Method of treating inflammatory lung disease with suppressors of CpG oligonucleotides
Inventors
KLINMAN, DENNIS M. • Yamada, Hiroshi
Assignees
US Department of Health and Human Services
Publication Number
US-8043622-B2
Publication Date
2011-10-25
Expiration Date
2023-10-07
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Abstract
The present disclosure relates to oligodeoxynucleotides that suppress an immune response. Methods are disclosed for inhibiting or treating inflammatory lung disease by administering a therapeutically effective amount of a suppressive oligodeoxynucleotide.
Core Innovation
The invention relates to the use of suppressive oligodeoxynucleotides (ODNs) that form G-tetrads to inhibit or treat inflammatory lung diseases by suppressing the immune response induced by CpG oligodeoxynucleotides. These suppressive ODNs are at least about 8 nucleotides in length, form a G-tetrad, have a circular dichroism (CD) value greater than about 2.9, and contain at least two guanosines. The suppressive ODNs can be administered locally, such as by inhalation, or systemically to treat diseases including pneumonia, acute respiratory distress syndrome (ARDS), respiratory distress of prematurity, chronic bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, and pulmonary sarcoidosis.
The problem being solved addresses the limitations of current therapies for inflammatory lung diseases, which are major causes of morbidity and mortality. Existing treatments for conditions like ARDS, such as monoclonal antibodies, corticosteroids, inhaled nitric oxide, and mechanical ventilation, have been largely unsuccessful or carry significant risks, including toxicity and complications. Inflammatory responses accompanying lung diseases are often more dangerous than the underlying infections or injuries. Therefore, there is a need for new therapeutic agents that specifically suppress lung inflammation associated with inflammatory lung diseases.
The disclosed methods provide the use of suppressive oligodeoxynucleotides that inhibit cytokine and chemokine production, reduce neutrophil infiltration, and decrease lung inflammation by interfering with the immune stimulation caused by CpG motifs. These suppressive ODNs form specific G-tetrad structures yielding unique physical properties and biological activities, allowing selective immune suppression without nonspecific immunosuppression or toxicity. They can be administered in various pharmaceutical formulations and delivery methods, providing clinical flexibility for treating inflammatory lung diseases in human and veterinary subjects.
Claims Coverage
The patent includes two independent claims that cover methods of reducing cytokine or chemokine production in subjects with inflammatory lung diseases and in cells using specific suppressive oligodeoxynucleotides. The claims define the structure, sequence, length, mode of administration, and use of these oligodeoxynucleotides and related combinations.
Use of suppressive oligodeoxynucleotides forming G-tetrads to reduce cytokine or chemokine production in subjects with inflammatory lung disease
Administering suppressive oligodeoxynucleotides comprising from 2 to 4 guanosine-rich sequences, forming G-tetrads, having sequences as SEQ ID NO: 1, 14, 17, 18, 19, or 21, and being 10 to 30 nucleotides in length to subjects with inflammatory lung diseases to reduce production of cytokines such as TNF, MIP-2, IL-6, or KC.
Various routes of administration of suppressive oligodeoxynucleotides
Administering the suppressive oligodeoxynucleotides via parenteral, oral, intravenous, intramuscular, subcutaneous, intranasal, intratracheal, or inhalation routes to treat inflammatory lung diseases.
Treatment of specific inflammatory lung diseases
Applying the suppressive oligodeoxynucleotide methods to treat acute respiratory distress syndrome, pneumonia, respiratory distress of prematurity, chronic bronchitis, COPD, cystic fibrosis, pulmonary fibrosis, and pulmonary sarcoidosis.
Use of specific nucleotide sequences in suppressive oligodeoxynucleotides
Employing suppressive oligodeoxynucleotides consisting of or comprising sequences SEQ ID NO: 1, 14, 17, 18, 19, or 21, with modifications to enhance stability and resistance to degradation, including phosphorothioate nucleotides.
Combination therapies with additional anti-inflammatory or respiratory agents
Administering an additional therapeutically effective anti-inflammatory agent or agents such as anti-infective agents, bronchodilators, enzymes, expectorants, leukotriene antagonists, leukotriene formation inhibitors, or mast cell stabilizers along with suppressive oligodeoxynucleotides.
Reduction of cytokine or chemokine production in cells in vitro
Contacting cells with suppressive oligodeoxynucleotides comprising specific sequences to reduce cytokine or chemokine production in vitro, targeting cytokines TNF-alpha, MIP-2, IL-6, or KC.
The independent claims cover the use of specific suppressive oligodeoxynucleotides that form G-tetrads and comprise defined nucleotide sequences, administered by various routes, including inhalation, to reduce inflammatory cytokines and chemokines in subjects and cells. The claims also address treatment of multiple inflammatory lung diseases and combinations with other therapeutic agents, emphasizing sequence specificity, molecular structure, and therapeutic application.
Stated Advantages
Suppressive oligodeoxynucleotides specifically inhibit lung inflammation induced by CpG motifs without nonspecific immunosuppression or toxicity.
The suppressive ODNs can be administered locally or systemically, providing flexible therapeutic options.
The methods reduce pro-inflammatory cytokines and chemokines and neutrophil infiltration, thus addressing harmful inflammation in lung diseases.
The ability to modify ODNs to increase stability and resistance to degradation enhances their therapeutic efficacy.
Documented Applications
Treatment, inhibition, or prevention of inflammatory lung diseases including pneumonia, acute respiratory distress syndrome (ARDS), respiratory distress of prematurity, chronic bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, and pulmonary sarcoidosis.
Reducing production of inflammatory cytokines (TNF, IL-6) and chemokines (MIP-2, KC) in subjects with inflammatory lung disease.
Reducing neutrophil infiltration in lung tissue of subjects with inflammatory lung disease.
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