Down syndrome (DS) occurs as a result of Trisomy 21 and is among the most complicated genetic conditions compatible with human survival – 80% of ts21 pregnancies end in miscarraige. The Reeves laboratory complements genetic analyses in human beings with the creation and characterization of animal models and molecular approaches to understand why and how gene dosage imbalance disrupts development in DS. The models provide a basis to explore therapeutic approaches to amelioration of DS features. We use chromosome engineering in ES cells to create defined dosage imbalance in order to localize the genes contributing to these anomalies and to test directly hypotheses concerning Down syndrome "critical regions" on human chromosome 21. Quantitative phenotypic assays that we have developed give a precise and sensitive readout of the relative effects on phenotype when overlapping subsets of genes are at dosage imbalance. Developmental analyses of these traits are underway to identify the timing and location of divergence between trisomic and euploid fetuses. We have used mouse models to:
- Demonstrate that Ts65Dn mice are trisomic for orthologs of Hsa21 genes and exhibit many of the same developmental and functional perturbations, including impaired hippocampal function, establishing this model as the basis for a substantial fraction of basic and translational research in DS (Reeves et al., 1995);
- Identify direct parallels in the development of the craniofacial skeleton in Down syndrome and trisomic mice (see numerous articles from Reeves and Richtsmeier, e.g. Starbuck et al., 2011);
- Create a mouse model to disprove the existence of a so-called “DS Critical Region” establishing the paradigm for development of a new generation of DS models Olson et al. 2004);
- Validate epidemiological findings suggesting a lower incidence of cancer in Down syndrome and identify the candidate genes (Sussan et al., 2008; Yang and Reeves, 2011; Yang et al., in review);
- Establish a deficit in a Shh-responsive population of cranial neural crest as the (initial) basis for the hypomorphic craniofacial skeleton (Roper et al., 2009);
- Substantiate the hypothesis that individually benign disomic modifiers can greatly exacerbate the frequency and morbidity of heart defects on a trisomic background or in combination with each other (Li et al., 2012); defining a set of disomic modifiers and the trisomic genes with which they interact is a major focus of ongoing research;
- Discover the basis for and potential “treatment” of a fundamental structural deficit in the trisomic brain with a Shh pathway agonist (SAG)(Roper et al., 2006; Das et al., 2013); exploration of the translational potential of SAG or other pathway modifiers is a major focus of ongoing research;
- Ongoing studies examine whether a deficit in response to Shh signaling is a “common denominator” that underlies multiple phenotypes of DS (Currier et al., 2012; Dutka et al., 2015).
Definition of the timing and location of divergence between trisomic and euploid phenotypes and of the gene(s) primarily contributing to those differences provides the necessary basis for genetic, pharmacologic and stem cell therapies to ameliorate these anomalies (Das and Reeves, 2011; Haydar and Reeves, 2012).
Genetic modifiers of Down syndrome features
Many features of Down syndrome have highly variable severity in different individuals with trisomy 21. In a multi-Institute collaboration we have combined genetic analysis of patient samples, candidate gene sequencing and mouse modeling to identify genetic modifiers producing congenital heart disease in human beings (DS Heart Project). The study is based on the 2000x elevation of complete AV canal or AVSD in Down syndrome. Congenital heart disease (CHD) is the most frequent birth defect in human beings regardless of ploidy. The increased “signal-to-noise” ratio for gene expression effects in Down syndrome will contribute to understanding and treatment of congenital heart disease in all people.
We have expanded this study to assess genetic contributions to variation in intellectual ability in the Down Syndrome Cognition Project (DS Cognition Project). We use the Arizona Cognitive Test Battery (Edgin et al., 2010) to assess cognitive ability based on functions mapped to different brain regions that are often affected in Down syndrome. These results were part of the evidence used by Hoffman-LaRoche to initiate a clinical trial of a drug to improve learning and memory in DS which is now in Phase 2; Johns Hopkins School of Medicine and the Kennedy Krieger Institute are a site for the ongoing Roche Clinical trial of BP 25543 (CLEMATIS).
Additional information is available at Clinicaltrials.gov.