Nucleic acid aptamers to treat histone-induced disease states

Inventors

Giangrande, Paloma H.Miller, FrancisUrak, Kevin

Assignees

University of Iowa Research Foundation UIRFUS Department of Veterans Affairs

Publication Number

US-11680079-B2

Publication Date

2023-06-20

Expiration Date

2035-12-22

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Abstract

The present invention relates to optimized aptamers and methods of using these aptamers.

Core Innovation

The invention provides optimized nucleic acid aptamers, specifically RNA aptamers, that selectively bind extracellular histones H3 and H4 with high affinity to prevent and treat the development of multiple organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) in high-risk patients. These aptamers interrupt the self-propagating cycle of tissue injury caused by extracellular histones, thereby potentially saving lives and reducing morbidity and financial costs associated with severe illnesses.

The problem addressed is the lack of effective pharmacotherapy to prevent or reverse MODS and ARDS, syndromes commonly developing in critically ill patients following trauma, sepsis, burns, ischemia-reperfusion injury, and other severe conditions. Current treatments are mainly supportive; high mortality and significant morbidity persist, and existing biologics show limitations such as toxicity, risk of bleeding, and storage challenges. Extracellular histones have been identified as mediators of tissue injury and inflammation, promoting endothelial damage, platelet aggregation, and pro-coagulant states, but no prior methods effectively neutralize histone-mediated damage.

Claims Coverage

The patent includes eight main inventive features corresponding to independent claims involving nucleic acid aptamers targeting extracellular histones and their therapeutic applications.

Nucleic acid molecule comprising an aptamer selectively binding histones H3 and H4

A nucleic acid molecule not more than 90 nucleotides long that includes an aptamer sequence with at least 95% sequence identity to KU5, KU7, or KU9, specifically binding extracellular histone 3 (H3) and histone 4 (H4) with high affinity.

Incorporation of modified nucleotides in aptamer

The nucleic acid molecule comprises one or more chemically modified nucleotides including 2′-O-methyl, 2′-fluoro, and others that enhance stability and binding properties.

Specific chemical modifications to improve stability and function

The modified nucleotides include specific sugar and base substitutions such as 2′-O-(2-methoxyethyl), 2′-fluoro pyrimidines, Locked nucleic acids (LNA), and phosphorothioate backbones to increase nuclease resistance and serum stability.

Conjugation of aptamer to therapeutic molecule

A conjugate wherein the nucleic acid aptamer is linked to a therapeutic molecule, including RNA interference (RNAi) molecules like siRNA or miRNA, for enhanced therapeutic effect.

Pharmaceutical composition containing the aptamer

A pharmaceutical composition comprising the nucleic acid aptamer molecule and a pharmaceutically acceptable carrier suitable for administration.

Method of treating histone-induced diseases via administration of the aptamer composition

A method of treating subjects having histone-induced injury or disease by administering the aptamer-containing pharmaceutical composition.

Routes and timing of administration

Administration of the composition by intravenous injection or inhalation, with timing within 0 to 24 hours after injury or diagnosis to prevent or treat histone-mediated injury.

Treatment of a broad range of histone-induced disease states

Treatment applications include autoimmune diseases, arthritis, sepsis, acute respiratory distress syndrome, ischemic injuries, cardiovascular diseases, cancer, multiple organ dysfunction syndrome (MODS)/ARDS, and other histone-related complications.

The claims comprehensively cover nucleic acid aptamers specifically targeting extracellular histones H3 and H4, their chemical modifications, conjugation to therapeutic agents, pharmaceutical compositions containing them, and methods for treating a variety of histone-induced disease states with specified administration routes and timing.

Stated Advantages

The aptamers offer high binding affinity and specificity for histones H3 and H4 with stability at room temperature and resistance to serum degradation.

They provide minimal immunogenicity compared to protein biologics, reducing the risk of allergic reactions.

Aptamers can be chemically modified to improve pharmacokinetic and pharmacodynamic properties, enhancing in vivo stability and efficacy.

They enable interruption of the self-propagating cycle of histone-induced tissue injury, potentially reducing morbidity, mortality, and associated healthcare costs in MODS/ARDS and related diseases.

Aptamers are easier and more economical to produce and store, tolerating conditions that limit the use of antibodies or recombinant proteins, and avoiding cold chain requirements.

The technology facilitates rapid advancement into preclinical and clinical testing due to the conservation of histones across species and cross-species compatibility of aptamers.

Documented Applications

Treatment and prevention of multiple organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) in critically ill patients.

Therapy for diseases and injuries involving extracellular histone-mediated tissue damage such as trauma, sepsis, burns, ischemia-reperfusion injury, toxic inhalation, and transfusion-related acute lung injury.

Treatment of autoimmune and auto-inflammatory disorders including systemic lupus erythematosus, rheumatoid arthritis, and juvenile arthritis.

Treatment of inflammation-related and thrombotic conditions including sepsis, septic shock, thrombosis, nephritis, inflammatory liver injury, and coagulopathies.

Therapeutic use in cardiovascular disease, atherosclerosis, myocardial infarction, ischemic stroke, and granulomatous diseases.

Treatment of complications from radiotherapy toxicity, cytokine therapy toxicity, graft-versus-host disease, cachexia, cancer, and burn effects.

Use as diagnostic or therapeutic agents linked to other molecules for improved delivery or detection in histone-induced disease states.

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