Home-monitoring of specific branched chain amino acids

Awardee: Lital Alfonta

Institution: Ben-Gurion University of the Negev

Grant Amount: $71,985.00

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

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Summary:

The project aims at developing a non-invasive home test for immediate monitoring of the orphan condition Maple Syrup Urine Disease (MSUD). MSUD is a serious genetic condition caused by a deficiency or a mutation in the enzyme keto-acid-dehydrogenase. Blood tests show high levels of three amino acids (leucine, isoleucine and valine), that can lead to life-threatening cerebral oedema and dysmyelination in affected individuals. The disease is more common in Ashkenazi Jews, and in the Bedouin population in the South region of Israel. Children with MSUD must remain on a special diet that restricts the consumption of those three amino acids. Currently, the amino acid levels of children with MSUD are monitored weekly at the hospital, and the results arrive only after several days. We propose to develop a technology based on bioelectrochemistry, which combines optimization of protein function with synthetic biology tools in order to create accurate and specific sensors for immediate monitoring of the relevant amino acids. This will enable real-time diet recommendations and forgo the need for a weekly hospital visit. In addition, neonates are routinely scanned for amino acid levels, and the novel technology can supply immediate results. Immediate monitoring of amino acids is especially crucial in the developmental phase of people (i.e. children and neonates).

Development of neuroprotective gene therapy for MSUD

Awardee: John R Counsell

Institution: UCL

Grant Amount: $71,985.00

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

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Summary:

We are seeking to develop a treatment for a severe metabolic disease called Maple Syrup Urine Disease (MSUD) that results from an inability to break down substances that most of us consume daily, when following a normal diet. MSUD patients are at risk of life-threatening brain damage unless they have their diet carefully managed from birth. Even then, patients remain at risk of brain damage during periods of illness, normally due triggered by infections. At University College London, we are developing a potential cure for MSUD using a technique called gene therapy, whereby a set of genes that are defective in MSUD can be restored in relevant parts of the body. However, it is not currently known whether gene therapy needs to be targeted to the brain as part of a curative strategy. Therefore, our research team aim to investigate this, using a mouse model of the disease, with our hypothesis being that brain cells will need to be targeted in order to fully restore healthy brain development during in early childhood.

Targeting mTOR signaling to improve neurologic outcomes in MSUD

Awardee: Rebecca Ahrens-Nicklas

Institution: The Children's Hospital of Philadelphia and The University of Pennsylvania

Grant Amount:

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

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Summary:

Maple Syrup Urine Disease arises from a defect in branched chain amino acid metabolism (BCAA), that leads to toxic increases in certain amino acids throughout the body. Dietary therapy and liver transplantation can improve levels of BCAAs; however, unfortunately, patients still have neurocognitive and psychiatric symptoms. Based on work in a mouse model of MSUD, we believe that an inability to use BCAAs as fuel in the brain changes mTOR signaling, an important pathway for neurodevelopment. Other disorders with abnormal mTOR activation are known to result in learning difficulties and psychiatric symptoms. In this application, we plan to study how abnormal mTOR signaling affects the brain in MSUD and to explore new therapeutic approaches aimed at correcting this difference.

Neurocognitive Outcomes and Quality of Life in Adults with MSUD

Awardee: Jessica Gold

Institution: Children's Hospital of Philadelphia

Award Amount: $54,465

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

Can we improve neurologic and psychiatric outcomes in MSUD? Studies in a new mouse model

Awardee: Rebecca Ahrens-Nicklas

Institution: The Children's Hospital of Philadelphia / The University of Pennsylvania

Award Amount: $44,037

A novel approach for identification of therapeutic leads to the Maple Syrup Urine Disease

Awardee: Ehud Gazit

Institution: Tel Aviv University

Awarded Amount: $44,037

Final Report Summary:

We have recently shown that metabolites, as simple as single amino acids and nucleobases, can form amyloid-like structures, thus providing a novel paradigm for inborn error of metabolism (IEM) disorders. Here, we wish to explore a never-tested hypothesis suggesting that the systemic pathology following branched-chain amino acids (BCAAs) abnormally high levels in the blood, serum and urine of Maple Syrup Urine Disease (MSUD) patients may be related to the formation of amyloid-like structures. Our preliminary data provide a proof-of-concept for this hypothesis, indicating that BCAAs can form unique assemblies with amyloid-like characteristics. Therefore, we postulate that high levels of BCAAs can lead to the formation of toxic structures that in turn can be involved in the cytotoxicity observed in the disorder. This discovery can offer new prospects for understanding the complex etiologies of the disease and finding the proper treatment for MSUD patients. Here, we set out to utilize our unique expertise and knowledge in metabolite self-assembly and yeast models for IEMs to address fundamental issues concerning MSUD and for the identification of therapeutic leads.

In the scope of the MDBR project, we were able to successfully establish a unicellular yeast model as well as a multicellular organism nematode model for MSUD. Our data indicate that the MSUD models are sensitive to isoleucine supplied in the growth medium, implying the involvement of isoleucine accumulation and self-assembly in cell toxicity and the pathology of MSUD.

Our yeast model was successfully used as a platform for high throughput phenotypic screening of potential therapeutic agents to target metabolite aggregation. Compounds found to suppress the toxicity conferred by isoleucine feeding of the mutant strain in the screen were further characterized and validated in the yeast system. Yet, the compounds that were identified in the selected screen did not show a significant effect in the nematode model and the neuroblastoma cells and therefore could not be used as a potential treatment. Nevertheless, our successful pilot screen proves the strength of our platform and its future potential for the identification of novel treatment for MSUD patients.

Muscle Directed Gene Therapy Application for Maple Syrup Urine Disease (MSUD)

Awardee: Jenny Greig

Institution: Gene Therapy Program, University of Pennsylvania

Award Amount: $112,893

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