Compositions and their uses directed to il-4r alpha

a technology of compositions and alpha, applied in the field of compositions and their uses directed to il-4r alpha, can solve the problems of less control of moderate and severe asthma, less effective total asthma control, and scarring and remodeling of airways,

Inactive Publication Date: 2007-07-12
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In asthma, the pathology manifests as inflammation, mucus overproduction, and reversible airway obstruction which may result in scarring and remodeling of the airways.
However, moderate and severe asthma are less well controlled, and require daily treatment with more than one long-term control medication to achieve consistent control of asthma symptoms and normal lung function.
Although LABA can decrease dependence on corticosteroids, they are not as effective for total asthma control as corticosteroids (e.g., reduction of episodes, emergency room visits) (Lazarus et al., JAMA.
Severe asthmatics often suffer from chronic symptoms, including night time symptoms; limitations on activities; and the need for emergency room visits.
Additionally, chronic corticosteroid therapy at any level has a number of unwanted side effects, especially in children (e.g., damage to bones resulting in decreased growth).
Antihistamines are utilized to block itching and sneezing and many of these drugs are associated with side effects such as sedation and performance impairment at high doses.
Decongestants frequently cause insomnia, tremor, tachycardia, and hypertension.
Nasal formulations, when taken improperly or terminated rapidly, can cause rebound congestion.
Anticholinergics and montelukast have substantially fewer side effects, but they also have limited efficacy.
Similarly, prescription medications are not free of side effects.
Nasal corticosteroids can be used for prophylaxis or suppression of symptom

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Cell Types

[0097] The effect of oligomeric compounds on target nucleic acid expression was tested in the following cell types.

A549:

[0098] The human lung carcinoma cell line A549 was obtained from the American Type Culture Collection (Manassas, Va.). A549 cells were routinely cultured in DMEM, high glucose (Invitrogen Life Technologies, Carlsbad, Calif.) supplemented with 10% fetal bovine serum, 100 units per ml penicillin, and 100 micrograms per ml streptomycin (Invitrogen Life Technologies, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached approximately 90% confluence. Cells were seeded into 96-well plates (Falcon-Primaria #3872) at a density of approximately 5000 cells / well for use in oligomeric compound transfection experiments.

b.END:

[0099] The mouse brain endothelial cell line b.END was obtained from Dr. Werner Risau at the Max Plank Institute (Bad Nauheim, Germany). b.END cells were routinely cultured in DMEM, high glucose (...

example 2

Real-Time Quantitative PCR Analysis of IL 4R-α mRNA Levels

[0105] Quantitation of IL 4R-α mRNA levels was accomplished by real-time quantitative PCR using the ABI PRISM™ 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer's instructions.

[0106] Prior to quantitative PCR analysis, primer-probe sets specific to the target gene being measured were evaluated for their ability to be “multiplexed” with a GAPDH amplification reaction. After isolation the RNA is subjected to sequential reverse transcriptase (RT) reaction and real-time PCR, both of which are performed in the same well. RT and PCR reagents were obtained from Invitrogen Life Technologies (Carlsbad, Calif.). RT, real-time PCR was carried out in the same by adding 20 μL PCR cocktail (2.5×PCR buffer minus MgCl2, 6.6 mM MgCl2, 375 μM each of dATP, dCTP, dCTP and dGTP, 375 nM each of forward primer and reverse primer, 125 nM of probe, 4 Units RNAse inhibitor, 1.25 Uni...

example 3

Antisense Inhibition of Mouse IL-4R Alpha by Oligomeric Compounds

[0111] A series of oligomeric compounds was designed to target different regions of mouse IL 4R-α RNA, using published sequences cited in Table 1. The compounds are shown in Table 3. All compounds in Table 3 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of 10 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′) by five-nucleotide “wings”. The wings are composed of 2′-O-(2-methoxyethyl) nucleotides, also known as 2′-MOE nucleotides. The internucleoside (backbone) linkages are phosphorothioate throughout the oligonucleotide. All cytidine residues are 5-methylcytidines. The compounds were analyzed for their effect on gene target mRNA levels by quantitative real-time PCR as described in other examples herein, using the target-specific primers and probes shown in Table 2. Data are averages from two experiments in which b.END cells were treated w...

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Abstract

Disclosed herein are compounds, compositions and methods for modulating the expression of IL-4R alpha in a cell, tissue or animal. Also provided are methods of target validation. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders related to expression of IL 4R-α, airway hyperresponsiveness, and/or pulmonary inflammation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application Ser. Nos. 60 / 656,760, filed Feb. 25, 2005; 60 / 688,897, filed Jun. 9, 2005; 60 / 700,656, filed Jul. 19, 2005; and 60 / 709,404 filed Aug. 18, 2005; all of which are incorporated herein by reference in their entirety.INCORPORATION OF SEQUENCE LISTING [0002] A copy of the sequence listing in both a paper and a computer-readable form is provided herewith and hereby incorporated by reference. The computer readable form is provided on 3.5″ diskette containing the file named RTS0792WOSEQ.txt BACKGROUND OF THE INVENTION [0003] Allergic rhinitis and asthma are widespread conditions with complex and multifactorial etiologies. The severity of the conditions vary widely between individuals, and within individuals, dependent on factors such as genetics, environmental conditions, and cumulative respiratory pathology associated with duration and severity of disease. Both diseases are...

Claims

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Application Information

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IPC IPC(8): A61K48/00C07F9/6533C07H21/02C12N15/113
CPCA61K38/00C12N15/1138C12N2310/11C12N2310/315C12N2310/321C12N2310/3525C12N2310/345C12N2310/3341C12N2310/341A61P11/00A61P11/02A61P11/06A61P11/08A61P29/00A61P37/08
Inventor KARRAS, JAMES G.GREGORY, SUSANFREIER, SUSAN M.DOBIE, KENNETH W.
Owner IONIS PHARMA INC
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