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Precision genetic cellular models identify therapies protective against ER stress
Irina V Lebedeva1, Michelle V Wagner2,3, Sunil Sahdeo2,3
1Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Abstract:
Rare monogenic disorders often share molecular etiologies involved in the pathogenesis of common diseases. Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are rare pediatric disorders with symptoms that range from mild to life threatening. A biological mechanism shared among CDG and CDDG as well as more common neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, is endoplasmic reticulum (ER) stress. We developed isogenic human cellular models of two types of CDG and the only known CDDG to discover drugs that can alleviate ER stress. Systematic phenotyping confirmed ER stress and identified elevated autophagy among other phenotypes in each model. We screened 1049 compounds and scored their ability to correct aberrant morphology in each model using an agnostic cell-painting assay based on >300 cellular features. This primary screen identified multiple compounds able to correct morphological phenotypes. Independent validation shows they also correct cellular phenotypes and alleviate each of the ER stress markers identified in each model. Many of the active compounds are associated with microtubule dynamics, which points to new therapeutic opportunities for both rare and more common disorders presenting with ER stress, such as Alzheimer's disease and amyotrophic lateral sclerosis.
Insights
Researchers identified drugs that alleviate endoplasmic reticulum (ER) stress in rare congenital disorders of glycosylation (CDG) and deglycosylation (CDDG). These findings offer potential new treatments for both rare and common neurodegenerative diseases like Alzheimer's.
Area of Science:
- Molecular Biology
- Genetics
- Drug Discovery
Background:
- Rare monogenic disorders, including Congenital Disorders of Glycosylation (CDG) and Congenital Disorders of Deglycosylation (CDDG), share molecular pathways with common diseases.
- Endoplasmic reticulum (ER) stress is a common pathogenic mechanism in CDG, CDDG, and neurodegenerative diseases like Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).
- Developing effective treatments for these debilitating conditions remains a significant challenge.
Purpose of the Study:
- To develop isogenic human cellular models for specific CDG and CDDG types.
- To identify and validate compounds capable of alleviating ER stress in these models.
- To explore novel therapeutic strategies for rare and common diseases associated with ER stress.
Main Methods:
- Creation of isogenic human cellular models for two CDG types and one CDDG type.
- Systematic phenotyping to confirm ER stress and identify other cellular abnormalities, such as elevated autophagy.
- High-throughput screening of 1049 compounds using a cell-painting assay to identify those correcting morphological phenotypes.
- Independent validation of identified compounds for correcting cellular phenotypes and alleviating ER stress markers.
Main Results:
- The study successfully developed cellular models exhibiting ER stress and other relevant phenotypes.
- A primary screen identified multiple compounds that corrected aberrant cellular morphology.
- Independent validation confirmed that these compounds also corrected cellular phenotypes and reduced ER stress markers.
- A significant number of active compounds were associated with microtubule dynamics.
Conclusions:
- The developed cellular models are valuable tools for discovering drugs targeting ER stress.
- Compounds targeting microtubule dynamics show promise for treating ER stress-related disorders.
- These findings open new therapeutic avenues for rare CDG/CDDG and common neurodegenerative diseases like AD and ALS.
