Grace Science Foundation

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“AVAILABLE UPON REQUEST.”

“BAYLOR COLLEGE OF MEDICINE TEAM continues genetic and pharmacological studies to gain insights into pathways regulated by NGLY1 and potential targets for therapy development. This research has uncovered a link between NGLY1 and AMP-regulated kinase (AMPK) a critical cellular energy sensor. AMPK activity is reduced in animal models of NGLY1 Deficiency and in patient cell lines. Restoring AMPK levels or activity by genetic or pharmacological tools restores energy homeostasis in NGLY1 deficient cells and organisms. Team is researching the mechanisms and cellular contexts of AMPK regulation by NGLY1 and testing potential therapies to reverse AMPK-associated pathologies in NGLY1 Deficiency. EXPENSES $94,084 INCLUDING GRANTS OF $94,084. REVENUE $0.”

“THE UNIVERSITY OF NORTH CAROLINA (HANTMAN LAB) Team has utilized a mouse model on NGLY1 Deficiency to analyze directed movement behavior and identify the affected brain circuits responsible for the movement phenotypes charcateristic of NGLY1 Deficiency. The studies involve training wild type and Ngly1-deficient mice to perform a "reach-grab" task, comparing the task performance and movement dynamics between typical and affected animals, and recording from specific brain circuits while the animals perform the task. Identified changes will help to better understand the neural basis of the NGLY1 Deficiency movement disorder, define the neural circuits that must be targeted to treat the disease, and establish a platform to test potential therapies. EXPENSES $93,773 INCLUDING GRANTS OF $93,773. REVENUE $0.”

“STANFORD UNIVERSITY (DIXON LAB) Team continues to characterize the role of ferroptosis, a form of cell death associated with oxidative stress, in the pathologies associated with NGLY1 deficiency. The group's earlier studies showed that loss of NGLY1 or its substrate NFE2L1 sensitizes cells to ferroptosis, and this ferroptosis senstiivity can be reversed by expression of an activated form of NFE2L1. The group has expanded that work to test the hypothesis that the related factor NFE2L3 may be functionally redundant with NFE2L1 and that inactivity of both factors may account for the cell stress sentiivity seen in NGLY1 Deficiency. These studies may help explain the causes of cell dysfunction and loss in NGLY1 Deficiency and suggest potential targets for candidate therapy development. EXPENSES $57,518. INCLUDING GRANTS OF $57,518. REVENUE $0.”

“PURDUE UNIVERSITY (ROCHET LAB) Team is developing and employing cellular models to test whether NGLY1 and its substrate NFE2L1 have a role in modulating cellular stress and preventing or clearing protein aggregates in the brain. These studies are testing whether loss or dysfunction of the NGLY1-NFE2L1 pathway may sensitize nerve cells to oxidative or protein misfolding stress, leading to neuronal damage and neurodegeneration. In addition, the team is testing the idea that enhancing NGLY1-NFE2L1 activity can prevent or slow neuronal loss using cellular models of Parkinson's disease, a neurodegenerative disorder associated with oxidative stress and protein aggregation. These studies aim to understand the cause of neurotoxicity in rare and common neurodegenerative disorders, explore mechanisms shared between NGLY1 Deficiency and Parkinson's disease, and provide insights for the development of disease-modifying neuroprotective therapies. EXPENSES $47,744. INCLUDING GRANTS OF $47,744. REVENUE $0.”

“THE SCRIPPS RESEARCH INSTITUTE (BOLLONG LAB) Team is testing the ability of small molecule modulators of the transcriptional regulators NRF1 (NFE2L1) and NRF2 (NFE2L2) for the rescue of phenotypic changes associated with NGLY1 Deficiency. The team has identified NRF1 modulating compounds that protect NGLY1 knockout cells from proteasomal stress and has been characterizing their activity. In addition, a potent and selective brain penetrant NRF2 modulating compound has been identified and is being characterized and formulated for in vivo testing. These compounds establish a proof of concept for NGLY1 Deficiency therapy development based on NRF1/2 modulation. EXPENSES $44,456. INCLUDING GRANTS OF $44,456. REVENUE $0.”

“HILLTOP LAB ANIMALS, INC. Team has imported and established a colony of Ngly1 knockout mice for use in testing therapies to treat NGLY1 Deficiency. A breeding colony has been established, and mutant phenotypes have been characterized. This model system has been used to test drug candidates for their ability to rescue NGLY1 Deficiency-associated neurological symptoms and for genetic studies to test whether blocking other pathways (including FBXO6) has potential to treat NGLY1 Deficiency. EXPENSES $28,084. INCLUDING GRANTS OF $28,084. REVENUE $0.”

“Albert Einstein College of Medicine (Kaushik Lab) Team is testing the hypothesis that defects in NGLY1 function leads to the impairment of cellular proteostasis pathways that recognize and clear misfolded and aggregated proteins and defective organelles. Using NGLY1 knockout rat and mouse tissues, NGLY1 mutant cell lines, and NGLY1 Deficiency patient fibroblasts, the team has observed significant impairment in macro- and chaperone mediated-autophagy and defects in lysosomal biogenesis. These results highlight the potential of drugs that target the autophagy-lysosome pathway to reverse cellular defects associated with NGLY1 Deficiency. The team has begun evaluating drug-like chemical modulators of the autophagy-lysosomal system for their ability to reduce cellular proteotoxicity in NGLY1 deficiency models. EXPENSES $24,250. INCLUDING GRANTS OF $24,250. REVENUE $0.”