Methods and compositions relating to p62/SQSTM1 for the treatment and prevention of inflammation-associated diseases
Inventors
Shneider, Alexander • Venanzi, Franco • Agas, Dimitrios • Concetti, Antonio • Sabbieti, Maria Giovanna • Gabai, Vladimir • Sherman, Michael • Shifrin, Victor
Assignees
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Publication Number
US-11098098-B2
Publication Date
2021-08-24
Expiration Date
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.
Core Innovation
The invention relates to p62/SQSTM1-based compositions for suppressing proinflammatory cytokine expression in a subject. The disclosed agents include p62 polypeptides and p62-encoding nucleic acids, including p62/SQSTM1 variants and deletions, and are described as modulating proinflammatory cytokines and related factors.
The invention addresses non-cancer-related chronic inflammatory diseases by preventing and treating inflammatory disease processes through p62/SQSTM1-linked modulation of proinflammatory cytokines. The partial content states that p62 regulates NF-κB/Stat-3-related pathways and autophagy, which is connected to cytokine suppression and inflammatory signaling changes.
The disclosed therapeutic approach is framed as suppressing expression of proinflammatory cytokines, with examples including TNFα, IL-6, IL-1β, IL-17, IL-23, CCL-1/MCP-5, and CXCL2. The partial content further describes downregulation of NF-κB/NF-κB signaling and summarizes therapeutic and preventive effects in mouse models for conditions including osteoporosis, ALS, MS, and metabolic/inflammatory disease models.
Claims Coverage
The independent claim covers a p62/SQSTM1 nucleic acid treatment method for neurodegenerative diseases that are non-cancer-related chronic inflammatory diseases, where the nucleic acid encodes a polypeptide at least 90% identical to SEQ ID NO: 2 and suppresses expression of a proinflammatory cytokine. The claim language includes 4 neurodegenerative disease options and specifies the agent’s relationship to cytokine suppression.
p62/SQSTM1 nucleic acid for treating neurodegenerative chronic inflammatory disease
Administering to a subject an agent comprising p62/SQSTM1 nucleic acid that encodes a polypeptide at least 90% identical to SEQ ID NO: 2.
Cytokine suppression by the p62/SQSTM1 nucleic acid agent
The agent suppresses the expression of a proinflammatory cytokine in a subject.
Neurodegenerative disease selection for non-cancer-related chronic inflammatory disease
Treating a non-cancer-related chronic inflammatory disease selected from amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease.
Across the independent claim, the core inventive coverage is a method of treating non-cancer-related chronic inflammatory neurodegenerative diseases by administering a p62/SQSTM1 nucleic acid encoding a SEQ ID NO: 2–like polypeptide (at least 90% identical) that suppresses expression of a proinflammatory cytokine.
Stated Advantages
Suppresses expression of a proinflammatory cytokine in a subject.
Treating, alleviating, ameliorating, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms of a non-cancer-related chronic inflammatory disease.
Documented Applications
Preventing and treating non-cancer-related chronic inflammatory diseases using p62/SQSTM1-based compositions, with examples including osteoporosis, ALS, MS, and metabolic/inflammatory disease models.
Application to neurodegenerative diseases described as non-cancer-related chronic inflammatory diseases, including ALS, Parkinson’s, Huntington’s, Alzheimer’s, and related neurodegenerative diseases mentioned in the partial content.
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