A Novel Drug Discovery Platform for Inborn Errors of Metabolism

A yeast-based screening system designed for each specific disease that recapitulates the metabolic state of patients and allows fast compound screening.
The use of high-throughput screening of small molecules can significantly accelerate both drug discovery and target identification.
The formation of amyloid fibrils is the hallmark of aging and various human pathologies, including neurodegenerations such as Alzheimer’s and Parkinson’s diseases. The Gazit Lab has recently extended the canonical amyloid hypothesis, demonstrating that simple metabolites (like amino acids and nucleobases) can undergo self-assembly to form cytotoxic amyloid-like structures. These results provide a novel etiology to Inborn Errors of Metabolism, such as Phenylketonuria, Tyrosinemia and Homocystinuria, suggesting that metabolite aggregation might be the molecular cause of these diseases rather the mere accumulation of the metabolites.
Currently, no effective and affordable treatment for managing IEM symptoms is available. In order to avoid the life-threatening symptoms of the diseases, that range from kidney failure to mental retardation and immunodeficiency, the patients have to follow a strict and almost impossible diet. Screening for potential small molecules that can inhibit intracellular metabolite self-assembly would require a simple yet robust model.
The simplicity and reliability of yeast as a model for human diseases make it highly suitable for performing high-throughput phenotypic screening assays for the identification of small molecules that can prevent the toxicity of metabolite assemblies.
Our integrated platform, established in collaboration with the BLAVTNIK CENTER for Drug Discovery, includes an initial screen in yeast models, followed by validation in cell lines and higher model organisms (nematodes and mice). We have recently established a novel in vivo yeast model for adenine accumulation and self-assembly, which demonstrated significant growth inhibition and elevated amyloid staining upon adenine feeding, marking them as potential drug candidates for the treatment of the modeled disease. The three lead candidates are currently tested in mice.
RAMOT filed a patent application titled: “Integrated drug discovery platform for Inborn Error of Metabolism disorders” in 2018, and it is now at PCT stage.




Endogenous in vivo model for studying metabolite aggregation. A novel yeast-based model for in vivo study of metabolite aggregation phenomena was recently established (Laor et al., 2019). In contrast to the classical yeast models of amyloid-associated diseases, this system does not rely on exogenous expression, but rather on the endogenous disruption of a gene-of-interest, thereby leading to the accumulation, and consequential aggregation of a disease-associated metabolite.


See press release here: https://medicalxpress.com/news/2019-01-yeast-metabolic-disorders-life-saving-therapies.html 





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