Cure Sanfilippo Co-Funds Research Into Treating Behavioral Symptoms of MPS III

Cure Sanfilippo Foundation has again collaborated with Sanfilippo Children’s Foundation of Australia to fund a new research project by TIGEM, investigating new therapeutic strategies for the treatment of the behavioral symptoms of Sanfilippo Syndrome (MPS III).

TIGEM (Telethon Institute of Genetics and Medicine) is an international research institute dedicated to the discovery of the mechanisms underlying rare genetic diseases and the development of innovative therapies.

Cure Sanfilippo Funds CRISPR Gene Editing of Neural Stem Cells

Team conducting CRISPIR gene editing for Sanfilippo Syndrome, MPSIIICure Sanfilippo Foundation is excited to grant funding to LA BioMed for the advancement of Dr. Michelina Iacovino’s work in the field of regenerative medicine for the treatment of Sanfilippo Syndrome (MPS III). This innovative work will utilize CRISPR gene editing to transform patients’ own iPSC derived neural stem cells to supply critical enzyme and regenerative factors to the brain.

Dr. Iacovino’s, Assistant Professor of Pediatrics at LA Biomed/Harbor UCLA, research career has focused on the use of stem cells in multiple disorders, MPS diseases, and blood coagulation. Her ongoing work in parallel to this research grant will further develop the iPSC approach to MPSIIIB in her lab. Dr. Iacovino commented: “We believe that this project will provide initial data essential for the development of a Neural Stem Cell therapy to treat Sanfilippo syndromes”.

The application of NSCs in neurodegenerative disorders such as Sanfilippo syndrome is particularly exciting because they could address both the underlying enzyme deficiency of Sanfilippo syndrome while also secreting special substances that help support and promote healthy brain tissue. This fascinating process transforms patients’ own skin cells back into the most basic stem cells in the human body. These newly formed primitive stem cells are then directed in the lab to become stem cells specialized to the brain (neural stem cells). Neural stem cells (NSCs) are the cells that give rise to neurons and supporting cells(glia) of the central nervous system. NSCs also supply the brain with factors
like brain derived neurotrophic factor to keep it healthy. CRISPR gene modification of the NSCs will then allow the cells to produce enough MPSIIIA enzyme to supply what is missing in the brain.

“Using a patient’s own cells and modifying them as needed, drastically reduces concerns about the body having a reaction to the cells, therefore allowing the regenerative cells to remain in the brain and provide benefit indefinitely. This would be an incredible achievement and benefit to the children suffering from MPSIII.”, says Dr. Cara O’Neill, Chief Scientific Officer at Cure Sanfilippo Foundation.

Link to Michelina Iacovino PhD: https://labiomed.org/michelina-iacovino-phd

Link to article on MPSIIIB iPSCs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076361/

Cure Sanfilippo Foundation Funds New Stem Cell Research

Cure Sanfilippo Foundation is pleased to support the work of Dr. Jan Nolta’s lab in collaboration with biotech partner Neuralstem. This project aims to develop an off-the-shelf neural stem cell therapy for patients with Sanfilippo Syndrome (MPS IIIA).

As the Director of the UC Davis Stem Cell Program and Institute for Regenerative Cures, Dr. Nolta brings a wealth of experience and expertise to this project. Prior research conducted by her team has focused on the use of stem cell therapies for Huntington’s Disease, 20+ years of work on lysosomal storage diseases, and involvement in prior clinical trials.

University of California, Davis, conducting research on Sanfilippo Syndrome, MPS III

Dr. Nolta commented, “We are very grateful to the Cure Sanfilippo Foundation and excited to work with Neuralstem to develop a gene-modified neural stem cell therapy for MPSIIIA. The data for retention of the Neuralstem product is compelling and gives us hope that an impact could potentially be made on this heartbreaking disease.”

Neuralstem is a clinical stage biopharmaceutical company developing treatment for neurologic diseases via small molecule and stem cell therapies. Our joint collaboration will enable the gene modification of Neuralstem’s proprietary neural stem cell line and testing of these cells in the immunodeficient MPSIIIA mouse model which was created in the Nolta lab as a part of Cure Sanfilippo Foundation’s previous support.

Neural stem cells (NSCs) are the cells that give rise to neurons and supporting cells(glia) of the central nervous system. The application of NSCs in neurodegenerative disorders such as Sanfilippo syndrome is particularly exciting. Gene modified (to express large amounts of the
deficient enzyme) neural stem cells could address the primary disease mechanism. However, NSCs are special in that they also offer the possibility to restore and support healthy brain tissue in patients.

“The opportunity to address multiple critical needs in this disease with one therapy would be an amazing thing for the children. Since we do not yet have newborn screening or an approved therapy for Sanfilippo syndrome, 99% of those diagnosed are already symptomatic and
experience ongoing brain damage. The ability to positively impact disease progression even after a child is symptomatic is of key importance to families today,” says Dr. Cara O’Neill, Chief
Scientific Officer at Cure Sanfilippo Foundation.

# # #

Cure Sanfilippo Foundation is a 501(c)(3) not-for-profit organization dedicated to advocating for and funding research directed towards a cure and treatment options for patients with Sanfilippo Syndrome. Sanfilippo Syndrome, also called MPS III, is an inherited disease of
metabolism that means the body cannot properly break down long chains of sugar molecules called mucopolysaccharides or glycosaminoglycans (i.e., GAGs). A genetic defect passed on
from each parent results in missing or poorly functioning enzymes needed for cells to work normally. Without these enzymes, cells are unable to break down and recycle cellular waste.

Over time, this waste builds up causing cells to act abnormally and then to die. Children with this genetic disease face a progressively debilitating and rapid decline in physical and intellectual abilities, leading to an early death.

For more information on the Cure Sanfilippo Foundation and Sanfilippo Syndrome, please visit www.CureSFF.org. Contact Cure Sanfilippo Foundation at curesff@gmail.com.

Cure Sanfilippo Announces Support for Autophagy Research

Penn State University research team investigating Sanfilippo Syndrome, MPSIIICure Sanfilippo Foundation is pleased to award funding support to Dr. Scott Selleck and the Pennsylvania State University (Penn State) to study the cellular process of autophagy as a central mechanism in MPS (mucopolysaccharidosis) disease progression in the central nervous system.

Dr. Selleck’s prior research specialized in neurodevelopment, proteoglycan genetics and biochemistry. His neurodevelopment work has investigated the genetic basis of autism spectrum disorder and gene-environment interactions. Preliminary work with the Multiple Sulfatase Deficiency (MSD) fruit fly model has shown autophagy suppression, prompting Dr. Selleck to translate that finding to the mouse model in another MPS disorder.

Autophagy is a process by which cells engulf and dispose of misfolded proteins and damaged mitochondria that occur during normal metabolism and even more so in disease states. Research has shown that in Sanfilippo syndrome, as well as many other neurodegenerative diseases, there is an impairment in the body’s ability to carry out the autophagy process. This causes other parts of the cell to function poorly and eventually leads to cell death.

“Our focus is to provide both the scientific underpinnings and means of rescuing neuronal loss in children with MPS disorders. We hope these findings and methods will also translate to other neurodegenerative diseases.” Scott Selleck, MD, PhD.

This project will specifically look at the effects of activating autophagy in the brains of MPSIIIA mice, either directly, or by inhibiting Tor, a master regulator and suppressor of autophagy. Since mTOR is a universal pathway that is not disease specific, findings here would be translatable across MPS conditions and neurodegenerative disorders. This pathway will be studied both through genetic modification and the use of an FDA approved class of drugs known to block mTOR activity. This drug is currently used to treat children with tuberous sclerosis complex and has been shown to reduce seizure frequency and severity.

“Dr. Selleck’s work will provide further insight into a possible way to impact the neurodegenerative process in Sanfilippo syndrome, beyond replacing the primary enzyme deficiency. Developing complementary strategies, such as this, to improve the life of children with this devastating disease is a critical need,” said Dr. Cara O’Neill, Scientific Director at Cure Sanfilippo Foundation.

# # #

Cure Sanfilippo Foundation is a 501(c)(3) not-for-profit organization dedicated to advocating for and funding research directed towards a cure and treatment options for patients with Sanfilippo Syndrome. Sanfilippo Syndrome, also called MPS III, is an inherited disease of metabolism that means the body cannot properly break down long chains of sugar molecules called mucopolysaccharides or glycosaminoglycans (i.e., GAGs). A genetic defect passed on from each parent results in missing or poorly functioning enzymes needed for cells to work normally. Without these enzymes, cells are unable to break down and recycle cellular waste. Over time, this waste builds up causing cells to act abnormally and then to die. Children with this genetic disease face a progressively debilitating and rapid decline in physical and intellectual abilities, leading to an early death.

For more information on the Cure Sanfilippo Foundation and Sanfilippo Syndrome, please visit www.CureSFF.org. Contact Cure Sanfilippo Foundation at curesff@gmail.com.

New Therapeutic Approach to Treat Central Nervous System in Sanfilippo

Target Amyloid Aggregation as a New Therapeutic Approach to Treat the Central Nervous System in Sanfilippo Syndrome
Cure Sanfilippo Foundation has awarded funds to the Telethon Institute of Genetics and Medicine (TIGEM) in Italy to study the effect of a new drug compound on the buildup of toxic proteins in the brains of those affected by Sanfilippo Syndrome.

TIGEM research team investigating Sanfilippo Syndrome, MPSIII

Project lead Alessandro Fraldi specializes in the study of neurodegeneration in lysosomal storage diseases (LSDs) and novel treatment approaches. Under his lead, the Fraldi team aims to build upon their preliminary data supporting the effects of a novel drug compound in reducing the effects of harmful accumulated proteins in the brain of Sanfilippo animals. The drug functions by a different mechanism of action than previously tried in other neurodegenerative diseases characterized by protein aggregation.

“We are pleased to support this new approach to addressing a key feature of neurodegeneration.  The many biochemical similarities among neurodegenerative conditions like Alzheimer’s Disease, Parkinson’s Disease and Sanfilippo Syndrome are striking. Research aimed at these common features offers the opportunity to find ways to improve the lives of loved ones with these devastating conditions”, said Dr. Cara O’Neill, Scientific Director of Cure Sanfilippo Foundation.

Initial proof of concept work has been conducted using the MPSIIIA mouse model. Inclusions of aggregated proteins was shown to be a general feature of MPSIIIA brain disease in which such aggregation progressively builds up as neurodegeneration is seen.  Preliminary data indicates that the drug is able to clear protein aggregation, thus reducing inflammation and oxidative stress.

In this project, a large efficacy study will be performed testing the drug’s effects on toxic protein clearance, inflammation, nerve signaling, and behavior in MPSIIIA mice. Dr. Fraldi has also assembled a team of collaborators to further evaluate these findings in the other subtypes of Sanfilippo syndrome (MPSIIIB-D).

Start Date: April 2018

Creating a Zebrafish Model of Sanfilippo Syndrome Type A

Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation (Australia) are delighted to announce we have collaborated again. This joint grant funding is to the Australian Regenerative Institute at Monash University in Melbourne to create a zebrafish model of Sanfilippo. The project, led by zebrafish disease modelling expert Dr. Jan Kaslin and team, aims to produce a new tool to be used in the fight against Sanfilippo!

Dr. Cara O’Neill, Scientific Director of Cure Sanfilippo Foundation said: “We’re pleased to support Dr. Kaslin’s work which will create a new experimental model for the study of Sanfilippo. Unique aspects of the zebrafish model offer the potential to accelerate the rate of drug discovery for children who are in dire need.”

“We’re excited to be funding this project that could open up new avenues for Sanfilippo research around the world, providing a new tool for understanding this devastating condition and developing much-needed new therapies,” said Megan Donnell, Executive Director of the Sanfilippo Children’s Foundation.

Zebrafish are a useful research tool because they allow quick and precise understanding of the mechanisms of disease and can be used in the search for drugs. Zebrafish have already been used to help unlock a number of biological processes behind diseases such as muscular dystrophy. Zebrafish are transparent so the cellular processes inside their bodies can be watched in real-time under a microscope.

Start Date: February 2018

New Therapy for Six Mucopolysaccharidoses

Cure Sanfilippo Foundation is co-funding this project in Collaboration with Sanfilippo Children’s Foundation (Australia).

Project Summary: Substrate reduction therapy by targeting the N-deacetylase/N-sulfotransferase (NDST) isozymes, NDST1, represents a promising approach to developing a therapy for multiple MPS disorders including MPS I, MPS II, MPS IIIA, MPS IIIC, MPS IIID, MPS IIIE.  One of the advantages of such small molecule therapy is the likely ability of the molecules to pass through the blood-brain barrier and thus treating the disease in the brain. It provides a potential strategy to enhance effectiveness of emerging therapies, i.e. enzyme replacement and gene delivery approaches, and it offers treatments for almost all disease sub-types. 

This study aims to decrease the synthesis of glycosoaminoglycans (GAGs) by targeting NDST1, a key enzyme in the pathway leading to modifications of heparan sulfate.  This project will screen a library of 6,000 compounds to identify drugs that reduce NDST1 activity by two independent approaches; via repression of NDST1 gene expression or via direct inhibition of NDST1 enzyme activity

Repurposing of approved drugs will be prioritized in this research for faster transition of drug candidates into clinical studies. The hospital’s CRISPR approach enables testing drug effects on the full regulatory circuity of the endogenous target gene and is expected to identify compounds that act via a wider range of pathways and thereby extending this therapeutic modality to larger set of patients independent of their age. Drugs showing signs of efficacy will be designated as lead substrate reduction compounds for further in vivo animal studies.

Start Date: March 2017

Cure Sanfilippo Foundation

501c3 non-profit
(Tax ID: 46-4322131)

curesff@gmail.com

P.O. Box 6901
Columbia, SC 29260

N