Methods and compositions for treating microbial inflammation
Inventors
Hawiger, Jack Jacek • Zienkiewicz, Jozef • Veach, Ruth Ann • Liu, Yan • WYLEZINSKI, Lukasz
Assignees
US Department of Veterans Affairs • Vanderbilt University
Publication Number
US-11771739-B2
Publication Date
2023-10-03
Expiration Date
2038-06-18
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Abstract
Disclosed are compositions and methods for treating microbial inflammation including its end-stage sepsis and conditions associated with the microbial inflammation such as thrombocytopenia and hypoglycogenemia. In one aspect, the compositions and methods disclosed herein can also be used to enhance clearance of microbes from infected tissues, organs, or systems in a subject. Also disclosed herein are compositions and methods for reducing levels of stress responsible transcription factors and metabolic transcription factors in a cell in a subject with microbial inflammation.
Core Innovation
The invention provides compositions and methods for treating microbial inflammation, including its severe stage sepsis, and complications related to the microbial inflammation such as thrombocytopenia and hypoglycogenemia. It also encompasses enhancing the clearance of microbes from infected tissues, organs, or systems by administering Nuclear Transport Modifiers (NTMs). These NTMs reduce levels of stress responsive transcription factors (SRTFs) and metabolic transcription factors, specifically Sterol Regulatory Element Binding Proteins (SREBPs), in cells of subjects suffering from microbial inflammation.
The background of the invention recognizes microbial inflammation as a response to infections by various pathogens, which in severe cases leads to sepsis characterized by microvascular endothelial injury and multiple organ failure. Current antimicrobial therapies often fail to prevent the damaging genomic reprogramming in immune and non-immune cells, mediated by nuclear transport of SRTFs such as NF-κB, AP-1, NFAT, and STAT1α. This genomic storm activates proinflammatory genes causing endothelial dysfunction and septic shock, which is difficult to reverse with existing treatments.
The invention solves this problem by targeting nuclear transport checkpoints via NTMs that inhibit the nuclear import of multiple SRTFs and SREBPs, thereby suppressing the genomic storm and reducing inflammatory gene expression. This form of immunotherapy modulates intracellular signaling downstream of pattern recognition receptors, maintaining microvascular integrity and organ function while supporting microbial clearance. The disclosed peptide-based NTMs, including variants of the cSN50.1 peptide, penetrate cells efficiently to modulate importins alpha and beta, blocking nuclear delivery of transcription factors that mediate microbial inflammation.
Claims Coverage
The patent contains one independent claim outlining methods for treating microbial inflammation by administering an anti-microbial agent and a composition comprising specific Nuclear Transport Modifiers (NTMs).
Using Nuclear Transport Modifiers (NTMs) with anti-microbial agents to treat bacterial-caused microbial inflammation
A method comprising administering both an anti-microbial agent and a composition containing one or more NTMs having sequences selected from SEQ ID NO: 2, 5, 6, 7, 8, 9, or 16, specifically for treatment of microbial inflammation caused by bacterial infections excluding Bacillus anthracis.
Flexibility of administering anti-microbial agents either separately or combined with NTM compositions
The method encompasses embodiments where the composition with NTMs does not include the anti-microbial agent and embodiments where the composition does include the anti-microbial agent.
Treatment of various types and locations of microbial inflammation
The methods cover treating acute, subacute, chronic, organ-specific, systemic inflammation, or sepsis localized in diverse tissues and organs including blood, brain, aural cavities, sinuses, respiratory tract, lungs, heart, bone marrow, spleen, liver, kidneys, genito-urinary tract, bladder, stomach, intestines, skin, eyes, teeth, and gingiva.
Targeting a broad range of bacterial pathogens
The method is applicable to infections caused by a wide range of bacteria other than Bacillus anthracis, including Mycobacterium species, Salmonella species, Shigella species, Yersinia species, Staphylococcus species, Streptococcus species, Escherichia coli, Pseudomonas aeruginosa, Haemophilus species, Clostridium species, and others as specifically enumerated in the claims.
The claim covers inventive features directed to methods of treating bacterial microbial inflammation using NTMs with specific peptide sequences combined with anti-microbial agents, including flexibility in compositions, broad inflammation types and sites, and a wide range of bacterial pathogens excluding Bacillus anthracis.
Stated Advantages
Treatment with NTMs reduces nuclear translocation of multiple stress-responsive transcription factors leading to diminished inflammatory gene expression and microvascular injury.
NTM administration enhances clearance of infecting microbes from blood and organs even without direct microbicidal activity.
Combination of NTMs with antimicrobial agents significantly improves survival and extends time to death in polymicrobial sepsis models.
NTMs prevent thrombocytopenia associated with microbial inflammation, preserving platelet counts in blood.
NTMs prevent hypoglycogenemia by protecting liver glycogen stores during inflammatory responses.
Documented Applications
Treatment or prevention of microbial inflammation including acute, subacute, chronic, organ-specific inflammation, systemic inflammation, and sepsis caused by bacterial, viral, fungal, or parasitic infections in diverse tissues and organs.
Reducing microbial burden or enhancing clearance of microbes from blood, brain, sinuses, respiratory tract, lungs, heart, bone marrow, spleen, liver, kidneys, genito-urinary tract, bladder, aural cavities, stomach, intestines, skin, eyes, teeth, or gingiva.
Treatment of thrombocytopenia associated with microbial inflammation.
Treatment or prevention of hypoglycogenemia linked to microbial inflammation.
Use alone or in combination with antimicrobial agents including antibiotics and other therapeutic agents to enhance treatment efficacy in microbial infections.
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