The mitochondrial-related defects in WDR45-defective cells and how to reverse them

Awardee: Mario Mauthe

Institution: University Medical Center Groningen (UMCG)

Grant Amount: $60,000.00

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

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Summary:

The WDR45 gene, which when mutated causes BPAN, produces a protein called WDR45. WDR45 is involved in autophagy, a process that is responsible for removing damaged cellular components. Furthermore, we have observed that the mutated WDR45 protein also affects critical cellular structures called mitochondria, which play vital roles in energy production and metabolism regulation. Similar malfunctioning of mitochondria is also observed in several BPAN-related diseases (other NBIA subtypes) such as PKAN, CoPan, PLAN and MPAN. Within this project, our team will investigate how mutations in WDR45 affects the mitochondria and thereby contribute to the BPAN pathology. Our final goal is to reverse the changes in mitochondria, which are caused by the mutated WDR45 protein, using pharmaceutical compounds. We will start working in cellular model systems, and then move to validating our findings in BPAN patient-derived cells.

Advancing gene therapy for BPAN

Awardee: Manju Kurian

Institution: UCL

Grant Amount: $60,000.00

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

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Summary:

For those affected by progressive, life-limiting brain disorders associated with high brain iron, there are currently no effective treatments. We wish to address this important issue by developing a new therapy for children and young people with Beta Propeller Protein Associated Neurodegeneration (BPAN), a devastating condition caused by a genetic fault (or ‘spelling mistake’) in the gene, ‘WDR45’. In BPAN, the body cannot properly recycle waste products and as a result, toxic iron builds up in the brain. BPAN touches the lives of several hundred people worldwide. Affected children have developmental delay and seizures in childhood. During adolescence, there is a rapid decline in abilities, which is often so progressive that by early adulthood, many are wheelchair bound with severe dementia. BPAN is sadly associated with a high risk of premature death. There are currently no therapies that prevent the progression of BPAN. As such, we believe that developing a new treatment for BPAN is a research priority with potential to benefit hundreds of people globally. With this aim, we propose to develop gene therapy to deliver a healthy copy of the faulty gene directly into the brain. We will establish a state-of the-art laboratory model of disease (a ‘brain in a dish’) and use an excellent mouse model that shows key features of human disease, to test our gene therapy approach to see whether it rescues the problems caused by the faulty gene in BPAN. A successful gene therapy study in our laboratory will allow us to accelerate a clinical gene therapy trial for children with BPAN. Our hope is that gene therapy will halt disease progression, increase life expectancy, and provide a better quality of life for individuals and their families living with this condition.

Establishing autophagy inducers as novel therapies in cellular and animal models of Beta-propeller Protein-Associated Neurodegeneration (BPAN)

Awardee: Bertrand Mollereau

Institution: Ecole Normale Supérieure of Lyon

Grant Amount: $69,775.00

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

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Summary:

beta-propeller associated neurodegeneration (BPAN is the most recently identified sub-type of neurodegeneration with brain iron accumulation (NBIA) and there are currently no effective treatments for the disease. BPAN is caused by mutations in an autophagy gene WDR45. Autophagy is an important mechanism regulating neuron survival. Defective autophagy has been observed in several BPAN cellular and models and it was proposed that reduced autophagy could be responsible for neurodegeneration in BPAN patients. Hence, identification of novel therapeutics that restores a functional autophagy constitutes research priority. We have previously identified small molecule compounds that correct autophagy in cultured cells isolated from BPAN patients. We now propose to further develop test and validate the most promising hits. For this purpose, we have developed an animal fly model of BPAN disease exhibiting hallmarks of the disease, such as autophagy defect, iron accumulation, neurodegeneration and locomotor disorder. We will select the best molecule compounds restoring autophagy in human cells to rescue the cellular and locomotor defects them in BPAN flies. From our study, the most promising compounds will then be ready to be tested in a larger animal, with an ultimate aim of clinical translation and tangible patient benefit as soon as possible.

Reversing Brain Iron Overload in BPAN by a Natural Small Molecule

Awardee: Young-Ah Seo

Institution: University of Michigan

Grant Amount: $66,366

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

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Summary:

The overall goal of this project is to develop new therapeutic strategies that can reduce brain iron overload and iron-induced neurodegeneration in BPAN patients. We have identified that a natural small molecule is exceptionally effective at promoting iron transport. We have now found that iron accumulates in the BPAN cell model and that the resulting iron overload can be mitigated by this small molecule. Building on these preliminary results, this proposal will extensively characterize the capacity for a small molecule to mobilize excess iron from inside cells and will test the overarching hypothesis that small molecule-mediated iron mobilization can mitigate neuronal cell death in BPAN cell models and patient-derived primary fibroblast cells. Completion of the proposed research will advance our fundamental understanding of the mechanistic underpinnings of brain iron overload in BPAN and will build a foundation for the potential therapeutic use of small molecule mobilizers of intracellular iron.

Development of novel human stem cell models of Beta-Propeller Protein- Associated Neurodegeneration (BPAN) for disease modelling and drug screening

Awardee: Paul Lockhart

Institution: Murdoch Children's Research Institute

Award Amount: $61,245