Awarded Grants

Awarded Grants

MDBR, MPS Million Dollar Bike Ride MDBR, MPS Million Dollar Bike Ride

Antisense Oligonucleotide as Substrate Reduction Therapy for Mucopolysaccharidoses type III

Manor Yehoshua

Sheba Medical Center

$57,645.00

Awardee: Manor Yehoshua

Institution: Sheba Medical Center

Grant Amount: $57,645.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

Our project aimed at finding a much-needed treatment for MPS type III, a condition that currently has limited treatment options. Leveraging the advanced capabilities of RNA-based therapy, specifically Antisense Oligonucleotides (ASOs), we are crafting a method to reduce the buildup of the harmful substance of heparan sulfate in the body and brain that is the hallmark of this illness. This technology has not only proven to be more effective but also more cost-efficient compared to other existing therapies. Moreover, it has demonstrated successful outcomes in both laboratory settings and preliminary human trials. By building on this innovative approach, we aspire to create a treatment that can significantly alleviate the CNS symptoms of all types of MPS III patients, potentially revolutionizing the management of this condition and offering hope for improved quality of life to those affected.

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IV Delivery of Ex Vivo Lentiviral Corrected CD34+ Bone Marrow Cells to Treat Systemic Disease in a Canine Model of Mucopolysaccharidosis VI

Margret L. Casal

University of Pennsylvania

$60,350.00

Awardee: Margret L. Casal

Institution: University of Pennsylvania

Grant Amount: $60,350.00

Funding Period: February 1, 2023 - January 31, 2024

Summary:

MPS VI causes severe skeletal disease and moderate systemic disease. Our canine model faithfully mimics the disorder in human patients with MPS VI. This projects examines the feasibility of harvesting stem cells from dogs affected with MPS VI, correcting the cells in tissue culture using viral vectors, and then returning the gene therapy corrected cells back to the affected neonatal dog. These experiments will show that this form of therapy is safe and effective, while not having the side effects of bone marrow transplantation (graft rejection, host versus graft disease, lifelong immunosuppression) or enzyme replacement therapy (repeated administration, expense, inability to correct bone disease).

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MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride

Preclinical study of Fluoxetine efficacy in MPS-I mouse model

NICOLINA CRISTINA SORRENTINO

FONDAZIONE TELETHON ETS-TIGEM

$60,000.00

Awardee: NICOLINA CRISTINA SORRENTINO

Institution: FONDAZIONE TELETHON ETS-TIGEM

Grant Amount: $60,000.00

Funding Period: February 1, 2023 - January 31, 2024

Summary:

Mucopolysaccharidosis type I (MPS-I) is a severe inherited disorder characterized by deficient activity of lysosomal enzyme α-L-Iduronidase (IDUA) responsible for the degradation of the glycosaminoglycans, leading to systemic symptoms and a shortened lifespan. Current therapies are mainly palliative with no benefit for the brain pathology. Several works indicated the importance of the lysosomal and autophagy alterations as major players in the development of brain and peripheral tissue pathology in Lysosomal Storage Disorders (LSD). Importantly, in our recent work we combined automated microscopy screening and repurposing of FDA compounds to identify approved drugs able to correct lysosomal dysfunction in LSD. Our drug survey resulted in the identification of Fluoxetine, a central nervous system drug and one of the most prescribed medicines in adults and children. Interestingly, we showed that Fluoxetine boosts lysosomal function and promotes glycosaminoglycans degradation in MPS-IIIA, MPS-I and MSD cell lines. Furthermore, our recent preclinical study demonstrated the effectiveness of Fluoxetine in the amelioration of brain and somatic pathological hallmarks of MPS-IIIA such as the accumulation of storage materials, inflammation, and slow-down cognitive deterioration in MPS-IIIA mouse model. Based on these promising results, we propose to validate the effectiveness of the Fluoxetine administration for the treatment of brain and peripheral pathology in a mouse model of MPS-I.

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MDBR, MPS Million Dollar Bike Ride MDBR, MPS Million Dollar Bike Ride

Understanding the role of inflammation in MPSIIIA disease to identify therapeutic approaches for older patients without treatment options

Brian Bigger

University of Manchester

$64,015

Awardee: Brian Bigger

Institution: University of Manchester

Grant Amount: $64,015

Funding Period: February 1, 2022 - January 31, 2023

Summary:

Many older patients with mucopolysaccharide diseases are ineligible for new treatment trials, and those with brain disease, such as type IIIA, have no current treatments available. To address this gap, we want to explore in the mouse model of MPSIIIA, the observed decline in cognition that follows repeated rounds of viral infection in patients and has been described in many dementias. Our aim is to first see if these effects can be recapitulated in the MPSIIIA mouse model, and later to develop novel immunotherapies to treat it. There are several drugs already available that may be re-purposable to this end, potentially offering rapid relief for MPS patients from behavioural and cognitive aspects of disease

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MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride

CNS disease severity assessment with quantitative neuroimaging

Igor Nestrasil

University of Minnesota

$64,645

Awardee: Igor Nestrasil

Institution: University of Minnesota

Grant Amount: $64,645

Funding Period: February 1, 2022 - January 31, 2023

Summary:

This project aims to find the underpinnings of brain magnetic resonance imaging (MRI) clinical/radiological severity in mucopolysaccharidosis type I (MPS I) and relate these findings to quantitative MRI outcomes. These links may ease the process of the central nervous system (CNS) disease severity assessment in the clinical setting.

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MDBR, MPS Million Dollar Bike Ride MDBR, MPS Million Dollar Bike Ride

Tissue inflammation in Mucopolysaccharidoses type II disease: molecular mechanism and therapy

Manoj Pandey

Cincinnati Children's Hospital Medical Center

$64,485

Awardee: Manoj Pandey

Institution: Cincinnati Children's Hospital Medical Center

Award Amount: $64,485

Funding Period: February 1, 2021 - January 31, 2022

Summary:

Due to iduronate 2-sulfatase enzyme deficiency, excess tissue accumulation of glycosaminoglycans (GAGs) lead to the chronic tissue inflammation in Mucopolysaccharidoses type II (MPSII) patients. The mechanisms underlying GAGs-mediated chronic tissue inflammation is remain elusive. Our preliminary data identified GAGs-induced complement activation as one of the main driver of immune inflammation that sparks tissue inflammation in MPSII. Proposed studies will now test if targeting complement activation directly in MPSII-mouse model and human cells could stop and/or slowdown the tissue inflammation. Additionally, complement activation at several steps and/or their signature cytokines could recognize as a novel biomarker for human MPSII.

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MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride MDBR, MPS Gene Spotlight, MPS Million Dollar Bike Ride

The “molecular tweezer” CLR01 as a new potent drug candidate to slow CNS pathology progression in MPS-I

Alessandro Fraldi

University of Naples "Federico", Dept of Translational Medicine

$65,040

Awardee: Alessandro Fraldi

Institution: University of Naples "Federico", Dept of Translational Medicine

Award Amount: $65,040

Funding Period: February 1, 2021 - January 31, 2022

Summary:

Progressive neurological deterioration characterizes both severe (Hurler) and intermediate (Hurler-Scheie) forms of MPS-I. Unfortunately, to date, there is no treatment for the CNS pathology in MPS-I patients.

Under different stress conditions, certain aggregation-prone proteins misfold and self-assemble into neurotoxic insoluble deposits called amyloids. Aggregation and deposition of amyloid proteins in the brain is a hallmark of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. By studying mouse models of Sanfilippo syndrome we have recently shown that deposition of amyloid proteins also occurs in the brain of these mice and is a key event contributing to the neurodegenerative processes. Furthermore, extending previous observations, we have shown that similarly to the Sanfilippo syndrome, amyloid deposition also occurs in the brain of other mouse models of MPS and, in particular, is associated to neurodegenerative processes in the brain of post-mortem patients with MPS-I.
To counteract these amyloid-mediated pathological processes, we made use of a potent and specific inhibitor of amyloid protein aggregation known as CLR01. CLR01 is a lead compound of the “molecular tweezers” class of small molecules that act by a unique mechanism to efficiently inhibit abnormal self-assembly of multiple amyloidogenic proteins. CLR01 has been shown to be effective in protecting against neurodegeneration in mouse models of Alzheimer’s and Parkinson’s diseases. Moreover, previous studies also have shown that CLR01 has a wide safety margin in mice and crosses the blood-brain barrier when administered systemically. We have shown that subcutaneous injection of CLR01 in the mouse model of MPS-IIIA, the most and severe form of Sanfilippo syndrome resulted in a striking reduction of amyloid protein deposition in the brain and correction of neuropathological phenotype, including cognitive function.

Here we want to extend the proof of efficacy of CLR01 beyond MPS-IIIA and test the hypothesis that inhibiting amyloid deposition by CLR01 is an effective therapeutic option to slow CNS manifestations in MPS-I forms with CNS involvement. Overall our results may open the possibility to develop effective CNS therapies for MPS-I based on parenteral administration of CLR01, a drug with a unique mechanism of action and with a high translational potential.

 

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Novel alpha-glucosaminidase for Sanfilippo C syndrome

Patricia Dickson

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

$59,449

Awardee: Patricia Dickson

Institution: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

Award Amount: $59,449

Funding Period: January 1, 2018 - December 31, 2018

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