Svitlana Garbuzova-Davis, Ph.D, D.Sc. and Paul R. Sanberg, Ph.D, D. Sc. Center for Aging & Brain Repair, Department of Neurosurgery, College of Medicine, University of South Florida

September, 2013

For more than decade, researchers at the University of South Florida have studied the potential of human umbilical cord blood (hUCB) stem cells to treat various neurodegenerative disorders as well as brain and spinal cord injuries. The mononuclear cell portion from hUCB (MNC hUCB) is a diverse group which includes stem cells, lymphocytes, and monocytes. A single cell dose has been shown to provide benefits in animal models of Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, and Parkinson’s disease, suggesting that MNC hUCB cells are able to repair a damaged or defective nervous system.

The research team lead by Dr. Sanberg has been investigating a new cell therapy approach for Sanfilippo syndrome type B (MPS III B) by administration of MNC hUCB cells. A deficiency of the Naglu enzyme, causing accumulation of heparan sulfate, is a major feature of this disease and MNC hUCB cells might be preferable to other cell sources for delivering the missing enzyme. The initial study (Garbuzova-Davis S, Willing AE, Desjarlais T, Davis CD, Sanberg PR. Transplantation of human umbilical cord blood cells benefits an animal model of Sanfilippo syndrome type B. Stem Cells Dev, 14(4): 384-394, 2005) demonstrated that administration of MNC hUCB cells into the lateral brain ventricle of early symptomatic mice modeling MPS III B has positive effects. Administered cells survived for a long time (7 months), migrated into different brain structures, improved neuronal architecture in the hippocampus and cerebellum, and reduced GAG accumulation in the liver of treated mice. Although all of these results indicate the benefits of MNC hUCB cells, we approached a less invasive method of cell delivery. In another study (Garbuzova-Davis S, Klasko SK, Sanberg PR. Intravenous administration of human umbilical cord blood cells in an animal model of MPS III B. Comp Neurol, 515(1): 93-101, 2009), a single dose of MNC hUCB cells was administered into the veins of Sanfilippo mice at early or late stage disease. Results showed behavioral improvements in enzyme-deficient mice, survival and wide distribution of administered cells within and outside the central nervous system. Also, heparan sulfate accumulation was reduced in the liver and spleen of mutant mice, 6 months after receiving hUCB cells. Additionally, an anti-inflammatory effect by MNC hUCB cell transplantation was determined.

However, most observed behavioral benefits in Sanfilippo mice were limited to a short period after transplantation, possibly due to declining production of the missing enzyme. This scarcity and the progressive nature of MPS III B disease suggested that repeated injections of lower cell doses might prove more effective than a single dose. To address this possibility, we investigated the effect of repeated MNC hUCB cell infusions. In this study (Willing A E, Garbuzova-Davis S N, Zayko O, Derasari HM, Rawls AE, James CR, Kuzmin-Nichols N, Sanberg CD, Sanberg PR. Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B. Cell Transplantation, under review), we tested whether repeated low doses of MNC hUCB cells would be more beneficial than a single dose of cells. The MNC hUCB cells were intravenously administered into Naglu mice monthly for 6 months. Behavioral (spontaneous locomotor activity and cognition) and various neuropathological tests were performed in these mice and results were compared to Naglu mice receiving a single: low cell dose, high cell dose, or media injection. Briefly, our study results showed that repeated cell doses reduced stereotyped behaviors and restored normal anxiety-like behavior in these mice. The repeated cell administrations also restored hippocampal cytoarchitecture, decreased GM3 ganglioside accumulation and decreased microglial activation, particularly in the hippocampus and cortex. It is our conclusion that the neuroprotective effect of MNC hUCB can be enhanced by repeated cell administrations and is likely associated with continuous delivery of the missing enzyme.

Thus, repeated MNC hUCB cell injections are likely to provide long-term benefit by affording sustained Naglu enzyme replacement in MPS III B as well as long-term trophic support against the progressive neuronal degeneration. In addition, the multiple smaller doses better translate to clinical settings. These studies therefore provide the groundwork for more comprehensive investigations to optimize the frequency and size of multiple injections in relation to safety and clinical applicability.

We are grateful for the support of our studies by The Children’s Medical Research Foundation, Inc. We especially want to thank Susan M. and R. Bradford Wilson for their marvelous support.