Exploring the profile of Extracellular Vesicles (EVs) in Lesch-Nyhan Syndrome (LNS)

Awardee: Giulia Bernardini

Institution: Università degli Studi di Siena, Dipartimento di Biotecnologie, Chimica e Farmacia

Grant Amount: $57,332

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Understanding Lesch-Nyhan Syndrome Through Tiny Messengers Lesch-Nyhan Syndrome (LNS) is a very rare genetic disease that mainly affects boys. It causes severe neurological problems, including involuntary movements and self-injury, as well as high levels of uric acid in the blood, which can lead to kidney stones. The current treatment can only help to lower the uric acid levels, but these cannot cope up with neurological and behavioural problems. While we know a lot about the disease, many aspects of how it affects the brain remain a mystery. Our project focuses on tiny particles called extracellular vesicles (EVs). These are small packages released by cells that carry important messages in the form of proteins, fats, and genetic material. They help cells communicate with each other, and in brain diseases, they may play a role in how the disease develops. We aim to develop new ways to study EVs in the blood of people with LNS. By doing this, we hope to: -Understand how EVs contribute to the brain and body changes in LNS. -Identify specific markers in EVs that are unique to LNS, which could help us develop better treatments. -Lay the groundwork for creating therapies that use EVs to target the disease directly. This research could not only improve the understanding of LNS but also open the door to new treatments for this challenging and neglected disease.

Unravelling HGprt functioning in fore- and midbrain development using brain organoids

Awardee: Sharon Kolk

Institution: Radboud University, Donders Institute for Neuroscience

Grant Amount: $68,367.00

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

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Summary:

LND is an incapacitating disease characterized by a neurobehavioral phenotype, cognitive deficits and self-injurious behavior caused by HPRT1 gene mutation(s). LND is specifically associated with a reduction of dopamine in the brain. Recently, we reported that proliferation and migration patterns of developing midbrain dopamine (mDA) neurons are disrupted in absence of the gene, resulting in abnormal brain development in an LND animal model. To dissect the role of the causative gene in human fore- and midbrain development, we intend to investigate human-specific brain organoids using patient-derived induced pluripotent stem cell (iPSC) lines carrying HGPRT loss-of-function (LOF) mutations, age-matched control lines as well as edited control lines carrying HGPRT mutations. In addition, assembloids -fusions of dorsal forebrain organoids and midbrain organoids- will be generated in various combinations of control versus LOF tissue at multiple time points. It is furthermore shown that folic acid plays a role in purine metabolism and that physiological levels lead to metabolite accumulation in LND patients. Therefore, we will add various concentrations to the culture medium of both the fore-as well as the midbrain organoids at multiple developmental timepoints. Eventually this will give us insight into the developmental time window where we can, either genetically or pharmacologically, intervene in the future to alleviate particularly the behavioral and/or cognitive characteristics associated with LND.

Dopamine in Lesch-Nyhan Disease

Awardee: Jasper Visser

Institution: Radboud University Medical Center, Nijmegen, The Netherlands

Grant Amount: $85,779.00

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

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Summary:

In Lesch-Nyhan disease (LND), it is unknown why the loss of a very generic protein that is present in all cells of the body causes such a specific brain dysfunction with abnormal movements and self-injury. It is thought that brain cells that use the neurotransmitter dopamine to pass on signals to other brain cells are particularly affected in LND, but it is not known whether these are the only brain cells that are affected. This project investigates in a mouse model for LND whether repairing these dopamine neurons alone would be sufficient to prevent or treat the brain abnormalities in LND. If that is the case, they could serve as the primary target for future therapies.

Publications:

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease