Preclinical Development

The greatest challenge facing hESC research is the derivation of high purity cell lineages from pluripotent hESCs. Most efforts to generate homogeneous populations have been based on selection of the desired phenotype based on expression of lineage-specific markers or transgenes, or ectopic expression of lineage-specific transcription factors, approaches which suffer from poor selection efficacy and the fact that genetic manipulations may impair the ability of the cells to undergo the full repertoire of lineage differentiation. The inherently low yield of cell sorting methods also diminishes or eliminates commercial viability, which in turn diminishes or eliminates clinical viability of the approach.

The likelihood of generating a high purity population of human cells from hESCs is directly proportional to the degree of existing knowledge concerning the developmental pathways of cellular specification. Thus, the first high purity population derived from any stem cell type was the oligodendrocyte, a central nervous system (CNS) cell type studied for over 30 years by multiple sclerosis researchers. That derivation was conducted by our Scientific Advisory Board Chairman Dr. Hans S. Keirstead with SAB member Dr. Gabriel Nistor. The pathways of motor neuron (MN) specification are also very well defined: In brief, ectodermal cells are induced by BMP, FGF and Wnt signaling to acquire a rostral neural character, and then acquire a spinal positional identity in response to caudalizing signals such as retinoic acid. Finally, these spinal progenitor cells acquire a MN progenitor phenotype in response to the ventralizing effect of sonic hedgehog. Sonic hedgehog signaling initiates a patterned expression of homeobox domain and basic helix-loop-helix transcription factors that establish a MN progenitor domain.

California Stem Cell (CSC) has successfully generated 95% pure human lower motor neuron progenitors (MNP) from hESCs; these conclusions are based on morphology, immunostaining, receptor profiling, and electrical profiling. Synapse formation with, and functional innervation of, human muscle cells has also been demonstrated. GMP-compliant production of batches containing 1-10 billion clinical grade MNPs is routine, allowing the clinical development of potential hESC-based therapies for neuromuscular diseases and conditions such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI) and cardiovascular disease (CVD).

CSC is currently in the pre-clinical development phase of cell transplant therapies for ALS and SMA Type I and it may be some time before we are FDA-approved to start human clinical trials. If you are interested in participating in future clinical trials, please sign up with the appropriate clinical trial registry.

GMP-compliant production of batches containing 1-10 billion clinical grade MNPs is now routine.