Modulation of spinal neurodegenerative diseases in swine by stem cell grafting

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 DESCRIPTION (provided by applicant): The development and characterization of large animal models of specific human diseases and their effective utilization in preclinical efficacy and safety studies is essential for a successful transition of cell replacement- based therapies into clinic. Depending on the disease to be targeted, the duration of post-cell transplantation survival, and the need for use of transient or continuous immunosuppression, routine use of such models is associated with a variable degree of technical/technological difficulties. In addition to general consideration in using large animal models, specific limitations exist depending on the diseased organ system and associated functional loss to be studied. In the field of spinal neurodegenerative disorders, for example, several specific challenges remain, including: i) long-term maintenance of spinally injured animals with fully developed paraplegic phenotype, ii) reliable and safe immunosuppression protocols to be used in xenograft or allogeneic grafting design, and iii) the availability of inbred partially or fully MHC-matched animals for generation of isogeneic or allogeneic neural precursor lines (NSCs) to be used for in vivo grafting. In addition, cell labeling techniques which would permit to study time dependent changes in grafted cell survival/maturation in living animals and perform postmortem gene activity profiling in differentially generated cell populations (iPS-derived NSCs or fetal tissue-derived NSCs, for example) after grafting into a single animal recipient are not available. The development of these protocols/techniques is critical for optimization and validation of large preclinical models and cell derivation protocols to be used in perspective human trials. By using fully or partially MHC- matched miniature swine, we first propose to characterize the survival, differentiation and gene activity profile of established porcine iPS or fetal tissue-derived NSCs after grafting into the lumbar spinal cord in naïve non- immunosuppressed or transiently immunosuppressed swine. Second, using well characterized porcine model of spinal contusion injury, we will define the treatment effect after spinal grafting of isogeneic or allogeneic iPS an FT-derived NSCs on the recovery of motor function and corresponding grafted cell survival.