TGFbeta Antagonists, Including AT1 Receptor Blockers, Rescue the Multisystem Pathogenesis of Marfan Syndrome

This invention is based on the discovery that excessive activity of an important signaling protein, TGF?likely underlies a variety of problems in Marfan syndrome, including the tendency to develop emphysema. The many problems associated with increased TGF?ignaling can be rescued by TGF?ntagonism. The inventors demonstrated that excessive TGF?ctivation 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 TGF?ignaling and can be rescued by TGF?ntagonism, as demonstrated in a mouse model. Therapeutic interventions that have demonstrated effectiveness include systemic administration of TGF?eutralizing antibody and administration of the angiotensin I1 type 1 (ATl) receptor antagonist losartan. Preliminary studies suggest a strong contribution of excess TGF?ignaling to common and nonsyndromic variants of disease including environmentally-induced emphysema. The inventors have also demonstrated that increased TGF?ignaling 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. Losartan, currently marketed by Merck, is used for symptoms of hypertension and diabetes. There are other drug companies with similar agents in this class. Genzyme is currently developing TGF?neutralizing antibodies for therapeutic use. Description (Set) Proposed Use (Set) 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

Inventor(s): Dietz, Harry C.

Type of Offer: Licensing

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