Myotonic dystrophy mouse models: towards rational therapy development

Abstract

DNA repeat expansions can result in the production of toxic RNA. RNA toxicity has been best characterised in the context of myotonic dystrophy. Nearly 20 mouse models have contributed significant and complementary insights into specific aspects of this novel disease mechanism. These models provide a unique resource to test pharmacological, anti-sense, and gene-therapy therapeutic strategies that target specific events of the pathobiological cascade. Further proof-of-principle concept studies and preclinical experiments require critical and thorough analysis of the multiple myotonic dystrophy transgenic lines available. This review provides in-depth assessment of the molecular and phenotypic features of these models and their contribution towards the dissection of disease mechanisms, and compares them with the human condition. More importantly, it provides critical assessment of their suitability and limitations for preclinical testing of emerging therapeutic strategies.

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

“…In neurodegenerative diseases in humans, access to affected tissue is generally limited to the end-stage of the disease and to biopsies, making animal models extremely useful (Gomes-Pereira et al, 2011; Wansink and Wieringa, 2003). In the present study, we have used DMSXL transgenic mice.…”

“…These mice express the DMPK gene in a variety of tissues with a pattern similar to the patterns of the murine Dmpk gene in mice and the DMPK gene in human tissues (Huguet et al, 2012). To address whether the DMSXL transgenic mice animal model, which carry a long CTG repeat and display DM1 features (Gomes-Pereira et al, 2011), have respiratory problems, we tested and compared the breathing function in DMSXL and control mice. To identify the pathological changes underlying any respiratory complications, we analyzed the diaphragm muscle and the neural network that generates, controls and transmits the respiratory rhythm.…”

Altered Replication in Human Cells Promotes DMPK (CTG)n · (CAG)n Repeat Instability

“…Transgenic and knock-in mouse models that recapitulate the expansion of the DMPK TNRs showed that the integration site and the amount of flanking human genomic sequence affect TNR instability (19,28,35,77,79). These findings suggest that cis-acting elements may play a crucial role in determining TNR stability during normal differentiation or pathological states.…”

RNA–protein interactions in unstable microsatellite diseases

“…This model shows features reminiscent of DM including myopathy, myotonia, intranuclear CUG RNA foci and centralized myonuclei with a positive correlation between pathology and transgene expression. Additional mouse models have also been generated to overcome the limitations of this model, which include a relatively short CTG exp , the absence of the endogenous DMPK 3′ UTR sequence and restricted muscle expression (Gomes-Pereira et al, 2011). These models include Cre-inducible transgenic mice expressing interrupted CTG 960 repeats (EpA960) or CTG 0 repeats (EpA0) and transgenic mice carrying insertions of a ~45 kb human genomic region with 20, 55, and 300 CTG repeats (Seznec et al, 2000; Wang et al, 2007).…”

“…DMSXL, derived from the DM300 line, is another transgenic model with >1000 CTG repeats due to intergenerational instability that led to ‘big jumps’ in CTG repeat number (Gomes-Pereira et al, 2007). These models exhibit different aspects of DM disease, such as muscle pathology, cardiac conduction problems, behavioral abnormalities accompanied by intranuclear RNA foci pathology and some tissue-specific splicing deficits (Gomes-Pereira et al, 2011; Hernandez-Hernandez et al, 2013; Huguet et al, 2012). Taken together, these mouse models serve as valuable tools to gain insight into DM disease mechanisms and for preclinical assessment of therapeutics targeting repeat expansion RNAs.…”