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7. The University of South Florida, Dr. Paul R. Sanberg During the last few years, our research group at the University of South Florida has studied the potential of human umbilical cord blood (hUCB) stem cells to treat various neurodegenerative disorders (stroke, ALS, Parkinson’s disease) as well as brain and spinal cord injuries. Data suggest that these cells are able to repair a damaged or defective nervous system. In Sanfilippo syndrome type B, a deficiency of the Naglu enzyme leads to accumulation of heparan sulfate, a major feature of this disease. Our previous results demonstrated that a single administration of hUCB cells into the veins of Sanfilippo mice at early or late stage disease had a beneficial effect, probably due to enzyme delivery into these enzyme-deficient mutant mice. The observed behavioral improvements, indicating advantages of the administered hUCB cells, were supported by the survival, distribution, and development into different cell types of the transplanted cells. After administration of hUCB cells, the cells were found widely distributed within and outside the central nervous system. Also, heparan sulfate accumulation was reduced in the liver and spleen of Naglu mice, mainly in females, 6 months after receiving hUCB cells. Additionally, an anti-inflammatory effect by hUCB cell transplantation was determined. However, most observed behavioral benefits in Sanfilippo mice were limited to the first months after transplantation, possibly due to declining production of the missing enzyme. To address this possibility, we investigated the effect of repeated hUCB cell infusions. We showed that multiple administrations of hUCB cells into mutant mice improved behavioral activity of both sexes for a prolonged period. The behavioral results were supported by detection of transfused hUCB cells in the blood circulation and peripheral organs of mutant mice; increasing cell numbers were noted after each cell injection. Another important advantage of repeated hUCB cell injections was significantly reduced heparan sulfate accumulation in the liver of Naglu mice compared to singly treated or non-treated mutants. Thus, our results demonstrated that multiple administrations of hUCB cells into Naglu mice at an early symptomatic stage of disease have a beneficial effect compared to a single injection, probably due to continuous enzyme delivery into the enzyme-deficient mutant mice. However, the potential for hUCB cell migration to the brain and identification of cell types developing from the cells grafted into mutant mice still need investigation. The objective of the proposal was to determine whether hUCB cells injected into a vein migrate to the brain and develop into appropriate cell types. The current study demonstrated that previously described benefits of multiple hUCB cell injections into Naglu mice probably occur from migration of the administered cells to the various structures of the brain, as indicated by the larger number of migrated cells found in repeatedly vs. singly treated mutant animals. The importance of this finding is probably continuous enzyme delivery to the brain due to the higher numbers of surviving cells after multiple injections; consequently, multiply treated animals show more neurological improvements than animals receiving a single dose of hUCB cells. The hUCB cells were found widely distributed among different brain structures, mainly in the hippocampus, a brain structure responsible for short term memory, formation of the new memories and spatial navigation. However, the multiply treated mice produced fewer cells able to develop into neurons or astrocytes compared to mice receiving a single injection of cells. Based on these results, it is possible to conclude that continuous enzyme delivery into enzyme deficient Naglu mice by repeated MNC hUCB cell administrations, rather than cell development to another cell type, might be more promising in developing a cell-based therapy for Sanfilippo Syndrome type B. The data collected so far are very hopeful; however, our current project addresses a number of areas needing further study. We will investigate the migration route of administered cells to the brains of mutant mice. First, we will determine the condition of the blood-brain barrier in Sanfilippo. Determining when, where, and if, this barrier is damaged in Sanfilippo is important not only for examining transplanted cells’ migration, but will also be crucial to increased understanding of this disease and developing a future drug-based treatment. |
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