Angiotensin peptides in treating marfan syndrome and related disorders

Abstract

The present invention provides, among other things, methods of treating Marfan Syndrome and/or a Marfan-related disorder including administering to a subject suffering from or susceptible to Marfan Syndrome and/or a Marfan-related disorder an angiotensin (1-7) peptide. In some embodiments, the angiotensin (1-7) peptide is administered at an effective dose periodically at an administration interval such that at least one symptom or feature of Marfan Syndrome and/or a Marfan-related disorder is reduced in intensity, severity, duration, or frequency or has delayed in onset.

We claim: 
     
         1 . A method of treating Marfan Syndrome and/or a Marfan-related disorder comprising administering to a subject suffering from or susceptible to Marfan Syndrome and/or a Marfan-related disorder an angiotensin (1-7) peptide. 
     
     
         2 . The method of  claim 1 , wherein the angiotensin (1-7) peptide is administered at an effective dose periodically at an administration interval such that at least one symptom or feature of Marfan Syndrome and/or a Marfan-related disorder is reduced in intensity, severity, duration, or frequency or has delayed in onset. 
     
     
         3 . The method of  claim 2 , wherein the at least one symptom or feature of Marfan Syndrome and/or a Marfan-related disorder is selected from the group consisting of aortic enlargement, aortic dissection, eye lens dislocation, mitral valve prolapse, joint hypermobility, retinal detachment, strabismus, cataracts, glaucoma, obstructive lung disease, scoliosis, temporomandibular joint disorder, dural ectasia, and osteopenia. 
     
     
         4 . The method of  claim 1 , wherein the Marfan-related disorder is selected from the group consisting of: Loeys-Dietz Syndrome, Familial Aortic Aneurysm, Bicuspid Aortic Valve with Aortic Dilation, Familial Ectopia Lentis (dislocated lens), Mitral Valve Prolapse Syndrome, Marfan Habitus, Congenital Contractural Arachnodactyly (Beals Syndrome), Stickler syndrome, Shprintzen-Goldberg syndrome, Weill-Marchesani syndrome, and Ehlers-Danlos syndrome. 
     
     
         5 . The method of  claim 1 , wherein the angiotensin (1-7) peptide is administered parenterally. 
     
     
         6 . The method of  claim 5 , wherein the parenteral administration is selected from intravenous, intradermal, inhalation, transdermal (topical), intraocular, intramuscular, subcutaneous, intramuscular, and/or transmucosal administration. 
     
     
         7 . The method of  claim 1 , wherein the angiotensin (1-7) peptide is administered orally. 
     
     
         8 . The method of any of the preceding claims, wherein the angiotensin (1-7) peptide is administered monthly, weekly, daily, or at variable intervals. 
     
     
         9 . The method of any of the preceding claims, wherein the angiotensin (1-7) peptide is administered at an effective dose ranging from about 1-1,000 μg/kg/day. 
     
     
         10 . The method of any of the preceding claims, wherein the angiotensin (1-7) peptide is administered at an effective dose ranging from about 50-500 μg/kg/day. 
     
     
         11 . The method of any of the preceding claims, wherein the angiotensin (1-7) peptide is administered at an effective dose ranging from about 400-500 μg/kg/day. 
     
     
         12 . The method of any of the preceding claims, wherein the angiotensin (1-7) peptide is administered in combination with one or more Marfan Syndrome and/or a Marfan-related disorder medications. 
     
     
         13 . The method of  claim 12 , wherein the one or more Marfan Syndrome and/or a Marfan-related disorder medications is selected from the group consisting of beta blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (e.g. losartan), anticoagulants, and combinations thereof. 
     
     
         14 . The method of  claim 1 , wherein the angiotensin (1-7) peptide comprises the naturally-occurring Angiotensin (1-7) amino acid sequence of Asp 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7  (SEQ ID NO:1). 
     
     
         15 . The method of  claim 1 , wherein the angiotensin (1-7) peptide is a functional equivalent of SEQ ID NO:1. 
     
     
         16 . The method of  claim 15 , wherein the functional equivalent is a linear peptide. 
     
     
         17 . The method of  claim 16 , wherein the linear peptide comprises a sequence that includes at least four amino acids from the seven amino acids that appear in the naturally-occurring Angiotensin (1-7), wherein the at least four amino acids maintain their relative positions as they appear in the naturally-occurring Angiotensin (1-7). 
     
     
         18 . The method of  claim 16 , wherein the linear peptide contains 4-25 amino acids. 
     
     
         19 . The method of  claim 16 , wherein the linear peptide is a fragment of the naturally-occurring Angiotensin (1-7). 
     
     
         20 . The method of  claim 16 , wherein the linear peptide contains amino acid substitutions, deletions and/or insertions in the naturally-occurring Angiotensin (1-7). 
     
     
         21 . The method of  claim 20 , wherein the linear peptide has an amino acid sequence of Asp 1 -Arg 2 -Val 3 -Ser 4 -Ile 5 -His 6 -Cys 7  (SEQ ID NO:2). 
     
     
         22 . The method of  claim 15 , wherein the functional equivalent is a cyclic peptide. 
     
     
         23 . The method of  claim 22 , wherein the cyclic peptide comprises a linkage between amino acids. 
     
     
         24 . The method of  claim 23 , wherein the linkage is located at residues corresponding to positions Tyr 4  and Pro 7  in naturally-occurring Angiotensin (1-7). 
     
     
         25 . The method of  claim 23 , wherein the linkage is a thioether bridge. 
     
     
         26 . The method of  claim 22 , wherein the cyclic peptide comprises an amino acid sequence otherwise identical to the naturally-occurring Angiotensin (1-7) amino acid sequence of Asp 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7  (SEQ ID NO:1). 
     
     
         27 . The method of  claim 22 , wherein the cyclic peptide is a 4,7-cyclized angiotensin (1-7) with the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 15 , wherein the angiotensin (1-7) peptide comprises one or more chemical modifications to increase protease resistance, serum stability and/or bioavailability. 
     
     
         29 . The method of  claim 28 , wherein the one or more chemical modifications comprise pegylation. 
     
     
         30 . A method of treating Marfan Syndrome and/or a Marfan-related disorder comprising administering to a subject who is suffering from or susceptible to Marfan Syndrome and/or a Marfan-related disorder an angiotensin (1-7) receptor agonist. 
     
     
         31 . The method of  claim 30 , wherein the angiotensin (1-7) receptor agonist is a non-peptidic agonist. 
     
     
         32 . The method of  claim 31 , wherein the non-peptidic agonist is a compound with the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of any one of  claims 30 - 32 , wherein the angiotensin (1-7) receptor agonist is administered orally.