Neural And Mesenchymal Stem Cell-Mediated Gene Therapy for Sanfilippo Syndrome Type B

March 30, 2017

Grant Summary

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).

Project Summary

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 Updates

February 2024

Dr. Heldermon and his team used human-derived mesenchymal stem cells and mouse-derived neural stem cells that could be tracked via a fluorescent label. To determine the best type of stem cells and delivery method, they injected the stem cells into the brain via three different injection sites. Their results indicate that the body’s immune system cleared away the mesenchymal stem cells, which did not last as long in the brain compared to the neural stem cells.

The team tested different administration routes of the neural stem cells and found that a combined approach, with injections in parts of the brain and in its fluid-filled spaces, may be most effective in delivering this type of stem cell therapy.

The project overcame delays due to COVID-19, mouse breeding issues, supply chain delays, and
delays in repairing key equipment for the project. The team presented their results in posters at the
2022 and 2023 WORLDSymposium, the major global conference focusing on lysosomal storage

Heldermon and team plan to continue work on stem cells for Sanfilippo towards getting data to
ultimately start a clinical trial for patients.

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.

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