Methods for treatment of and prophylaxis against inflammatory disorders

Abstract

An isolated and purified peptide, neonatal NET-inhibitory Factor (nNIF), is disclosed. Methods for treatment of and prophylaxis against inflammatory disorders are also disclosed, including methods of treatment of and prophylaxis against inflammatory disorders comprising administering NET-inhibitory peptides (NIPs), which may be a nNIF, a pharmaceutically acceptable salt of a nNIF, a nNIF analog, a pharmaceutically acceptable salt of a nNIF analog, a nNIF-Related Peptide (nNRP), including the nNRP, Cancer-Associated SCM-Recognition, Immune Defense Suppression, and Serine Protease Protection Peptide (CRISPP), a pharmaceutically acceptable salt of a nNRP, a nNRP analog, or a pharmaceutically acceptable salt of a nNRP analog, to an individual.

1 . A method for treating a patient having, or at risk of developing, an inflammatory disorder, comprising:
 administering to the patient an effective amount of a pharmaceutical composition comprising a NET-Inhibitory Peptide (NIP) and a pharmaceutically acceptable carrier to reduce a pathological effect or symptom of the inflammatory disorder, or to reduce the risk of developing the inflammatory disorder.   
     
     
         2 . The method of  claim 1 , wherein the NIP is one of a neonatal NET-Inhibitory Factor (nNIF), a pharmaceutically acceptable salt of a nNIF, a nNIF analog, a pharmaceutically acceptable salt of a nNIF analog, a nNIF-Related Peptide (nNRP), a pharmaceutically acceptable salt of a nNRP, a nNRP analog, or a pharmaceutically acceptable salt of a nNRP analog. 
     
     
         3 . The method of  claim 1 , wherein the inflammatory disorder is selected from the group consisting of an acute inflammatory disorder, a chronic inflammatory disorder, and an immune disorder. 
     
     
         4 . The method for  claim 1 , wherein the inflammatory disorder is an autoimmunity disorder. 
     
     
         5 . The method of  claim 1 , wherein the inflammatory disorder is selected from at least one of acute respiratory distress syndrome (ARDS), bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, inflammation in cancer, inflammatory bowel disease (IBD), inflammatory lung disease (ILD), influenza-induced pneumonitis, necrotizing enterocolitis (NEC), neonatal chronic lung disease (CLD), periodontitis, pre-eclampsia, retinopathy of prematurity (ROP), sepsis, systemic inflammatory response syndrome (SIRS), thrombosis, transfusion-related acute lung injury (TRALI), vasculitis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener's granulomatosis (WG), or a disorder of nonresolved inflammation. 
     
     
         6 . The method of  claim 5 , wherein the thrombosis is venous thrombosis. 
     
     
         7 . The method of  claim 5 , wherein the thrombosis in arterial thrombosis. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutical composition substantially inhibits NET-mediated inflammatory tissue damage. 
     
     
         9 . The method of  claim 1 , wherein the patient is human. 
     
     
         10 . A method of treating a patient having, or at risk of developing, a complication of prematurity, comprising:
 administering to the patient an effective amount of a pharmaceutical composition comprising a NET-Inhibitory Peptide (NIP) and a pharmaceutically acceptable carrier to reduce a pathological effect or symptom of the complication of prematurity, or to reduce the risk of developing the complication of prematurity.   
     
     
         11 . The method of  claim 10 , wherein the NIP is one of a neonatal NET-Inhibitory Factor (nNIF), a pharmaceutically acceptable salt of a nNIF, a nNIF analog, a pharmaceutically acceptable salt of a nNIF analog, a nNIF-Related Peptide (nNRP), a pharmaceutically acceptable salt of a nNRP, a nNRP analog, or a pharmaceutically acceptable salt of a nNRP analog 
     
     
         12 . The method of  claim 10 , wherein the complication of prematurity is selected from at least one of necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), pneumonia, bronchopulmonary dysplasia (BPD), neonatal chronic lung disease (CLD), neurodevelopmental delay, retinopathy of prematurity (ROP), or sepsis. 
     
     
         13 . The method of  claim 10 , wherein the pharmaceutical composition substantially inhibits NET-mediated inflammatory tissue damage. 
     
     
         14 . The method of  claim 10 , wherein the patient is human. 
     
     
         15 . A pharmaceutical composition, comprising:
 a NET-Inhibitory Peptide (NIP); and   a pharmaceutically acceptable carrier.   
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the NIP is one of a neonatal NET-Inhibitory Factor (nNIF), a pharmaceutically acceptable salt of a nNIF, a nNIF analog, a pharmaceutically acceptable salt of a nNIF analog, a nNIF-Related Peptide (nNRP), a pharmaceutically acceptable salt of a nNRP, a nNRP analog, or a pharmaceutically acceptable salt of a nNRP analog. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition comprises a nNIF, or the salt thereof, and wherein the nNIF, or the salt thereof, comprises the amino acid sequence (SEQ ID NO: 1):
 KAVLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNTKSPLFMGK VVNPTQK.   
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein at least one amino acid of the nNIF, the salt of the nNIF, the nNIF analog, the salt of the nNIF analog, the nNRP, the salt of the nNRP, the nNRP analog, or the salt of the nNRP analog, is bound to a chemical modifier, and
 wherein the chemical modifier is selected from at least one of a lipid, a polyethylene glycol (PEG), or a saccharide.   
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the nNIF, the salt of the nNIF, the nNIF analog, the salt of the nNIF analog, the nNRP, the salt of the nNRP, the nNRP analog, or the salt of the nNRP analog, is present in an amount effective to substantially inhibit damage selected from at least one of inflammatory tissue injury, or inflammatory vascular injury. 
     
     
         20 . The pharmaceutical composition of  claim 16 , wherein the nNIF, the salt of the nNIF, the nNIF analog, the salt of the nNIF analog, the nNRP, the salt of the nNRP, the nNRP analog, or the salt of the nNRP analog, does not globally depress polymorphonuclear leukocyte (PMN) function. 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein the nNIF, the salt of the nNIF, the nNIF analog, the salt of the nNIF analog, the nNRP, the salt of the nNRP, the nNRP analog, or the salt of the nNRP analog, does not substantially inhibit one or more activities of a polymorphonuclear leukocyte (PMN) selected from the group consisting of chemotaxis, chemokine synthesis and secretion, cytokine synthesis and secretion, extracellular bacterial killing, intracellular bacterial killing, phagocytosis, and reactive oxygen species (ROS) generation. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is chemotaxis. 
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is chemokine synthesis and secretion. 
     
     
         24 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is cytokine synthesis and secretion. 
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is extracellular bacterial killing. 
     
     
         26 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is intracellular bacterial killing. 
     
     
         27 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is phagocytosis. 
     
     
         28 . The pharmaceutical composition of  claim 21 , wherein the activity of the PMN is ROS generation. 
     
     
         29 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition comprises a nNIF analog, a salt of a nNIF analog, a nNRP analog, or a salt of a nNRP analog, and
 wherein the analog or the salt thereof is not a naturally occurring analog or salt thereof.   
     
     
         30 . The pharmaceutical composition of  claim 16 , wherein the nNIF, the salt of the nNIF, the nNIF analog, the salt of the nNIF analog, the nNRP, the salt of the nNRP, the nNRP analog, or the salt of the nNRP analog, is present in an amount effective to substantially inhibit neutrophil extracellular trap (NET) formation. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the NET formation is stimulated by at least one of a bacterium, a fungus, a parasite, or a virus. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the virus is a hemorrhagic fever virus. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein the virus is a filovirus. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the filovirus is Ebola virus. 
     
     
         35 . The pharmaceutical composition of  claim 33 , wherein the filovirus is Marburg virus. 
     
     
         36 . The pharmaceutical composition of  claim 31 , wherein the virus is an arenavirus. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the arenavirus is Lassa virus. 
     
     
         38 . The pharmaceutical composition of  claim 31 , wherein the virus is a hantavirus. 
     
     
         39 . The pharmaceutical composition of  claim 31 , wherein the virus is a flavivirus. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the flavivirus is dengue virus. 
     
     
         41 . The pharmaceutical composition of  claim 39 , wherein the flavivirus is yellow fever virus. 
     
     
         42 . The pharmaceutical composition of  claim 30 , wherein the NET formation is stimulated by at least one of a  Bacillus  species, an  Escherichia  species, a  Francisella  species, a  Staphylococcus  species, a  Streptococcus  species, or a  Yersinia  species. 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the  Bacillus  species is  Bacillus anthracis.    
     
     
         44 . The pharmaceutical composition of  claim 42 , wherein the  Escherichia  species is  Escherichia coli.    
     
     
         45 . The pharmaceutical composition of  claim 42 , wherein the  Francisella  species is  Francisella tularensis.    
     
     
         46 . The pharmaceutical composition of  claim 42 , wherein the  Staphylococcus  species is  Staphylococcus aureus.    
     
     
         47 . The pharmaceutical composition of  claim 30 , wherein the NET formation is stimulated by at least one of beta-defensin 1, HIV-1, lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or  Staphylococcus aureus  alpha-toxin. 
     
     
         48 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition comprises a nNRP or the salt thereof, and wherein the nNRP or the salt thereof is selected from at least one of a Cancer-Associated SCM-Recognition, Immune Defense Suppression, and Serine Protease Protection Peptide (CRISPP), or a CRISPP analog. 
     
     
         49 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition comprises a nNRP, and wherein the nNRP is an isolated and purified component of umbilical cord blood. 
     
     
         50 . A composition for inhibiting NET formation in a mammal, comprising:
 a NET-Inhibitory Peptide (NIP); and   a pharmaceutically acceptable carrier.   
     
     
         51 . The composition of  claim 50 , wherein the NIP is one of a neonatal NET-Inhibitory Factor (nNIF), a pharmaceutically acceptable salt of a nNIF, a nNIF analog, a pharmaceutically acceptable salt of a nNIF analog, a nNIF-Related Peptide (nNRP), a pharmaceutically acceptable salt of a nNRP, a nNRP analog, or a pharmaceutically acceptable salt of a nNRP analog, 
     
     
         52 . The composition of  claim 50 , wherein the mammal is human. 
     
     
         53 . An isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein comprising six or more contiguous amino acids of SEQ ID NO: 1. 
     
     
         54 . The isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein of  claim 53  comprising at least twelve contiguous amino acids of SEQ ID NO: 1. 
     
     
         55 . The isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein of  claim 53  comprising at least twenty-four contiguous amino acids of SEQ ID NO: 1. 
     
     
         56 . The isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein of  claim 53  comprising SEQ ID NO:1. 
     
     
         57 . An isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein, wherein a sequence of the nNIF protein is at least twenty percent identical to SEQ ID NO: 1. 
     
     
         58 . The isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein of  claim 57 , wherein the sequence is at least forty percent identical to SEQ ID NO: 1. 
     
     
         59 . The isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein of  claim 57 , wherein the sequence is at least sixty percent identical to SEQ ID NO: 1. 
     
     
         60 . The isolated and purified neonatal NET-Inhibitory Factor (nNIF) protein of  claim 57 , wherein the sequence is at least eighty percent identical to SEQ ID NO: 1.