Low adenosine anti-sense oligonucleotide agent, composition, kit and treatments
Nyce, Jonathan W.
A composition comprises a nucleic acid comprising an oligo anti-sense to a target such as polypeptide(s) associated with an ailment afflicting lung airways, genes and mRNAs encoding them, genomic and mRNA flanking regions, intron and exon borders and all regulatory and functionally related segments of the genes and mRNAs encoding the polypeptides, their salts and mixtures. Various formulations contain a requisite carrier, and optionally other additives and biologically active agents. The agent of the invention may be prepared by selecting a target gene(s), genomic flanking region(s), RNA(s) and/or polypeptide(s) associated with a disease(s) or condition(s) afflicting lung airways, obtaining the sequence of the mRNA(s) corresponding to the target gene(s) and/or genomic flanking region(s), and/or RNAs encoding the target polypeptide(s), selecting at least one segment of the mRNA which may be up to 60 % free of thymidine (T) and synthesizing one or more anti-sense oligonucleotide(s) to the mRNA segments which are free of adenosine (A) by substituting a universal base for A when present in the oligonucleotide. The agent may be prepared by selection of target nucleic acid sequences with GC running stretches, which have low T content, and by optionally replacing A in the anti-sense oligonucleotides with a AUniversal base@. The agent, composition and formulations are used for prophylactic, preventive and therapeutic treatment of ailments associated with impaired respiration, allergy(ies) and/or inflammation, such as pulmonary vasoconstriction, inflammation, allergies, asthma, impeded respiration, lung pain, cystic fibrosis, bronchoconstriction, pulmonary hypertension and bronchoconstriction, chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), ischemic conditions including ischemia itself, and cancers such as leukemias, lymphomas, carcinomas, and the like, e.g. colon cancer, breast cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, kidney cancer, melanoma, hepatic metastasis, etc., as well as all types of cancers with may metastasize or have metastasized to the lung(s), including breast and prostate cancer. The present treatment is suitable for administration in combination with other treatments, e.g. before, during and after other treatments, including radiation, chemotherapy, antibody therapy and surgery, among others. The present agent is effectively administered preventatively, prophylactically or therapeutically by itself for conditions without known therapies, or as a substitute for, or in conjunction with, other therapies exhibiting undesirable side effects. The treatment of this invention may be administered directly into the respiratory system of a subject, so that the agent has direct access to the airways and the lungs.
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