CSF dynamics in mucopolysaccharidosis type I

Awardee: Igor Nestrasil

Institution: University of Minnesota

Grant Amount: $60,655.00

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

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Summary:

This project aims to measure the motion of the cerebrospinal fluid (CSF) through the brain with magnetic resonance imaging (MRI) and associate these measures with disease severity in mucopolysaccharidosis type I (MPS I). The findings may determine whether CSF motion is impaired in MPS I with implications for the disease severity or the drug distribution administered to the intrathecal space (space surrounding the spinal cord) or subarachnoid space (space around the brain).

Preclinical study of Fluoxetine efficacy in MPS-I mouse model

Awardee: NICOLINA CRISTINA SORRENTINO

Institution: FONDAZIONE TELETHON ETS-TIGEM

Grant Amount: $60,000.00

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

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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.

CNS disease severity assessment with quantitative neuroimaging

Awardee: Igor Nestrasil

Institution: University of Minnesota

Grant Amount: $64,645

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

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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.

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

Awardee: Alessandro Fraldi

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

Award Amount: $65,040

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

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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.

Attention-deficit and hyperactivity links to the brain connectivity of MPS I subjects: multimodal MRI study

Awardee: Igor Nestrasil

Institution: University of Minnesota

Award Amount: $61,589

Biomarker correlates of neurocognitive outcomes in the cerebrospinal fluid in MPS I

Awardee: Julie Eisengart

Institution: University of Minnesota

Award Amount: $103,560

Funding Period: February 1, 2019 - January 31, 2020