Ex vivo therapy for Parkinson's disease with bone marrow stromal cells
Description
Parkinson's Disease (PD) is a devastating neurodegenerative disease affecting up to 1% of persons over age 60. PD is marked by a loss of dopaminergic neurons in the substantia nigra pars compacta and clinical symptoms that include bradykinesia, tremor at rest, and rigidity. Although the disease course is progressive, almost all patients experience a normal life span. The mainstay of therapy for PD is oral administration of L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor compound for dopamine. However, the efficacy of L-DOPA therapy decreases with time, presumably due to fluctuations in L-DOPA levels within the central nervous system Several strategies for improving treatment for PD involve implantation of therapeutic cells in the brain, including allogeneic and xenogeneic fetal dopaminergic neurons and L-DOPA/Dopamine-producing cells. An alternative donor cell source for neural transplantation is adult stem cells from bone marrow stroma. Marrow stromal cells (MSCs) are multipotential stem cells that can differentiate into osteoblasts, adipocytes, chondrocytes, and myoblasts. Recent evidence suggests that MSCs are also stem cells for non-mesenchymal tissue. For example, human and rat MSCs express markers indicative of neurons when incubated with anti-oxidants in the absence of serum. Isolated simply by their adherence to plastic, human MSCs (hMSCs) can be easily obtained from the PD patient's iliac crest. They are then expanded and engineered in culture, and finally transplanted autologously into the patient We thus propose that MSCs can be used as cellular therapeutic vehicles for treatment of PD when transplanted into the brain. For treatment of PD, undifferentiated MSCs were gene engineered to produce L-DOPA by retroviral transduction to act as a 'biological pump' in the brain. In an alternate strategy, the potential of MSCs to develop into neuronal cells was studied both in culture and in the adult damaged and undamaged rat brain. The overall behavior and immunogenicity of MSCs in the rat brain was explored. We thus performed experiments both in the tissue culture dish and in animal models for PD to determine whether MSCs could be used for cell and gene therapy in PD