Patent CA-2330022-A1 (CA)
Title: Low adenosine anti-sense oligonucleotide, compositions, kit and method for treatment of airway disorders associated with bronchoconstriction, lung inflammation, allergy(ies) and surfactant depletion
Inventor: NYCE JONATHAN W
IPC: A61P37/08
Filed: 2000-03-24
Abstract: An in vivo method of selectively delivering a nucleic acid to a target gene or mRNA, comprises the topical administration, e.g. to the respiratory system, of a subject of a therapeutic amount of an oligonucleotide (oligo) that is anti - sense to the initiation codon region, the coding region, the 5' or 3' inton- exon junctions or regions within 2 to 10 nucleotides of the junctions of the  gene or antisense to a mRNA complementary to the gene in an amount effective  to reach the target polynucleotide and reducing or inhibiting expression. In  addition a method of treating and adenosine mediated effect, comprises topically administering to a subject an anti-sense oligo in an amount effective to treat the respiratory, pulmonary, or airway disease. In order t o minimize triggering adenosine receptors by their metabolism, the administere d oligos have a low content of or are essentially free of adenosine. A pharmaceutical composition and formulations comprise the oligo anti-sense to  an adenosine receptor, genes and mRNAs encoding them, genomic and mRNA flanking regions, intron and exon borders and all regulatory and functionall y related segments of the genes and mRNAs encoding the polypeptides, their sal ts and mixtures. Various formulations contain a requisite carrier, and optional ly other additives and biologically active agents. The low adenosine or adenosi ne free (des-A) agent for practicing the method of the invention may be prepare d 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 t o 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 i n the anti-sense oligonucleotides with a "Universal or alternative base". The agent, composition and formulations are used for prophylactic, preventive an d therapeutic treatment of ailments associated with impaired respiration, lung  allergy(ies) and/or inflammation and depletion lung surfactant or surfactant  hypoproduction, such as pulmonary vasoconstriction, inflammation, allergies,  allergic rhynitis, asthma, impeded respiration, lung pain, cystic fibrosis, bronchoconstriction. 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. Alternatively, the present agent is effectively administered prophylactically or therapeutically by itself for conditions without known therapies or as a substitute for therapies exhibiting undesirable side effects. The treatment of this invention may be administered directly into t he respiratory system of a subject so that the agent has direct access to the lungs, or by other effective routes of administration, e.g. topically, transdermally, by implantation, etc., in an amount effective to reduce or inhibit the symptoms of the ailment.