Nucleic acid aptamers to treat histone-induced disease states
Inventors
Giangrande, Paloma H. • Miller, Francis • Urak, Kevin
Assignees
Urak Kevin H • University of Iowa Research Foundation UIRF • US Department of Veterans Affairs
Publication Number
US-10633410-B2
Publication Date
2020-04-28
Expiration Date
2035-12-22
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Abstract
The present invention relates to methods of using optimized aptamers. In certain embodiments, the present invention provides a method for treating a subject having or being disposed to having a histone-induced injury or disease comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (i) a nucleic acid molecule not more than 90 nucleotides in length comprising an aptamer KU1, KU2, KU3, KU4, KU5, KU6, KU&, KU8, or KU9, wherein the aptamer specifically targets extracellular histones, wherein the nucleotides are RNA; or (ii) a conjugate comprising a nucleic acid molecule not more than 90 nucleotides in length comprising an aptamer KU1, KU2, KU3, KU4, KU5, KU6, KU&, KU8, or KU9, wherein the aptamer specifically targets extracellular histones, wherein the nucleotides are RNA, wherein the nucleic acid molecule is linked to a therapeutic molecule.
Core Innovation
The invention provides methods using optimized RNA aptamers specifically targeting extracellular histones, particularly histones H3 and H4, for the treatment and prevention of histone-induced injuries or diseases such as multiple organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS). These aptamers are short nucleic acid molecules, generally not more than 90 nucleotides in length, designed to bind with high affinity and specificity to extracellular histones and neutralize their harmful effects.
The problem addressed is the absence of effective therapies to prevent or reverse MODS and ARDS, which are significant causes of morbidity and mortality in critically ill patients. Current treatments are limited to supportive care, with no direct pharmacotherapy available to prevent the self-propagating cycle of histone-mediated tissue injury. Extracellular histones released during tissue injury mediate multiple mechanisms of cellular damage, inflammation, coagulation abnormalities, and organ dysfunction, leading to high mortality and prolonged recovery periods in affected patients.
The invention overcomes the limitations of existing approaches, such as TLR neutralizing antibodies and biologics with risks of bleeding or toxicity, by utilizing RNA aptamers that possess advantages including high stability, resistance to serum degradation, minimal immunogenicity, ease of chemical modification, and ability to specifically bind extracellular histones. The invention further provides methods of administration, including intravenous injection or inhalation, with compositions comprising pharmaceutically acceptable carriers, and optionally linked therapeutic molecules to improve pharmacokinetics or deliver additional therapeutic effects.
Claims Coverage
The claims include one independent method claim for binding extracellular histones H3 or H4 using a specific RNA aptamer or conjugate thereof, and one independent claim for contacting extracellular histones with the RNA aptamer. Below are the main inventive features extracted from these claims.
Use of specific RNA aptamers targeting extracellular histone H3 or H4
Administering to a subject a pharmaceutical composition comprising an RNA aptamer having at least 95% identity to KU7 (SEQ ID NO: 7741) that specifically targets extracellular histone H3 or H4.
Conjugate comprising the RNA aptamer linked to a therapeutic molecule
Administering a conjugate composition comprising the RNA aptamer (at least 95% identity to KU7) linked to a therapeutic molecule for targeted binding to extracellular histones H3 or H4.
Routes and timing of administration
The composition can be administered by intravenous injection or inhalation within 0-24 hours after injury or diagnosis of disease, including trauma, burn, transfusion-related acute lung injury, organ ischemia or infarction, or inhalation lung injury.
Treatment of diverse histone-induced diseases
The method applies to treating a range of diseases induced by histones including autoimmune diseases, arthritis, edema, sepsis, septic shock, inflammation, thrombosis, acute respiratory distress syndrome (ARDS), cardiovascular diseases, atherosclerosis, radiotherapy toxicity, and multiple organ dysfunction syndrome (MODS).
Modification of RNA aptamers for enhanced properties
The RNA aptamers comprise modified nucleotides such as 2′ substituted sugars (e.g., 2′-O-methyl, 2′-fluoro) and can include RNAi molecules to improve stability and binding characteristics.
Overall, the claims cover methods of using chemically modified RNA aptamers and their conjugates that specifically target extracellular histones H3 and H4 to treat histone-induced diseases, with defined administration routes, timing, and potential co-administration of other therapeutic agents.
Stated Advantages
The aptamers have significant advantages over other biologics including stability at room temperature, resistance to serum degradation, minimal immunogenicity, and the ability to be chemically modified to improve properties and nuclease resistance.
They can selectively bind histones with high affinity and specificity to interrupt the self-propagating histone-mediated tissue injury cycle responsible for MODS/ARDS, thereby potentially saving lives and reducing morbidity and financial costs.
The small size of aptamers allows for improved tissue penetration and dosing efficiency compared to antibodies.
Aptamers are easier and more economical to produce and do not require special handling, storage, or cold chain logistics, making them suitable for various clinical settings including military applications.
Documented Applications
Treatment and prevention of multiple organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) in critically ill patients suffering from trauma, burns, sepsis, transfusion-related acute lung injury, organ ischemia, inhalation injury, and other high-risk conditions.
Treatment or prophylaxis of histone-induced diseases including autoimmune diseases (e.g., systemic lupus erythematosus), arthritis, edema, sepsis, septic shock, inflammation, thrombosis, nephritis, inflammatory liver injury, acute pancreatitis, cardiovascular disease, atherosclerosis, radiotherapy and cytokine therapy toxicity, asthma, graft-versus-host disease, cachexia, coagulopathies, cancer, and related complications.
Use of aptamer conjugates for delivering therapeutic or diagnostic molecules targeting extracellular histones in these diseases.
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