Compositions and methods for treating hepatic fibrosis

Abstract

This disclosure provides pharmaceutical compositions and purified or isolated naturally occurring exosome products that have therapeutic use for treating an unmet medical need. The exosome compositions contain an effective amount of exosomes isolated from a body fluid of a non-diseased subject. The compositions are useful in the treatment of a variety of fibrotic diseases.

1 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of exosomes isolated from a body fluid of a non-diseased subject, wherein optionally:
 (a) the microRNA (miR) profile of the exosomes comprises one or both of: lack of up-regulation of one or both of the markers miR-26b and/or -122, as compared to the miR profile of a subject that is suffering from a fibrotic or hepatic disease or an associated disorder and/or lack of down-regulation of one or both of miR-9 and/or -196b as compared to the miR profile of a subject that is suffering from a fibrotic or hepatic disease or an associated disorder; or   (b) the microRNA (miR) profile of the exosomes comprises lack of up-regulation of miR-26b and -122, and lack of down-regulation of miR-9, and -196b, as compared to the miR profile of a subject that is suffering from a fibrotic or hepatic disease or an associated disorder; or   (c) the microRNA (miR) profile of the exosomes comprises lack of up-regulation or high expression of one or more, two or more, three or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, or sixteen or more, or seventeen or more, or eighteen or more, or all of -7a, -26b, -122, -1906, -21, -22, -24, -34a, -155, -195, -677, -541, -125b, -500, -466j, -544, -1a-2, -1194, and/or -700 and/or lack of down-regulation or low expression of one or more, two or more, three or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, or fifteen or more, or all of miR-27a, -192, -214, -377, -196b, -9, -455, -23b, -106a, -200b, -532, -34c, -151, -653, -687, and/or -483, as compared to the miR profile of a subject that is suffering from a fibrotic or hepatic disease or an associated disorder.   
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the body fluid comprises one or more of blood, urine, saliva, breast milk, lymphatic fluid, serum and/or plasma. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises one or more of saline, glycerol, PBS and optionally, a protease inhibitor. 
     
     
         7 . The pharmaceutical composition of  claim 1 , formulated for low temperature storage below about '70° C., freeze-drying or lyophilisation. 
     
     
         8 . A pharmaceutical composition comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, or alternatively all of miR-9, -196b, -27a, -192, -214, -377, -455, -23b, -106a, -200b, -532, -34c, -151, -653, -687, and/or -483 and a pharmaceutically acceptable carrier. 
     
     
         9 . The composition of  claim 1  further comprising one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, or alternatively all of miR-9, -196b, -27a, -192, -214, -377, -455, -23b, -106a, -200b, -532, -34c, -151, -653, -687, and/or -483. 
     
     
         10 . A method for one or more of: a) inhibiting the progression of, b) preventing, and/or c) treating, a fibrotic disease or an associated disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 1 , wherein the exosomes are isolated from a subject that is not diagnosed as having the fibrotic disease or associated disorder that is to be inhibited, prevented or treated. 
     
     
         11 . The method of  claim 10 , wherein the fibrotic disease or associated disorder is a liver disease, a fibrotic liver disease or an associated disorder and the associated disorder is selected from the group of: inflammation of one or more of the liver, the heart, the kidney, the lung, the pancreas, a joint, the eye; high deposition of lipids, high deposition of insoluble collagen; high deposition of extracellular matrix components; cirrhosis, hepatocarcinoma; scleroderma, keloids, rheumatoid arthritis, or end-stage liver disease. 
     
     
         12 . The method of  claim 10 , further comprising determining the level of one or more miR-26b, -122, -9, or -196b in a sample isolated from the patient to monitor the therapy. 
     
     
         13 . The method of  claim 10 , further comprising determining the expression level of one or more of two or more, three or more, or four or more, or five or more, or six or more, or seven or more, or eight or more, or nine or more, or ten or more, or eleven or more, or twelve or more, or thirteen or more, or fourteen or more, or fifteen or more, or sixteen or more, or seventeen or more, or eighteen or more, or nineteen or more, or twenty or more, or twenty-one or more, or twenty-two or more, or twenty-three or more, or twenty-four or more, or twenty-five or more, or twenty-six, or twenty-seven or more, or twenty-eight or more, or twenty-nine or more, or thirty or more, or thirty-one or more, or thirty-two or more, or thirty-three or more, or thirty-four or more, or all of miR-7a, -21, -22, -24, -34a, -155, -195, -27a, -192, -214, -377, -455, -23b, -106a, -200b, -532, -34c, -26b, -122, -9, -196b, -151, -653, -687, -483, -1906, -677, -541, -125b, -500, -466j, -544, -1a-2, -1194, and/or -700, in a sample isolated from the patient to monitor the therapy. 
     
     
         14 . The composition of  claim 1 , wherein the subject is a mammal. 
     
     
         15 . The composition of  claim 1 , wherein the subject is a human. 
     
     
         16 . The composition of  claim 1 , wherein an effective amount comprises from 0.1 mg to about 1,000 mg per kg of body weight of the subject to be treated, in a single or multiple doses. 
     
     
         17 . The method of  claim 10 , wherein the exosomes are allogeneic or autologous to the subject receiving the exosomes. 
     
     
         18 . A purified or isolated population of exosomes isolated from a body fluid of a non-diseased subject, wherein optionally:
 (a) the microRNA (miR) profile of the exosomes comprises lack up-regulation of one or both of the exosome markers miR-26b and/or -122, as compared to the exosome miR profile of a subject that is suffering from a liver or fibrotic disease or an associated disorder and/or comprise lack of down-regulation of one or both of miR-9and/or -196b, as compared to the exosome miR profile of a subject that is suffering from a liver or fibrotic disease or an associated disorder; or   (b) the microRNA (miR) profile of the exosomes comprises lack of up-regulation of one or both of miR-26b or -122 or lack of down-regulation of miR-9, or -196b, as compared to the exosome miR profile of a subject that is suffering from a liver or fibrotic disease or an associated disorder.   
     
     
         19 .- 20 . (canceled) 
     
     
         21 . The purified or isolated population of exosomes of  claim 18 , wherein the exosomes further comprise a miR profile comprising lack of up regulation one or more of miR-7a, -21, -22, -24, -34a, -155, -26b, -122, -1906, -195, -677, -541, -125b, -500, -466j, -544, -1a-2, -1194, and/or -700, and/or lack of down-regulation of miR-27a, -192, -214, -377, -196b, -9, -455, -23b, -106a, -200b, -532, -34c, -151, -653, -687, and/or -483, as compared to the exosome miR profile of a subject that is suffering from a liver or fibrotic disease or an associated disorder. 
     
     
         22 . A purified or isolated population of exosomes of  claim 18 , wherein the fluid is selected from the group of urine, saliva, lymphatic fluid, breast fluid, blood, serum or plasma. 
     
     
         23 . A purified or isolated population of exosomes of  claim 18 , further comprising a pharmaceutically acceptable carrier. 
     
     
         24 . A purified or isolated population of exosomes of  claim 23 , formulated for low temperature storage below about −70° C., freeze-drying or lyophilisation. 
     
     
         25 . A kit for one or more of: a) inhibiting the progression of, b) preventing or c) treating, a fibrotic disease or an associated disorder in a subject in need thereof, comprising an effective amount of the pharmaceutical composition of  claim 1 , and reagents and instructions for use.