Mesenchymal stem cell-derived extracellular vesicles and uses thereof for treating and diagnosing fibrotic diseases

Abstract

The described invention provides compositions and methods for treating a fibrotic condition in a subject. The methods include administering a therapeutic amount of a pharmaceutical composition comprising synthetic extracellular vesicles (EVs) and a pharmaceutically acceptable carrier.

1 .- 62 . (canceled) 
     
     
         53 . A precision medicine method for optimizing therapeutic benefit for a subject, comprising:
 a) obtaining a urine tissue or body fluid sample from the subject and from a healthy control;   b) isolating EVs from the urine tissue or body fluid sample obtained from the subject and healthy control;   c) measuring a level of expression of each of a plurality of miRNAs in the EVs from the urine sample from the subject and in the EVs from the urine sample from the healthy control;   d) determining that expression of the one or more of the miRNAs in the EVs from the subject is dysregulated compared to the healthy control;   e) identifying the patient as one that can benefit therapeutically from being treated for a fibrotic disease:
 (1) when the presence of one or more dysregulated miRNAs in the EVs from the tissue or body fluid sample obtained from the subject is detected; 
 (2) when an increase in levels of one or more WNT proteins in the EVs from the tissue or body fluid sample from the subject compared to the control is detected; or 
 (3) when the presence of one or more dysregulated miRNAs and an increase in levels of one or more WNT proteins in the EVs from the tissue or body fluid sample from the subject compared to the control is detected; and 
   f) tailoring an effective medical treatment for the fibrotic disease based on genetic, environmental and lifestyle factors.   
     
     
         54 . The method according to  claim 53 , wherein the dysregulated miRNAs comprise one or more of miR-134-5p, miR-196b-5p, miR-629-5p, miR-206, miR-192-5p, miR-320c, miR-125a-3p, miR-215-5p, miR-642a-3p, miR-576-3p, miR-3679-5p, miR-134-5p, miR-196b-5p, miR-629-5p, or miR-206. 
     
     
         55 . The method according to  claim 53 , wherein the one or more miRNAs is downregulated compared to the healthy control. 
     
     
         56 . The method according to  claim 53 , wherein the one or more miRNAs is upregulated compared to the healthy control. 
     
     
         57 . The method according to  claim 53 , wherein the EVs are characterized by: sedimentation at about 100,000×g, a buoyant density in sucrose of about 1.10-1.21 g/ml, and an average diameter of from 30 nm to about 200 nm. 
     
     
         58 . The method according to  claim 57 , wherein the average diameter of the EVs ranges from about 140 nm to about 150 nm. 
     
     
         59 . The method according to  claim 53 , further comprising the step of detecting a level of expression of one or more WNT proteins in the EVs from the tissue or body fluid sample and determining that expression of one or more of the WNT proteins in the tissue or body fluid sample from the subject is dysregulated compared to the healthy control. 
     
     
         60 . The method of  claim 53 , wherein the one or more WNT proteins comprise WNT-5A. 
     
     
         61 . The method according to  claim 53 , further comprising
 (g) obtaining a second body fluid sample from the subject and from the healthy control;   (h) detecting a level of expression of one or more biomarkers selected from KL-6/MUC1, SP-A, SP-D, CCL18, MMP-1, and MMP-7 in the second body fluid samples; and   (i) comparing the levels of expression of the one or more biomarkers in the second body fluid samples from the subject and from the healthy control;
 wherein an increase in the levels of the one or more biomarkers in the second body fluid sample from the subject compared to the healthy control indicates a poor prognosis in the subject. 
   
     
     
         62 . The method according to  claim 53 , further comprising the steps of obtaining a bronchoalveolar lavage fluid (BALF) sample from the subject and from the healthy control; isolating EVs from the BALF samples; detecting a level of expression of one or more WNT proteins in the EVs; and comparing the level of expression of the one or more WNT proteins in the EVs from the subject and from the healthy control; wherein an increase in the levels of the one or more WNT proteins in the EVs from the subject indicates the subject has a fibrotic disease. 
     
     
         63 . The method according to  claim 62 , wherein the one or more WNT proteins comprise WNT-5A. 
     
     
         64 . The method according to  claim 53 , wherein the fibrotic disease is selected from one or more of a fibrotic lung disease, a fibrotic cardiac disease, a fibrotic renal disease, a fibrotic hepatic disease, a fibrotic skin disease, a fibrotic pancreatic disease, a fibrotic eye disease, a fibrotic joint disease, a fibrotic bone marrow disease, a fibrotic brain disease, a fibrotic intestinal disease, a fibrotic peritoneum disease, a fibrotic retroperitoneum disease, a fibrotic condition of the nerves, a fibrotic condition of a nervous system, nerve compression, or injury due to fibrosis. 
     
     
         65 . The method according to  claim 64 , wherein the fibrotic disease is a fibrotic lung disease. 
     
     
         66 - 96 . (canceled) 
     
     
         97 . The method according to  claim 53 , wherein the tissue sample is a tissue autologous to the subject; a tissue allogeneic to the subject; or a placental tissue. 
     
     
         98 . The method according to  claim 97 , wherein the tissue sample is an adipose tissue, bone marrow, dental pulp, lung tissue, or heart tissue. 
     
     
         98 . The method according to  claim 97 , wherein the placental tissue is amniotic membrane, chorionic membrane or umbilical cord. 
     
     
         99 . The method according to  claim 98 , wherein
 (a) the adipose tissue is subcutaneous white adipose tissue; or   (b) the adipose tissue comprises adipose-derived stem cells.   
     
     
         100 . The method according to  claim 53 , wherein the body fluid is peripheral blood, serum, umbilical cord blood, amniotic fluid or urine. 
     
     
         101 . The method according to  claim 53 , wherein the body fluid is urine. 
     
     
         102 . The method according to  claim 61 , wherein the body fluid is peripheral blood or serum.