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Preclinical In Vitro Studies of Prenatal Treatment of Down Syndrome to Improve Brain Development and Neurocognition

Down syndrome results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. There are no effective treatments for Down syndrome that improve brain development and neurocognition. Altered brain development occurs before birth in Down syndrome, which suggests that the optimal time to initiate therapeutic treatment is during prenatal development.

In this study, neural progenitor cell (NPC) cultures were derived from induced pluripotent stem cells (iPSCs), to provide an in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the ability of pharmacological interventions to alleviate these effects. Gene expression was examined using bulk RNA-Seq in untreated T21 and euploid (control) NPCs and in NPCs treated with the candidate therapeutic molecules fasudil, apigenin, epigallocatechin-3-gallate (EGCG), isoxsuprine, and sphingosine. The results showed that the Rho-associated coiled-coil kinase (ROCK) inhibitor fasudil significantly downregulated expression of inflammatory pathway genes in T21 NPCs, of relevance because elevated inflammatory pathways are present in T21 and may contribute to deleterious phenotypes.

Data available through dbGaP include five bulk RNA-Seq datasets from euploid and T21 NPC treated with the five molecules listed above, along with untreated euploid and T21 NPCs. Global protein expression data and phosphoproteomic profile data summary files, generated by tandem mass tag (TMT) mass spectrometry, are also available from untreated euploid and T21 iPSCs and NPCs.