Chapter 14 - In vivo and in vitro models for research on Down syndrome

Abstract

The extra chromosome 21 (HSA21) in Down syndrome (DS) has been explored in patients with full and partial trisomies. The impact of trisomic gene-dosage and co-operating effect of disomic genes have been reported in myriads of studies in DS-patients, including DS autopsies, DS-derived cell lines, and DS-derived organoids of different cell/tissue types. Owing to limitation of in vivo study in humans, several mouse models of DS (DS-models) have been generated with full HSA21 or trisomic orthologous segments syntenic to HSA21 through chromosomal rearrangements and recombinant and gene-editing technologies. The target was to understand the genetic consequences of dosage imbalance on expression of DS pathophysiology. Over decades, the studies have heralded with information on several aspects of DS features; however, the complex interactive expression of gene-transcription-translation function and regulation of the entire mechanism could not yet be resolved. There is a continual urge for better dissection of the genotype–phenotype association in different DS models for ultimate understanding of human DS. Further contribution of versatile genetic, environmental, and epigenetic backgrounds in DS patients and models did not allow drawing a conclusion. Nevertheless, the models with different trisomic segments, cell lines, and organoids have significantly contributed in understanding gene-dosage consequences of DS, and also, for identification and testing of targeted therapeutic candidates for dysregulating the aberrant expressions and reversal of DS-pathomechanism or gene expression. Indeed, in vitro inactivation of HSA21, and single or combinatorial therapies, are being tested on DS models, and some are considered for clinical trials. The chapter focuses on several avenues and models of DS-research.