Unmet Need:
Loeys-Dietz Syndrome (LDS) is a rare genetic connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan Syndrome. Marfan Syndrome and related disorders, such as LDS, have an incidence of 1 in 3000 to 5000 individuals (see UpToDate). LDS is specifically caused by heterozygous missense mutations in either TGF receptor gene (TGFBR1 or TGFBR2). Current management of the disease includes frequent imaging surveillance, prophylactic surgical repair, and vascular management, including the use of blood pressure-lowering medication and exercise restrictions (see MacCarrick et. al). These interventions are targeted to managing the disease rather than treating the pathogenic mechanism of the mutation. Therefore, there is a high demand for preclinical model systems of LDS that would promote a better scientific understanding of the disease and lead to the development of more targeted therapies.
Technology Overview:
Researchers at Johns Hopkins developed the first Loeys-Dietz Syndrome (LDS) mouse models. Two strains of mice were made to model the disease; JAX Stock # 024634 (Tgfbr2G357W/+) and JAX Stock # 036511 (Tgfbr1M318R/+). In both strains, heterozygous mice recapitulate classic and severe features of the LDS phenotype. Mice at 24 weeks of age have detectable elastic fiber formation in aortic roots, aortic wall shows progressive thickening with excessive collagen, and mice have a predisposition to early death (hemothorax or hemopericardium is observable in approximately 60% of deaths). These mice also develop skeletal manifestations associated with LDS, such as kyphosis and craniosynstosis. These features all together make the mouse models a valuable tool in studying LDS in a preclinical setting.
Stage of Development:
Pre-clinical mouse lines are available.
Publication:
Gallo EM, Loch DC, Habashi JP, et al. J Clin Invest. 124(1):448-460, 2014
