Grace Science Foundation

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“AVAILABLE UPON REQUEST.”

“AVAILABLE UPON REQUEST.”

“THE UNIVERISTY OF TEXAS SOUTHWESTERN MEDICAL CENTER (YAN LAB) Team continues work generating and characterizing several mouse models of NGLY1 Deficiency, including models in which the gene is inactivated in certain tissues and conditionally after birth. These mouse models have allowed them to characterize neurological phenotypes including neuronal loss, neuropathological changes, inflammation, sensory and motor defects, and disease associated biomarkers, all of which are also observed in NGLY1 Deficiency patients These animal models provide a foundation for testing candidate therapies, including gene therapies and small molecule drugs. The team has also found that NGLY1 Deficiency in mice triggers a specific innate immune pathway mediated by the cGAS/STING pathway. Using genetic and pharmacological approaches, the team has uncovered three different targets that can be modulated to reduce disease associated phenotypes and improve survival. suggest potential targets for candidate therapy development. EXPENSES $114,390. INCLUDING GRANTS OF $114,390. REVENUE $0.”

“THE NEW YORK STEM CELL FOUNDATION Team has developed and validated four additional patient-derived induced pluripotent stem cell (iPSC) lines to complement and expand human cell models of NGLY1 Deficiency. CRISPR-mediated genome editing was used to produce isogenic control lines to establish disease-specific characteristics. Team has further used these iPSC lines to generate human neuronal models of NGLY1 Deficiency and has characterized NGLY1-dependent neuronal phenotypes including changes in cellular architecture, mitochondrial function, intracellular aggregates, neuronal activity, and patterns of gene expression. Team has tested whether these pathologies can be reversed by restoring NGLY1 function or blocking oxidative stress-induced cell death. EXPENSES $55,000. INCLUDING GRANTS OF $55,000. REVENUE $0.”

“THE BOSTON CHILDREN'S HOSPITAL (YU LAB) Team is developing tools and resources to determine whether knockdown of the gene FBXO6 (F-box gene 6) can rescue phenotypic consequences associated with NGLY1 Deficiency. The team established a cellular assay system to test the ability of anti-sense oligonucleotides (ASOs) to knockdown FBXO6 and designed and tested a series of candidate ASOs. The team identified a series of ASOs that inhibit FBXO6 by >75% and initiated studies to assess their activity to block FBXO6 function in cells. These studies set the stage for subsequent research to test rescue of NGLY1-associated phenotypes in cellular and in vivo systems. EXPENSES $49,110. INCLUDING GRANTS OF $49,110. REVENUE $0.”

“THE 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 $48,500. INCLUDING GRANTS OF $48,500. REVENUE $0.”

“THE 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 $37,934. INCLUDING GRANTS OF $37,934. REVENUE $0.”

“THE BAYLOR COLLEGE OF MEDICINE (JAFAR-NEJAD LAB) 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 $25,367. INCLUDING GRANTS OF $25,367. REVENUE $0.”

“Description:consulting total fees:139219”