Unmet Need: Marfan syndrome is a disorder of the body's connective tissues. One out of every 5,000 people in the world has Marfan syndrome, or a related connective tissue disorder. Features of the disease include, emphysema (which frequently results in spontaneous lung rupture), eye problems, skeletal abnormalities, heart valve and aortic problems that are deadly if not caught early and surgically repaired. Many major pharmaceutical companies are rapidly expanding their research in the areas that affect Marfan syndrome patients. There are currently no effective medical treatments for many of these manifestations. Collectively, these phenotypes represent a significant public health burden.
Technology Overview:This invention is based on the discovery that excessive activity of an important signaling protein, TGFB likely underlies a variety of problems in Marfan syndrome, including the tendency to develop emphysema. The many problems associated with increased TGFB signaling can be rescued by TGFB antagonism. The inventors demonstrated that excessive TGFB activation and signaling is central to the pathogenesis of Marfan syndrome, a common connective tissue disorder. Relevant phenotypes include emphysema due to impaired distal alveolar septation, thickening and dysfunction of the atrioventricular valves, aortic aneurysm and dissection, and skeletal muscle myopathy due to failed satellite cell proliferation and muscle regeneration. Each of these phenotypes associates with increased TGFB signaling and can be rescued by TGFB antagonism, as demonstrated in a mouse model. Therapeutic interventions that have demonstrated effectiveness include systemic administration of TGFB neutralizing antibody and administration of the angiotensin I1 type 1 (ATl) receptor antagonist losartan. Preliminary studies suggest a strong contribution of excess TGFB signaling to common and non-syndromic variants of disease including environmentally-induced emphysema. The inventors have also demonstrated that increased TGFB signaling compromises muscle regeneration in Duchenne muscular dystrophy, and that both neutralizing antibody and losartan can rescue muscle architecture in this common and progressive form of myopathy. Currently, there are many major pharmaceutical companies focused on treatments to improve the symptoms of Marfan syndrome, specifically valve disease, emphysema, myopathy, scoliosis, and eye disease. The recent identification of the chromosome, gene and component of connective tissue (fibrillin-l) in which the mutation for Marfan syndrome is located, has renewed much hope in the area of research and treatments.
Associated Material: These mice are available via The
Jackson Laboratory Strain: 012885 (C1039G)Mice homozygous for this
Fbn1 (fibrillin 1) Cys1041Gly missense mutation (previously identified as Cys1039Gly) are small and die before two weeks of age. A similar mutation in man (Cys1039Tyr) is known to cause classic manifestations of Marfan syndrome in humans. Heterozygous mice develop proximal aortic aneurysms, mitral valve thickenings, pulmonary alveolar septation defects, mild thoracic kyphosis, and skeletal myopathy, but 90% reportedly live to one year of age.
Site-directed mutagenesis was used to create a single G->T base pair alteration in the mouse gene resulting in a Cys->Gly change at amino acid 1041 (previously identified in the literature as C1039G). This corresponds with the human C1039Y mutation. The mutation was created in (129X1/SvJ x 129S1/Sv)F1-
Kitl+-derived R1 embryonic stem (ES) cells. A loxP-flanked neomycin resistance cassette placed in intron 24 was excised through a cross with a CMV-cre mouse. This strain was backcrossed to C57BL/6 for more than nine generations by the donating laboratory.
©The Jackson Laboratory 2016 used with permission
Publications: J Clin Invest. 2004 Jul;114(2):172-81.
