SAFETY OF MESENCHYMAL STEM CELL ADMINISTRATION TO THE CNS OF RHESUS MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Lysosomal storage disorders are rare autoimmune genetic diseases caused by a deficiency of lysosomal enzymes some of which are involved in myelination of central and peripheral nervous system. Non-hematopoietic mesenchymal (stromal) stem cells (MSCs) isolated from bone marrow have shown immuno-modulative properties including relatively low allo-immunogenicity when transplanted into MHC-mismatching recipients. In this study we intracranially injected 1.25 million allogeneic ex-vivo expanded MSCs to a 1 month old rhesus macaque affected with early on-set Krabbe's disease and repeated the injection at 6 months. The initial GALC level was vertually zero and correlated with an early on-set of the disease. The allo-immune response to the transplanted MSCs was observed 10 days after the 1st and 2nd surgeries as increased numbers of neutrophils, monocytes, and lymphocytes. During 30-60 days post-surgery the numbers gradually returned to the pre-surgical values. The pattern of the immune allo-response was similar to that seen in healthy age-matched rhesus MSC recipients. There were no transplantation or surgery related side effects. A temporary amelioration of disease symptoms was observed after both transplantations. Additionally, after the 2nd surgery, some improvement in fine motor movement and cognition was noticed. The observed improvement correlated with results of the electro-myogram performed throughout the study. Also, MRI taken 3 months after the 1st surgery showed some myelination including areas where the donor male DNA was found later using a real-time PCR assay targeting Y-chromosome. In addition, the extensive neuro-behavior testing of the Krabbe's affected infant showed an improvement in large motor movement after both surgeries and lower levels of agitation and fearfulness after the second surgery. The study revealed potential benefits of the adult mesenchymal stem cells for developing treatment of the lysosomal storage disorders with neurological sequels.