Precision genetic cellular models identify therapies protective against endoplasmic reticulum stress

Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are a collection of rare pediatric disorders with symptoms that range from mild to life threatening. They typically affect multiple organ systems and usually present with neurological abnormalities including hypotonia, cognitive impairment, and intractable seizures. Several genes have been implicated in the thirty-six types of CDG, but currently NGLY1 is the only known CDDG gene. A common biological mechanism among CDG types and in CDDG is endoplasmic reticulum (ER) stress. Here, we develop two isogenic human cellular models of CDG ( PMM2 , the most prevalent type of CDG, and DPAGT1 ) and of the only CDDG ( NGLY1 ) in an effort to identify drugs that can alleviate ER stress. Systematic phenotyping identified elevated ER stress and autophagy levels among other cellular and morphological phenotypes in each of the cellular models. We screened a complex drug library for compounds able to correct aberrant morphological phenotypes in each of the models using an agnostic phenotypic cell painting assay based on >300 cellular features. The image-based screen identified multiple candidate compounds able to correct aberrant morphology, and we show a subset of these are able to correct cellular and molecular defects in each of the models. These results provide new directions for the treatment of rare diseases of glycosylation and deglycosylation and a framework for new drug screening paradigms for more common neurodegenerative diseases characterized by ER stress. Summary sentence Novel drug screening modality identifies compounds that correct aberrant molecular phenotypes in precision cellular models of glycosylation defects. ### Competing Interest Statement D.B.G. is a founder of and holds equity in Praxis, serves as a consultant to AstraZeneca, and has received research support from Janssen, Gilead, Biogen, AstraZeneca and UCB. M.B.H. serves as a consultant to the Muscular Dystrophy Association, and receives research support from Biogen. All other authors declare no competing interests.