Botulinum toxin cell binding domain polypeptides and methods of use for treatments of fibrosis associated disorders

Abstract

A polypeptide having an amino acid sequence corresponding to a binding domain of a botulinum toxin is described. The polypeptide modulates expression of genes involved in, for example, collagen production and extra cellular matrix organization, and finds use, therefore in treating or reducing the occurrence of a disease such as a disease of the ECM, a connective or epithelial tissue disease, an endothelial disease or a fibrotic disease, e.g., a fibrotic disease of the ECM, connective tissue, or endothelium. Nucleic acids encoding the polypeptide, as well as vectors, host cells, and systems comprising the nucleic acids, are further described.

1 . A method for treating and/or reducing the occurrence of an extracellular matrix (ECM) disease, connective tissue disease, endothelial disease or a fibrotic disorder in a subject in need thereof, comprising:
 administering to the subject a composition comprising an effective amount of a polypeptide having an amino acid sequence with at least about 90% sequence identity to a binding domain of a botulinum toxin, wherein the molecular weight of the polypeptide is between about 4 kDa to about 60 kDa, and wherein treating and/or reducing the occurrence of an ECM disease, connective tissue disease, endothelial disease or a fibrotic disorder does not involve paralysis of a target muscle.   
     
     
         2 . The method of  claim 1 , wherein the fibrotic disorder is selected from the group consisting of, dermal scars, wound scars, surgical scars, postoperative intraperitoneal adhesions, fibroma, liver fibrosis, cirrhosis, pancreatitis, benign prostatic hyperplasia, fibrotic bladder, interstitial cystitis, pulmonary fibrosis, kidney fibrosis, glomerulosclerosis, atrial fibrosis, endomyocardial fibrosis, glial scar, arterial stiffness, arthrofibrosis, cystic fibrosis, non-cystic fibrosis, crohn's disease, dupuytren's contracture, mediastinal fibrosis, myelofibrosis, peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, adhesive capsulitis, mixed connective tissue disease, ocular fibrosis, osteoarthritis, scleroderma, and asthma. 
     
     
         3 . The method of  claim 1 , wherein the fibrotic disorder is selected from the group consisting of fibrotic breast disease; keloid scar; liver fibrosis; fibrotic bladder; hyperplasia of fibrous tissue; pancreatitis; adhesion; scarring; or combinations thereof. 
     
     
         4 . The method of  claim 1 , wherein the subject is a human subject. 
     
     
         5 . The method of  claim 1 , wherein the molecular weight of the polypeptide is between about 10 kDa to about 60 kD. 
     
     
         6 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence with at least about 95% sequence identity to a binding domain of a botulinum toxin. 
     
     
         7 . The method of  claim 1 , wherein the botulinum toxin is selected from the group consisting of Botulinum toxin serotype A (BoNT/A), Botulinum toxin serotype B (BoNT/B), Botulinum toxin serotype C 1  (BoNT/C 1 ), Botulinum toxin serotype D (BoNT/D), Botulinum toxin serotype E (BoNT/E), Botulinum toxin serotype F (BoNT/F), Botulinum toxin serotype F (BoNT/FA), Botulinum toxin serotype G (BoNT/G), Botulinum toxin serotype H (BoNT/H), Botulinum D/C mosaic (BoNT/DC), Botulinum C/D mosaic (BoNT/CD), Botulinum toxin serotype X (BoNT/X), and  Enterococcus  sp. BoNT J (eBoNT/J). 
     
     
         8 . The method of  claim 1 , wherein the polypeptide comprises an amino acid sequence having at least 30% homology to a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 19, SEQ ID NOs: 3-5, SEQ ID NO: 6, SEQ ID NO: 20, SEQ ID Nos: 7-10, SEQ ID NO: 11, SEQ ID NO: 21, SEQ ID NOs: 12-18 and SEQ ID NOs: 25-27. 
     
     
         9 . The method of  claim 1 , wherein the polypeptide comprises, consists essentially of, or consists of a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 19, SEQ ID NOs: 3-5, SEQ ID NO: 6, SEQ ID NO: 20, SEQ ID Nos: 7-10, SEQ ID NO: 11, SEQ ID NO: 21, SEQ ID NOs: 12-18 and SEQ ID NOs: 25-27.