University of South Florida researchers led the preclinical study exploring a cell therapy for Sanfilippo syndrome
TAMPA, Fla. (April 1, 2014) – A University of South Florida-led study provides new insight into treating an inherited metabolic disorder that causes serious neurological and behavioral disabilities in children, usually leading to death in the teen years.
The preclinical study explored the effects of human umbilical cord mononuclear cells (hUCB MNCS) injected to counter the symptoms and progression of Sanfilippo syndrome type III B (MPS III B). Researchers found that repeated injections into laboratory mice modeled with the disorder showed clear benefits for the mice receiving multiple injections, compared to mice receiving either a single high or low dose.
The study will be published in a future issue of Cell Transplantation but is currently freely available on-line as an unedited early e-pub at: http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-ct1121willing.
MPS III B results from a genetic deficit of the Naglu enzyme. This missing enzyme creates a build-up of the complex carbohydrate heparan sulfate, which accumulates in lysosomes, cells responsible for waste disposal. With MPS III B, accumulations of heparan sulfate inside cells cause damage to multiple organs, including the brain.
“Cell therapy has recently received attention as a potential treatment for lysosomal storage diseases,” said study lead author Alison E. Willing, PhD, a professor in the Department of Neurosurgery and Brain Repair, USF Health Morsani College of Medicine. “We have previously shown that a single hUBC injection into the cerebral ventricle of pre-symptomatic MPS III B mice, or intravenous cell delivery at different disease stages, was beneficial to the enzyme-deficient mice. In the current study, we examined whether administering repeated doses of hUBC MNCs would have a greater effect than a single dose and help to prevent progressive neurodegeneration.”
Using three groups of mice modeled with Naglu deficiency by knocking out the Naglu enzyme, the researchers injected one group with repeated doses of hUBC MNC over a six-month period. They administered single doses—either high or low doses—to the other two groups of mice. The group receiving repeated hUBC MNC doses demonstrated a variety of improvements.
The researchers measured several behavioral and clinical outcomes before and after six months of treatment. Outcome data included anxiety levels, heparan sulfate accumulation, and subsequent pathology in different anatomical brain locations.
“Repeated injections of hUBC MNCs produced the greatest neuroprotection,” said Svitlana Garbuzova-Davis, PhD, associate professor in the USF Department of Neurosurgery and Brain Repair, a co-principal investigator for this study. “Hippocampal structural architecture remained intact in the repeated cell dose-treated mice as compared to the other groups. Also, there was restoration of the dendritic tree in the group receiving repeated cell doses. We also saw a striking reduction in microgliosis and microglial activation after hUBC MNC treatment.”
The researchers speculated that administering hUBC MNCs may not only deliver missing enzyme but also decrease neuropathy through modulation of inflammatory and immune processes as the hUBC MNCs produced numerous neurotrophic and growth factors.
“We demonstrated that hUBC MNCs were particularly effective at modulating anxiety in the Naglu knockout mice,” concluded Willing.
“Our results suggest that repeated administrations of hUBC MNCs produce greater amelioration of the underlying disease pathology,” said senior author Paul R. Sanberg, distinguished professor at USF and principal investigator of the Children’s Medical Research Foundation funded project. “However, further studies will be needed to determine if this treatment regimen can slow the progression of the disease, increase survival while minimizing symptoms, and determine whether improved outcomes are a function of enzyme administration, decreased inflammation, or both.”
This study was supported in part by the Children’s Medical Research Foundation, the International Organization of Glutaric Acidemia and Saneron CCEL Therapeutics, Inc.
Repeated Administrations of Human Umbilical Cord Blood Cells Improve Disease Outcomes in a Mouse Model of Sanfilippo Syndrome Type III B. Willing AE, Garbuzova-Davis SN, Zayko O, Derasari HM, Rawls AE, James CR, Mervis RF, Sanberg CD, Kuzmin-Nichols N, Sanberg PR. Cell Transplant. 2013 Dec 30. PMID: 24380668
Disclosure: AEW and SGD are consultants to, and PRS is founder of Saneron CCEL Therapeutics, Inc.
News release by Florida Science Communications www.sciencescribe.net