Institution: University of Florida
Primary Investigator: Coy Heldermon, MD, PhD
Duration: 5.75 years
Start Date: March 2017
Type of Sanfilippo studied: Types B
Cure Sanfilippo Foundation is co-funding this gene therapy-approach project with Sanfilippo Children’s Foundation (Australia).
Current therapy for Sanfilippo Syndrome (MPS III) is aimed at restoring functional enzyme or reducing heparan sulfate storage, but does not address restoration of the damage done prior to therapy. Regeneration of damaged central nervous system and prevention or reversal of immune activation by neural stem cells (NSC) and mesenchymal stem cells (MSC) may be necessary in the treatment of MPSIIIB.
This study will evaluate the effect of transplanting NSC and MSC on immune system modulation and regenerative repair. Using lentiviralvector gene-modified stem cells to over express N-acetylglucosaminidase (NAGLU), the study will evaluate the response and therapeutic benefit of each cell type on MPSIIIB mice and controls.
This strategy uses a cell-based, gene-therapy approach to address two priority areas:
- Halt disease progression (Enzyme replacement, gene therapy, cell therapy to stop progression) and
- Repair Damage (Repair and reverse cell damage).
Project Update: July 2023
Dr. Heldermon reported the following regarding the project:
1. We have determined that human adipose derived mesenchymal stem cells have a limited delivery dose due to cell adhesion of ~50,000-60,000 cells and have very limited detectable lifespan after delivery to the central nervous system of mice with-out immune suppression. After neonatal MSC injections at either intraparenchymal, ventricular or cisternal injection sites, no MSCs were detectable at 5 weeks. Time-course experiments showed that this depletion/elimination was also true in both normal and MPS IIIB mice brains 12 days, 8 days and 4 days after injection.
Our assessment is that applicability of MSC approaches will be limited due to low cell numbers deliverable. Poor persistence will also limit applications unless potentially accompanied by immune suppression of as yet undetermined duration.
2. Mouse NSCs were administered at either intraparenchymal, ventricular, or cisternal injection sites in normal and MPS IIIB mice as well, both at a lower 50,000 cell dose and higher 1,000,000 cell dose. Initial dose studies were analyzed using cryosectioning and revealed limited numbers of cells and mainly seemed to be near injection sites. Subsequent studies have been switched to analysis using iDISCO, a half brain clarification and immunohistochemistry method. The iDISCO studies better demonstrate the distribution of NSCs in the brain is least efficacious by cisternal delivery. The parenchymal injection method gives the broadest distribution of NSCs but the ventricular method yields the highest amount fluorescent staining, mostly in brain regions adjacent to the lateral ventricles and draining ventricles. Both parenchymal and lateral ventricle injections result in distribution to the cerebellum.
Our conclusions from the studies thus far are that parenchymal injections will best provide cortical distribution and ventricle injections will best provide medullary distribution. A combination of these methods will likely be best to provide widespread distribution of NSCs and provide the best opportunity to correct disease pathology.
Dr. Heldermon (right) with members of his research team.