA-4) could be used to enhance delivery into the nervous system. VLA-4 is involved in the recruitment of immune cells from the blood to sites of inflammation in inflammatory disorders. Currently, several large-animal preclinical studies are underway to assess this approach for cell-based therapy. The initial indication for theses cells in humans is transverse myelitis, a disorder of a single focal lesion in the spinal cord.