An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome
Faycal Guedj1, Jeroen LA Pennings2, Lauren J Massingham1
1Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, MA, United States.
Abstract:
Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls, and embryonic day 15.5 forebrains from Ts1Cje, Ts65Dn, and Dp16 mice. The new datasets were compared to other publicly available datasets from humans with DS. We used the human Connectivity Map (CMap) database and created a murine adaptation to identify FDA-approved drugs that can rescue affected pathways. USP16 and TTC3 were dysregulated in all affected human cells and two mouse models. DS-associated pathway abnormalities were either the result of gene dosage specific effects or the consequence of a global cell stress response with activation of compensatory mechanisms. CMap analyses identified 56 molecules with high predictive scores to rescue abnormal gene expression in both species. Our novel integrated human/murine systems biology approach identified commonly dysregulated genes and pathways. This can help to prioritize therapeutic molecules on which to further test safety and efficacy. Additional studies in human cells are ongoing prior to pre-clinical prenatal treatment in mice.
Insights
This study identifies common gene and pathway abnormalities in Down syndrome (DS) brain development using human and mouse models. It proposes a drug discovery approach to find prenatal treatments for DS by targeting these perturbed pathways.
Area of Science:
- Neurodevelopmental disorders
- Genetics and Genomics
- Pharmacology
Background:
- Down syndrome (DS) is characterized by brain abnormalities starting prenatally.
- Identifying effective prenatal treatments for DS is a significant unmet need.
Purpose of the Study:
- To identify novel prenatal treatment targets for Down syndrome by analyzing perturbed signaling pathways.
- To discover FDA-approved drugs capable of rescuing these pathways.
Main Methods:
- Comparative transcriptome analysis of human fetal DS tissues and mouse models (Ts1Cje, Ts65Dn, Dp16).
- Utilized the Connectivity Map (CMap) database and a murine adaptation for drug screening.
- Integrated human and murine systems biology approaches.
Main Results:
- Identified dysregulated genes USP16 and TTC3 common to human DS and mouse models.
- Revealed DS-associated pathway abnormalities stem from gene dosage effects or cellular stress responses.
- Discovered 56 molecules with high potential to correct abnormal gene expression in both species.
Conclusions:
- An integrated human/murine systems biology approach effectively identified common Down syndrome-related molecular targets.
- This strategy prioritizes therapeutic molecules for further preclinical evaluation.
- Findings pave the way for developing novel prenatal interventions for Down syndrome.
