Compositions and methods for treating hepatic fibrosis
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 method for inhibiting the progression of or treating a fibrotic liver disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of exosomes comprising a microRNA (miR)-26b level not higher than a miR-26b level and optionally a miR level of one or more miR-122, miR-9 or miR-196b of a subject that is not diagnosed as having the fibrotic liver disease that is to be inhibited or treated and wherein the exosomes are isolated from the serum of a subject not diagnosed with fibrotic liver disease.
2. The method of claim 1 , wherein the fibrotic liver disease is caused by inflammation of the liver; high deposition of lipids, high deposition of insoluble collagen; or high deposition of extracellular matrix components; or wherein the subject has cirrhosis, hepatocarcinoma, or end-stage liver disease caused by the fibrotic liver disease.
3. The method of claim 1 , further comprising determining the level of one or more of miR-26b, miR-122, miR-9, or miR-196b in a sample isolated from the subject prior or subsequent to the administration of the pharmaceutical composition.
4. The method of claim 1 , further comprising determining the expression level of one or more, or two or more, or 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, miR-21, miR-22, miR-24, miR-34a, miR-155, miR-195, miR-27a, miR-192, miR-214, miR-377, miR-455, miR-23b, miR-106a, miR-200b, miR-532, miR-34c, miR-26b, miR-122, miR-9, miR-196b, miR-151, miR-653, miR-687, miR-483, miR-1906, miR-677, miR-541, miR-125b, miR-500, miR-466j, miR-544, miR-1a-2, miR-1194, or miR-700, in a sample isolated from the subject prior or subsequent to the administration of the pharmaceutical composition.
5. The method of claim 1 , wherein the subject is a mammal.
6. The method of claim 1 , wherein the subject is a human.
7. The method 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.
8. The method of claim 1 , wherein the exosomes are allogeneic or autologous to the subject receiving the exosomes.
9. The method of claim 1 , wherein the exosomes further comprise the miR-122 level of the subject that is not diagnosed as having the fibrotic liver disease.
10. The method of claim 9 , wherein the exosomes further comprise the miR-9 level or the miR-196b level of the subject that is not diagnosed as having the fibrotic liver disease.
11. The method of claim 1 , wherein the exosomes further comprise the miR-9 or miR-196b level of the subject that is not diagnosed as having the fibrotic liver disease.
12. The method of claim 1 , wherein the exosomes further comprise the miR-9 level and the miR-196b level of the subject that is not diagnosed as having the fibrotic liver disease.
13. The method of claim 1 , wherein the exosomes further comprise the miR-122 level, the miR-9 level and the miR-196b level of the subject that is not diagnosed as having the fibrotic liver disease.
14. The method of claim 1 , wherein the exosomes further comprise a miR level of 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 sixteen or more, or seventeen or more, or all of miR-7a, miR-122, miR-1906, miR-21, miR-22, miR-24, miR-34a, miR-155, miR-195, miR-677, miR-541, miR-125b, miR-500, miR-466j, miR-544, miR-1a-2, miR-1194, or miR-700 of the subject that is not diagnosed as having the fibrotic liver disease.
15. The method of claim 1 , wherein the exosomes further comprise a miR level of 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 all of miR-27a, miR-192, miR-214, miR-377, miR-196b, miR-9, miR-455, miR-23b, miR-106a, miR-200b, miR-532, miR-34c, miR-151, miR-653, miR-687, or miR-483 of the subject that is not diagnosed as having the fibrotic liver disease.
16. The method of claim 1 , wherein the exosomes further comprise a miR level of 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 sixteen or more, or seventeen or more, or eighteen or more, nineteen or more, twenty or more, twenty one or more, twenty two or more, twenty three or more, twenty four or more, twenty five or more, twenty six or more, twenty seven or more, twenty eight or more, twenty nine or more, thirty or more, thirty one or more, thirty two or more, thirty three or more, or all of miR-7a, miR-122, miR-1906, miR-21, miR-22, miR-24, miR-34a, miR-155, miR-195, miR-677, miR-541, miR-125b, miR-500, miR-466j, miR-544, miR-1a-2, miR-1194, miR-700, miR-27a, miR-192, miR-214, miR-377, miR-196b, miR-9, miR-455, miR-23b, miR-106a, miR-200b, miR-532, miR-34c, miR-151, miR-653, miR-687, or miR-483 of the subject that is not diagnosed as having the fibrotic liver disease.
17. The method of claim 1 , wherein the pharmaceutically acceptable carrier comprises one or more of saline, glycerol, or PBS.
18. The method of claim 17 , wherein the pharmaceutically acceptable carrier further comprises a protease inhibitor.
19. The method of claim 1 , wherein the pharmaceutical composition is formulated for low temperature storage below about 70° C., freeze-drying or lyophilisation.