Methods of treating sepsis using anti-sepsis lipid a (ASLA) based therapeutics
Inventors
Ernst, Robert K. • Harberts, Erin M. • Scott, Alison J.
Assignees
University of Maryland Baltimore
Publication Number
US-12295965-B2
Publication Date
2025-05-13
Expiration Date
2037-10-04
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Abstract
The present invention provides a method of treating sepsis in a subject, comprising administering to the subject an effective amount of a compound of the formulawherein R1 and R2 may be H, OH, protonated phosphate, a phosphate salt, a sugar phosphonate, or a mono-, di- or poly-saccharide,R3 may be OH or a mono-, di- or poly-saccharide,R4, R5, R6 and R7 may be an alkyl or alkenyl chain of up to 13 carbons (for a chain of 16 carbons), andR8, R9, R10 and R11 may be H, OH, or an alkyl or alkenyl ester of up to 16 carbons, or a salt thereof.
Core Innovation
The invention provides anti-sepsis lipid A (ASLA) based therapeutic compounds, pharmaceutical compositions, and methods of using these compounds to treat and prevent sepsis in a subject. Specifically, it discloses compounds with a specific chemical formula that can include various substitutions for R1–R11, such as H, OH, phosphate groups, sugar phosphonates, and alkyl or alkenyl chains up to certain lengths, or salts thereof. The invention includes methods for both therapeutic and prophylactic administration of these compounds to subjects at risk for or suffering from sepsis.
The problem addressed by the invention is the high mortality rate and significant complications associated with sepsis, which arises from overwhelming inflammatory response, particularly mediated by the interaction of lipopolysaccharide (LPS), and more specifically, its lipid A component, with the host's innate immune system through the MD2/TLR4 complex. Existing treatments have not been effective in reducing sepsis mortality, partly due to the inability of synthetic molecules to sufficiently mimic natural LPS interactions that drive the disease.
This invention introduces rationally designed anti-sepsis lipid A molecules that act as competitive inhibitors of pro-inflammatory lipid A binding to the MD2/TLR4 complex, potentially blocking the cascade of harmful immune activation. These ASLA compounds can be produced using genetically engineered Gram-negative bacteria, such as engineered Yersinia pestis strains, employing bacterial enzymatic combinatorial chemistry (BECC) to tailor structural features that minimize pro-inflammatory signaling. The technology enables efficient, scalable production of ASLA compounds for use in treating or preventing sepsis, by directly interfering with the molecular trigger of inflammatory signaling in sepsis.
Claims Coverage
There is one independent claim in the patent that defines the main inventive features related to methods of treating and reducing sepsis using ASLA-based therapeutics.
Method of treating and reducing sepsis with ASLA compounds
A method for treating and reducing the incidence and/or severity of sepsis in a subject by administering an effective amount of a compound selected from a defined group of ASLA lipid A-based therapeutics. The therapeutic compounds are structurally characterized and may include specific modifications as described. Key inventive elements include: - Selecting ASLA compounds from the disclosed group with specified structural features. - Administration of these compounds to a subject suffering from or at risk of sepsis. - Administration routes include intraperitoneal, intraarterial, and intravenous methods. - Applicable for sepsis attributed to Gram-negative microorganism infection, or sepsis associated with SIRS or MODS. - The dosage for administration is specified to be between about 2 mg/kg and about 30 mg/kg of subject body weight.
The claims broadly cover a method of treating or reducing sepsis severity using administration of rationally designed ASLA compounds with specific structural attributes, routes, dosages, and indications, particularly for Gram-negative infection-related sepsis.
Stated Advantages
The invention enables protection from lethal sepsis both prophylactically and therapeutically by interfering with TLR4:lipid A binding events, leading to competitive inhibition of pro-inflammatory lipid A and reduction of clinical symptoms associated with sepsis.
ASLA molecules can be efficiently and inexpensively produced using engineered bacteria, allowing for the rapid and scalable generation of structurally tailored therapeutics.
Administration of ASLA therapeutics reduces pathological inflammatory responses, such as cytokine storm, and decreases clinical markers including pro-inflammatory cytokines and tissue injury markers in treated subjects.
ASLA compounds have demonstrated capability to rescue mice from lethal endotoxic shock, and offer potential treatment for sepsis across a wide range of Gram-negative bacterial infections.
Documented Applications
Treatment and prevention of sepsis, including severe sepsis, septic shock, SIRS, and MODS in subjects at risk or suffering from sepsis.
Therapeutic and prophylactic administration to both human and animal subjects, including veterinary uses for domestic animals and birds.
Administration to subjects with or at risk of Gram-negative bacterial infections, such as during combat wound care, surgical procedures, or antibiotic treatment of infections, to prevent onset of sepsis.
Combination therapies with antibiotics and/or vasoactive agents for enhanced management of sepsis.
Screening and identification of novel anti-sepsis compounds using BECC method in genetically engineered bacteria.
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