ICOC Funds Committed:
In humans, injury or diseases resulting in impairment of oligodendrocyte (OL) function leads to myelin loss or defects manifesting as developmental and/or adult disabilities and mental retardation. At the present time remyelination of the human CNS is not yet possible. Oligodendrocytes synthesize and maintain myelin, the sheath that insulates axons for a fast nervous impulse transmission in the central nervous system (CNS). Myelin deficiency whether inherited or acquired, like Pelizaeus Merzbacher’s disease and Multiple Sclerosis in humans, results from OL dysfunction. These are progressive degenerative disorders, resulting in deterioration of sensory and motor functions. Neural stem/progenitor cells are present in the embryonic, postnatal and adult brain and they represent a potential source of cells for therapy. Yet, the CNS appears not to have all the elements to successfully sustain autonomous remyelination. Human embryonic stem cells offer a great potential to identify appropriate neurotrophic factors or molecules necessary for these cells to acquire neural characteristics as a source of specific cell types such as Neural Stem Cell. Human embryonic stem cells provide novel prospects for cellular replacement strategies because of their ability to provide seemingly unlimited stem cell numbers in vitro, their flexibility to genetic engineering, and their broad developmental capacity. hES-derived oligodendrocytes could potentially address the needs to benefit the outcome of demyelinating diseases by helping to promote survival, growth of host tissue, and/or replacement of cells lost. The work we propose here is to study the conditions to obtain homogeneous OL populations (in the absence of other cell types) in high numbers that will allow us to understand the needs of these cells as they develop from a progenitor (young) cell into a mature and functional cell able to myelinate naked axons. The data derived from the studies we are proposing, will have direct relevance on the long term development of standardized methodology that would be made available for future clinical research using cell replacement therapies in cases of myelin deficient CNS of both inherited and acquired disorders, e.g. Pelizaeus Merzbacher’s disease, spinal cord injury, traumatic brain injury, AIDS dementia, periventricular leucomalacia, cerebral palsy, autism, and multiple sclerosis.
Statement of Benefit to California:
Myelin is a sheet of fat (80%) and proteins (20%) that wraps around axons, speeding messages through the brain by insulating these neural connections. Although myelinogenesis takes place in perinatal stages, in humans, myelination continues through childhood and well into adulthood ( Bartozkis, Neurobiology of Aging, January 2004). New evidence points to disruption of myelination as a key neurobiological component behind childhood developmental disorders. Many factors can disrupt myelination and contribute to or worsen disorders such as autism, attention deficit/hyperactivity disorder (ADHD) and schizophrenia. (Bartzokis, G., 2005). Other disorders like Multiple Sclerosis and trauma result in myelin loss with a concomitant reduction or even impairment of the central nervous system (CNS) function. Approximately 1 in 700 or 0.14% or 388,571 people in the United States are afflicted with Multiple Sclerosis (source NIAID). Therefore, besides autism, ADHD, and schizophrenia, environmental toxins and drugs of addiction may contribute to demyelination. Moreover, in Periventricular Leucomalacia (PVL), the white matter can be prevented from being formed in the fetus if infection, inflammation or other alterations of the mother’s metabolism occur during gestation, preventing the progression of oligodendrocyte progenitors (OLPs) into mature oligodendrocytes (OL) and therefore resulting in myelin deficit. Although babies with PVL generally have no outward signs or symptoms of the disorder, they are at risk for motor disorders, delayed mental development, coordination problems, and vision and hearing impairments. PVL may be accompanied by a hemorrhage or bleeding in the periventricular-intraventricular area (the area around and inside the ventricles), and can lead to cerebral palsy. It is estimated that some 500,000 children and adults in the United States manifest one or more of the symptoms of cerebral palsy. Currently, about 8,000 babies and infants are diagnosed with the condition each year. To date there is no cure for myelin diseases in the sense that no treatment is aimed at myelination/remyelination but rather treatments are directed to alleviate the symptoms. The work proposed here will allow us to acquire the knowledge necessary to obtain a homogeneous source of OL derived from human embryonic stem cells (ES) in adequate numbers by identifying the specific factors and conditions that are needed to obtain ES-derived OLPs in a reproducible and cost efficient manner. The implementation of a successful propagation and cryopreservation method for OL committed cells in defined conditions will allow us to obtain a dependable source of OL to be used for potential cell therapy. With these progresses and other pertinent issues overcome, considerable enthusiasm continues to be generated about treating disorders of white matter degeneration; diseases once thought to be a totally incurable condition.