|
|
|
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 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. Our results demonstrated that a single administration of hUCB cells into the veins of Sanfilippo mice at different stages of disease (early symptomatic or late stage) had a beneficial effect, probably due to enzyme delivery into these enzyme-deficient mutant mice. These previously shown behavioral improvements, indicating advantages of the administered hUCB cells, were supported by our results on 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. Although many cells were associated with blood vessels, confirming that transplanted cells were still present in the blood circulation, some cells were found in the brain and peripheral organs. Our results also showed that 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 a declining production of the missing enzyme over time. To address this limitation, it was necessary for us to investigate the effect of repeated hUCB cell infusions during the disease over time. The aim of our pre-clinical translational study was to determine the effect of multiple intravenous transfusions of hUCB cells into a mouse model of Sanfilippo type B. We investigated the ability of repeated hUCB cell administration to ameliorate/prevent behavioral dysfunction in mutant mice. As we showed previously, the Sanfilippo mice demonstrated early hypoactivity (3 months of age, early symptomatic stage of disease) with impaired learning (mostly, in males) followed by hyperactivity and memory impairment with aging (8-9 months of age) of both sexes. Multiple administrations of hUCB cells into mutant mice showed improved behavioral activity of both sexes with increased repeat cell transplants. Interestingly, learning improved in mutant males treated multiple times mainly at the 3rd and 4th months after cell grafting; whereas their ability to remember (memory) tended to improve at 4th and 6th post-transplant months. During learning, Sanfilippo female mice treated multiple times showed learning improvement at months 4 through 6 after cell injection, although their improved memory was observed early, in the 3rd month post-transplant. The behavioral results were supported by analysis for the presence of transfused hUCB cells in the blood circulation and peripheral organs of mutant mice, showing increasing cell numbers after each cell injection. Additionally, neuronal architecture in the hippocampus, analyzed by using a sensitive Golgi staining of dendritic domain of the neurons, was improved in Naglu mice of both sexes after multiple administrations of hUCB cells. Another important advantage of therapeutic tactic of repeated hUCB cell injections was that heparan sulfate accumulation was significantly reduced in the liver of Naglu mice after receiving multiple deliveries of hUCB cells over 6 months compared to single cell treated Naglu mice and non-treated mutants. The data collected so far are very hopeful; however, our current project addresses a number of areas needing further study. We will investigate potential migration of intravenously administered cells to the various structures of the brain of mutant mice. Also, analysis of specific immunophenotypes of these transfused cells will be performed, since this is an important criteria for evaluating/confirming the nature of the significant beneficial effects of hUCB cells in Sanfilippo mice. The repeated administration of hUCB cells into the blood circulation of Sanfilippo mice may lead to the development of a new strategy for enzyme replacement for Sanfilippo. Our therapeutic tactic of continuous delivery of the missing Naglu enzyme by multiple cell administrations may be critical to developing a cell transplant strategy. |
Questions or problems regarding this web site should be directed to curekirby@sbcglobal.netCopyright © 2000-2007 Children's Medical Research Foundation ®. All rights reserved. Last modified: Sunday October 21, 2007. |
