Neural And Mesenchymal Stem Cell-Mediated Gene Therapy for Sanfilippo Syndrome Type 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).
Start Date:  March 2017

Research Strategy for Pre-Existing AAV Antibodies

Cure Sanfilippo Foundation has awarded a grant to Haiyan Fu, PhD, at Nationwide Children’s Hospital in Columbus, OH, to research strategies for overcoming a patient’s pre-existing AAV (Adeno-Associated Virus) antibodies so gene therapy using AAV is accessible to them. 

Project Summary: As the field moves forward with AAV9-gene therapy approaches for clinical applications, a critical challenge is the presence of pre-existing antibodies  against AAV9.  Many AAV serotypes infect humans, including AAV9.  As a result of infection, pre-existing antibodies to AAV are common in humans.

In the setting of gene therapy, individuals with pre-existing AAV9 antibodies would not be eligible for treatment using AAV9 vectors due to diminished efficacy.

There are currently no effective approaches available which deplete pre-existing antibodies enough to allow for effective gene transfer in antibody positive patients.

Small-scale preliminary experiments in Dr Fu’s lab have shown the potential of appropriate immuno-supporessive regimens in overcoming the pre-existing Abs.

The goal of this study is to identify immuno-suppressive regimens that can effectively overcome pre-existing AAV Abs, in order to be able to treat all individuals who have the target diseases, as well as those who have received AAV9 gene therapy treatment and may need vector re-administration later.

Start Date:  March 2017

Re-Purposing of FDA-Approved Drugs for LSD

Re-Purposing of FDA-Approved Drugs for the Treatment of LYSOSOMAL STORAGE DISEASES (LSD)

Project is funded by Cure Sanfilippo Foundation

Project Summary: The study aims to identify FDA-approved compounds that activate the clearance of pathologic lysosomal accumulation in MSD cellular models independently of the missing enzyme in each particular disease.

Relevant cell-based, high-content (HC) screening assays have been developed, targeting common features of most MPS diseases, such as expansion and aggregation of lysosomal compartment and lysosomal degradation impairment.

These assays will be used to screen a FDA collection of 1,280 compounds that are marketed drugs. Thus, the hits derived from the HCS, once validated in secondary assays, could in principle be immediately tested in patients to allow repositioning of known drugs as correctors of MPS.

Repositioning of FDA-approved drugs may reduce the clinical translation time of the findings.

Dates: March 2017 – March 2018

UPDATE: October 2019

In October 2019, TIGEM presented preliminary results of this study at the Conference of Telethon Fundamental Associations in Italy. Read more

Synaptic Dysfunction in Sanfilippo Type C

Cure Sanfilippo Foundation has awarded a grant to Alexey Pshezhetsky, PhD, of St. Justine University Hospital (Montreal, CA) to explore the synaptic dysfunctions in Sanfilippo Syndrome Type C.

Project Summary: The study’s major objective is to understand the pathophysiological mechanism underlying cognitive decline and behavioral abnormalities in the genetic metabolic disease Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) and to develop new strategies for its therapy.

The hypothesis is that early decline in CNS functions in MPS III is caused not by neuronal death, but rather by breakdown in neurotransmission due to synaptic defects.

Confirmation of this hypothesis, which will be tested by studying synaptic function in gene-targeted mouse model of MPS IIIC, would mean that MPS III patients could benefit from therapeutic approaches based on restoration of the synaptic function to a point sufficient to reverse disease symptoms.

Date: January to December 2016

Testing Compounds on MPS III Fibroblasts

Cure Sanfilippo Foundation has awarded a grant to Alexey Pshezhetsky, PhD, of St. Justine University Hospital (Montreal, CA) to conduct compound testing on MPS III fibroblasts.

Project Summary: Results of two previously-published studies in which MPS IIIA fibroblasts were treated with calcium channel blockers showed partial rescue of enzyme activity.

This study further evaluates the suitability of this drug class as chaperones in MPS III. It will investigate the action of L-type Ca2+ channel blocker and potential chaperone, diltiazem, on the residual level of the enzyme activity in skin fibroblasts from the MPSIIIA, MPSIIIC, and MPSIIID patients affected with missense mutations.

Also investigated was the possibility that diltiazem could be synergistic with the known MPSIIIC chaperone, glucosamine, the two substances were co-administered to cells.

Start Date: May 2015

Update February 2017: Study did not indicate rescue of enzyme activity in the presence of diltiazem or diltiazem/glucosamine combination in MPSIIIA cells. MPSIIIC cells did not show increased enzyme activity with diltiazem but did have an increase in activity with glucosamine.

Intranasal Delivery of Sulfamidase for Sanfilippo

Cure Sanfilippo Foundation is funding research by Jeff Esko, PhD, Co-Director Glycobiology Research & Training Center of University of California San Diego School of Medicine, to explore intranasal delivery of sulfamidase as a therapy for Sanfilippo Syndrome.

Project Summary: This study focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA. In this method, the missing enzyme is produced in cells, purified and then attached to a small chemical entity that acts as a carrier. Previous work has shown that cells derived from MPS IIIA patients take up conjugated enzyme and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans (GAGs) in a mouse model of MPS IIIA (Sgsh-/- ). Unexpectedly, intranasal administration of modified enzyme demonstrated high levels of delivery to the brain and reduction of pathological GAGs in a short-term experiment.

The purpose of this study is to optimize the transfer of enzyme into the central nervous system in the MPS IIIA mouse. The results will provide the pre-clinical information needed to proceed towards a novel treatment of the disease in humans.

Dates: October 2015 – September 2016

Update – April 2017: An improved enzyme assay has been created to more reliably evaluate the activity levels in organs, earliest safe age of administration in animal model has been established, long term dosing study is underway. Manuscript has been submitted for publication on GNeo carrier conjugation with enzyme (MPSI and early MPSIIIA work).

Mesenchymal Stem Cells to Produce Sulfamidase for Intrathecal Delivery

Cure Sanfilippo Foundation awarded Jan Nolta, PhD, Director of UC Davis Stem Cell Program, University of California Davis, Institute for Regenerative Cures to engineer mesenchymal stem Cells (MSCs) to produce sulfamidase for intrathecal treatment of Sanfilippo Syndrome (MPS III).

Project Summary: This study aims to evaluate the use of non-embryonic mesenchymal stem cells (MSCs) for delivery of sulfamidase, the deficient enzyme in MPSIIIA, into the spinal fluid compartment.

MSCs will be gene modified to overexpress a normal copy of the SGSH gene (the MPSIIIA gene) and compared to unmodified MSCs.

In order to administer human MSCs to the mouse model, an immunodeficient strain of the MPSIIIA mouse model will be created.

Once complete, this new mouse model will be available for the scientific community at large.

The approach to use human MSCs to deliver enzyme, offers the possibility to deliver enzyme in a steady and physiologic fashion in the brain.

In addition, MSC-based delivery could avoid issues of pre-existing neutralizing antibodies that are inherent in AAV based gene therapies.

Due to the relative immune privilege of MSCs, they could be re-dosed with less concern of antibody development.

MSCs also inherently secrete neuroprotective and neurotrophic factors which could be beneficial in this neurodegenerative disease.

Update April 2017: MSCs have been gene-modified. Characterization of their enzyme expression is underway. An immunodeficient MPSIIIA mouse model is being cross bred and expanded for adequate study numbers after which animal dosing will begin.

Start Date: December 2015

Support for AAV9 Gene Therapy for MPS IIIA and MPS IIIB

Cure Sanfilippo Foundation made a grant to Nationwide Children’s Hospital (Columbus, OH) to conduct gene therapy to treat Sanfilippo Type A (MPS IIIA) and Type B (MPS IIIB).

Project Summary: Funding support of staff to enable necessary clinical trial preparatory steps to move forward. The positions are 1) Genetics Clinical Research Fellow (1 year), and 2) Program Manager (2 years).

The duties of these positions include, but not limited to: analysis of the data from the natural history study; drafting of manuscripts related to it; participation in aspects of preparing for gene transfer trials; and analysis and presentation of the data derived from them, participation in the development and filing of regulatory documents, development of standard operating procedures and source documents, management of interactions with contracted services (such as the hospital’s clinical research services and outside monitoring contract researchers organizations), and interactions with the Institutional Review Board, FDA submission of IND and other needed paperwork, additional program coordination, finalizing publication of natural history study data.

Dates: June 2015 – May 2017

March 2017: MPSIIIA gene therapy clinical trial is underway. Safety has been established in the low dose cohort (3 patients) to date.  Data presented at the World Symposium in February 2017 noted a 67% decrease in spinal fluid heparan sulfate (the toxic storage material) levels, lowered urine heparan sulfate levels and continued reduced liver and spleen sizes. High dose cohort patient dosing is proceeding. The IND has been approved for commencement of MPSIIIB gene therapy trial.

Intravenous AAV9 Gene Therapy for MPS IIIA and MPS IIIB

Cure Sanfilippo Foundation awarded a grant to Abeona Therapeutics, a privately-traded company that is managing license & toxicology/drug production for the AAV9 gene therapy clinical trial at Nationwide Children’s Hospital. 

Project Summary: Support of formal GMP toxicology study in preparation for human clinical trial; Support for Gene therapy Drug Production to be used in human clinical trial.

Start date: October 2014

March 2017: MPSIIIA trial was initiated in May 2016. IND has been approved for commencement of MPSIIIB gene therapy trial.

Cure Sanfilippo Foundation

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(Tax ID: 46-4322131)

P.O. Box 6901
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