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Long-term survival and maturation of spinally grafted human fetal and embryonic stem cellderived neural precursors in implantable tacrolimus pellet- immunosuppressed ALS SOD1-G93A model rat

  • Author(s): Goldberg, Danielle S.
  • et al.
Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the specific degeneration of upper and lower motor neurons. Current investigative translational therapies focus on neuroprotective and cell replacement benefits demonstrated by transplanted neural precursor cells (NPCs) or fate- restricted NPC derived astrocyte precursors. Long-term survival in relevant animal models is necessary for demonstration of cell differentiation and assessment of therapeutic potential, however aggressive immunosuppression is necessary to achieve such survival. Biodegradable immunosuppressant pellets represent a novel alternative to currently implemented labor intensive and unreliable delivery methods (such as repetitive daily subcutaneous injections). In the present study we demonstrate long-term survival and differentiation of astrocyte precursors grafted spinally in the disease environment of the SOD1-G93A ALS model rat spinal cord using this alternative Tacrolimus pellet immunosuppression method. We found that the Tacrolimus dose of 5.1 mg/kg/day was associated with optimal graft survival and differentiation of transplanted human ES- derived neural precursor cells for up to three months in ALS model SOD1- G93A rats. T-mediated host immune response and inflammation was near completely blocked in 5.1 mg/kg/day pellet implanted animals up to two months post transplantation. In addition, we found that the long-term survival, differentiation and integration of neural precursor cells resulted in increased alpha motor neurons survival if compared to media-injected SOD+ rats. Our results indicate that transplantable Tacrolimus pellets provide a safe, effective, and and efficient method of immunosuppression that can be used in a long-term xenograft experimental design

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