Development of Astrocyte-Restricted Precursors for Cell Therapy and Drug Screenin

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a cell therapy for the treatment of neurological disorders that are due to dysfunctional astrocytes. Current approaches to cure or manage these diseases by small molecule drugs are limited due to the polygenic and multifactorial nature of the disease. In addition, the blood brain barrier creates a significant hurdle for these drugs to target the diseased cell population. Using a targeted strategy of cell-transplant based therapy, diseases as diverse as lysosomal storage disorders and leukodystrophies, Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig's Disease), and Parkinson's Disease may all be approachable. Unlike small molecule therapeutics, natural proteins and compounds may be expressed at sufficient levels, at appropriate times, and at proper organ location by the transplanted cells to counteract the dysfunctional imbalance of the endogenous diseased cells. This proposal describes development of a human derived astrocyte-restricted precursor (ARP) cell population to meet the long-term objectives stated above. This population of cells has been defined in the CNS of rodents and we intend to build on this knowledge for isolation of the human cellular ortholog. We will first define optimal purification and growth conditions for ARPs using fully defined medium conditions, and then assess the ability of ARPs to differentiate into astrocytes after transplantation into the CNS of an animal model. Successful completion of these studies will form the basis for additional pre-clinical analysis of these cells in a rat model for ALS. In addition to their use as a therapy, Invitrogen and several other pharmaceutical companies have expressed interest in obtaining these cells for drug screening purposes. Another goal of this project is to provide a pure and consistent astrocyte population derived from ARPs to these companies. PUBLIC HEALTH RELEVANCE: Recent data suggest that dysfunctional astrocytes lead to disease progression in Amyotrophic Lateral Sclerosis (ALS; Lou Gerhig's Disease). Development of an astrocyte-restricted precursor cell population may hold promise as a therapy for this disease.