Methods and compositions relating to p62/SQSTM1 for the treatment and prevention of inflammation-associated diseases

Abstract

Provided herein are novel p62 compositions for the modulation of expression of a proinflammatory cytokines, osteogenic transcription factors, a bone resorptive factors and endogenous p62. Consequently, such p62 compositions are useful for prophylaxis and treatment of inflammatory diseases and related methods. In certain embodiments the inflammatory diseases are not cancer-related. In various embodiments, the inflammatory diseases include, but are not limited to osteoporosis, obesity, metabolic syndrome, type 2 diabetes, fat liver, inflammatory bowel disease, chronic pancreatitis, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), osteoarthritis, multiple sclerosis (MS), psoriasis, congestive heart failure (CHF), atherosclerosis, neurodegenerative diseases (ALS, Parkinson, Alzheimer's, Huntington disease), depression, schizophrenia, gout, asbestosis and silicosis.

1 - 27 . (canceled) 
     
     
         28 . A method to treat, alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce severity of, or reduce incidence of one or more symptoms of a non-cancer-related chronic inflammatory disease in a subject comprising administering to said subject an agent comprising:
 a. at least 30 consecutive amino acids of a p62/SQSTM1 polypeptide;   b. a p62/SQSTM1 encoding nucleic acid, wherein said p62/SQSTM1 encoding nucleic acid encodes at least 30 consecutive amino acids of a p62/SQSTM1 polypeptide;   c. a p62/SQSTM1 polypeptide at least 90% identical to SEQ ID NO. 2;   d. a p62/SQSTM1 polypeptide with at least one or more domain deletions;   e. a p62/SQSTM1 nucleic acid that encodes a polypeptide at least 90% identical to SEQ ID NO: 2; or   f. a p62/SQSTM1 nucleic acid that encodes a polypeptide with at least one or more domain deletions;   
     
     
         29 . The method according to  claim 28 , wherein said agent comprises a p62/SQSTM1 polypeptide that is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous to SEQ. ID. NO. 2. 
     
     
         30 . The method according to  claim 28 , wherein said agent comprises a p62/SQSTM1 nucleic acid that encodes a polypeptide that is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology to SEQ. ID. NO. 2. 
     
     
         31 . The method according to  claim 28 , wherein said p62/SQSTM1 nucleic acid comprises the sequence of SEQ ID NO:1. 
     
     
         32 . The method according to  claim 28 , wherein said p62/SQSTM1 nucleic acid that encodes a polypeptide with at least one or more domain deletions comprises a domain deletion selected from the group consisting of: PB1, ZZ, NLS2, TB, NLS1, NES, LIR, KIR, and UBA. 
     
     
         33 . The method according to  claim 28 , wherein said agent comprises a p62/SQSTM1 nucleic acid and further comprises a plasmid, RNA or a viral vector. 
     
     
         34 . The method according to  claim 28 , wherein said p62/SQSTM1 polypeptide or p62/SQSTM1 encoding nucleic acid further comprises a fusion polypeptide or nucleic acid encoding for a fusion polypeptide, respectively. 
     
     
         35 . The method according to  claim 28 , wherein said agent comprises a vaccine. 
     
     
         36 . The method according to  claim 35 , further comprising administering an adjuvant to said subject. 
     
     
         37 . The method according to  claim 36 , wherein said adjuvant is selected from the group consisting of: gel-type, microbial, particulate, oil-emulsion, surfactant-based, and synthetic adjuvant. 
     
     
         38 . The method according to  claim 28 , wherein said non-cancer chronic inflammatory disease is selected from the group consisting of: obesity, metabolic syndrome, type 2 diabetes, fat liver, Crohn's Disease, pancreatitis, asthma, chronic obstructive pulmonary disease, arthritis, osteoporosis, osteoarthritis, multiple sclerosis, psoriasis, congestive heart failure, atherosclerosis, neurodegenerative disease, depression, schizophrenia, gout, asbestosis, and silicosis. 
     
     
         39 . The method according to  claim 38 , wherein said neurodegenerative disease is selected from the group consisting of: amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease. 
     
     
         40 . The method according to  claim 28 , further comprising administering an anti-inflammatory therapy to said subject. 
     
     
         41 . The method according to  claim 28 , wherein said agent comprises a p62/SQSTM1 encoding nucleic acid, further comprising a strategy for improving the efficiency of nucleic acid-based expression of p62/SQSTM1 in subjects. 
     
     
         42 . The method according to  claim 41 , wherein said strategy is selected from the group consisting of: including a self-replicating viral replicon, codon optimization, in vivo electroporation, incorporation of a CpG stimulatory motif, including a sequence for targeting of the endocytic or ubiquitin-processing pathways, including a Marek's disease virus type 1 VP22 sequence, a prime-boost regimen, a mucosal delivery vector, and a nucleic acid delivery system. 
     
     
         43 . The method according to  claim 42 , wherein said nucleic acid delivery system is selected from the group consisting of: a polymer gene delivery system, a liposomal delivery system, and a cell-penetrating peptide gene delivery system. 
     
     
         44 . The method according to  claim 28 , further comprising administering an anti-inflammatory chemotherapeutic or biological agent. 
     
     
         45 . The method according to  claim 44 , wherein said chemotherapeutic agent is selected from the group consisting of: a nonsteroidal anti-inflammatory drug, a glucocorticoid, methotrexate, cyclosporine, and rapamycin. 
     
     
         46 . The method according to  claim 45 , wherein said anti-inflammatory biological agent is selected from the group consisting of: an anti-TNF antibody, an anti-IL1 antibody, an anti-IL6 antibody, an anti-IL6 receptor antibody, an anti-IL12/23 antibody, an anti-IL17 antibody, an anti-IL1R antibody, an anti-IL1 receptor antagonist, and a soluble IL-1 receptor. 
     
     
         47 . A method to modulate in a subject the expression of:
 a. a proinflammatory cytokine;   b. an osteogenic transcription factor; or   c. a bone resorptive factor   
       comprising administering to said subject an agent comprising:
 a. at least 30 consecutive amino acids of a p62/SQSTM1 polypeptide; 
 b. a p62/SQSTM1 encoding nucleic acid, wherein said p62/SQSTM1 encoding nucleic acid encodes at least 30 consecutive amino acids of a p62/SQSTM1 polypeptide; 
 c. a p62/SQSTM1 polypeptide at least 90% identical to SEQ ID NO. 2; 
 d. a p62/SQSTM1 polypeptide with at least one or more domain deletions; 
 e. a p62/SQSTM1 nucleic acid that encodes a polypeptide at least 90% identical to SEQ ID NO: 2; or 
 f. a p62/SQSTM1 nucleic acid that encodes a polypeptide with at least one or more domain deletions; 
 
     
     
         48 . The method according to  claim 47 , wherein:
 a. said proinflammatory cytokine is selected from the group consisting of: TNFα, IL-6, IL-1b, RANTES, IL-17, IL-23, CCL-1, MCP-5, and CXCL2;   b. said osteogenic transcription factor is selected from the group of osterix and runx2; or,   c. said bone resorptive factor is selected from the group of TNFα and RANKL.