Variants of C-Type Natriuretic Peptide

Abstract

The present disclosure provides variants of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising CNP variants, and methods of making CNP variants. The CNP variants are useful as therapeutic agents for the treatment of diseases responsive to CNP, including but not limited to bone-related disorders, such as skeletal dysplasias (e.g., achondroplasia), and vascular smooth muscle disorders (e.g., restenosis and arteriosclerosis).

1 - 43 . (canceled) 
     
     
         44 . A variant of C-type natriuretic peptide (CNP) comprising the amino acid sequence LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 160). 
     
     
         45 . The CNP variant of  claim 44  further comprising a synthetic polymeric group. 
     
     
         46 . The CNP variant of  claim 45  wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. 
     
     
         47 . The CNP variant of  claim 46  wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). 
     
     
         48 . The CNP variant of claim of  46  wherein the hydrophilic polymeric moiety is coupled to the amino acid sequence through a stable linkage. 
     
     
         49 . The CNP variant of claim of  46  wherein the hydrophilic polymeric moiety is coupled to the amino acid sequence through a hydrolysable linkage. 
     
     
         50 . A pharmaceutical composition comprising a variant of C-type natriuretic peptide (CNP) consisting of the amino acid sequence LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 160) as the active agent. 
     
     
         51 . The pharmaceutical composition of  claim 50  further comprising a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         52 . A method of treating a bone-related disorder or skeletal dysplasia, comprising administering the pharmaceutical composition according to  claim 50  to a subject, wherein the administering treats the bone-related disorder or skeletal dysplasia. 
     
     
         53 . The method of  claim 52  wherein the bone-related disorder or skeletal dysplasia is achondroplasia and wherein administration treats achondroplasia. 
     
     
         54 . A method of increasing long bone growth comprising administering the pharmaceutical composition according to  claim 50  to a subject in need thereof, wherein the administering increases long bone growth. 
     
     
         55 . A method of increasing long bone growth comprising contacting chondrocytes of a subject in need thereof with an effective amount of a CNP variant having the amino acid sequence LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 160). 
     
     
         56 . The method of  claim 55  wherein the chondrocytes are located within a bone growth plate of the subject. 
     
     
         57 . The method of  claim 55  wherein the CNP variant binds to and activates natriuretic peptide receptor B (NPR-B) on the chondrocytes. 
     
     
         58 . A method of treating a bone-related disorder or skeletal dysplasia comprising contacting chondrocytes of a subject in need thereof with an effective amount of a CNP variant having the amino acid sequence LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 160). 
     
     
         59 . The method of  claim 58  wherein the chondrocytes are located within a bone growth plate of the subject. 
     
     
         60 . The method of  claim 58  wherein the CNP variant binds to and activates natriuretic peptide receptor B (NPR-B) on the chondrocytes. 
     
     
         61 . The method of  claim 58  wherein the bone-related disorder or skeletal dysplasia is achondroplasia.