Asthma associated factors as targets for treating atopic allergies including asthma and related disorders

a technology of asthma and associated factors, which is applied in the field of modulating activities associated with the il9 pathway for the treatment of atopic allergies and related disorders, can solve the problems of allergic inflammation, huge burden on health-care resources, damage to surrounding tissues, etc., and achieves the effects of increasing calcium-dependent chloride secretion, enhancing th2-associated responses, and increasing chloride secretion

Inactive Publication Date: 2009-03-12
HOLROYD KENNETH J +7
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]In a further embodiment, Applicants identify a disease state, which can be treated through the up-regulation of ICACC-1. Applicants provide a method for treating the defect in cAMP-mediated chloride secretion in cystic fibrosis airway epithelia by further increasing calcium-dependent chloride secretion through up-regulation of ICACC-1. This up-regulation of ICACC-1 resulting in increased chloride secretion and thus restoration of the cellular chloride gradient resulting in normal airway epithelial cell function. Applicants provide a method for treating inflammatory bowel disease (IBD) with local delivery of ICACC-1 via gene therapy or up regulation of ICACC-1 to enhance TH2-associated responses for suppressing the TH1-associated IBD autoimmune disease.

Problems solved by technology

While the battle against foreign entities may be necessary for the body's survival, some defense systems respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing battle.
Activation of the immune system by these antigens leads to allergic inflammation and may occur after ingestion, penetration through the skin or after inhalation.
Thus, an enormous burden is placed on health-care resources.
Both the diagnosis and treatment of these disorders are problematic (Gergen et al., 1992).
The assessment of inflamed lung tissue is often difficult and frequently the source of the inflammation cannot be determined.
It is now generally accepted that failure to control pulmonary inflammation leads to significant loss of lung function over time.
In addition, constant use of β agonists results in desensitization which reduces their efficacy and safety (Molinoff et al., 1995).
Second, differences in expression of the murine IL-9 candidate gene are associated with biologic variability in bronchial responsiveness.
It does not adequately compensate for this defect, however, because normal chloride gradients are not maintained.

Method used

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  • Asthma associated factors as targets for treating atopic allergies including asthma and related disorders
  • Asthma associated factors as targets for treating atopic allergies including asthma and related disorders
  • Asthma associated factors as targets for treating atopic allergies including asthma and related disorders

Examples

Experimental program
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Effect test

example 1

cDNA Difference Analysis of IL-9 Expressed Genes

[0138]Lungs extracted from transgenic IL-9 mice (Tg5) were used to isolate IL-9 induced genes. Tg5 is a FVB mouse overexpressing the IL-9 gene as previously described (Renauld et al., 1994). This strain has been shown to overexpress IL-9 in most tissues of the mouse. In order to identify specific IL-9 induced genes, suppressive PCR cDNA difference analysis was performed on mRNA from lungs of Tg5 mice and parental FVB mice using a commercially available PCR-select cDNA subtraction kit (Clonetech).

[0139]cDNA synthesis. Total RNA was prepared from lungs of FVB and Tg5 mice using Trizol as described by the manufacturer (Gibco / BRL). Lungs were removed from euthanized mice and frozen in liquid nitrogen. Frozen lungs were then placed in Trizol and pulverized using a tissue grinder. Polyadenylated RNA was purified from total RNA with oligo(dT) cellulose columns (Pharmacia). Double stranded cDNA was prepared using Superscript II reverse transcr...

example 2

Identification of the Murine ICACC-1 cDNA in the Lung of IL-9 Transgenic Mice

[0141]ICACC-1 probes as described in Example 1 were used to probe a murine lung cDNA library (Clonetech) according to the manufacturers recommendation. One million recombinant clones were screened and several overlapping phage were identified. Subsequent screens enabled identification and isolation of a single plaque containing a phagemid which was then transformed into a double-stranded plasmid by phage rescue according to the manufacturers protocol. Recombinant clones were prepared and sequenced using primers directed to the plasmid vector as well as internal sequences identified from the partially subtracted probe. Clones were then aligned and contiged to generate the full-length sequence.

[0142]The 2931 bp cDNA isolated contained an open reading frame encoding a protein of 925 amino acids. FIG. 2 shows the nucleotide and amino acid sequence of the murine ICACC-1 cDNA. A nucleotide BLAST (Altschul et al.,...

example 3

ICACC-1 is Induced in vivo by IL-9 in Murine Cells

[0143]To confirm that ICACC-1 is induced by IL-9 in the lung, RNA from the lungs of Tg5 and FVB mice were isolated as described in Example 1. cDNA was generated using random hexamers (Pharmacia) and Superscript II (Gibco / BRL) as suggested by the manufacturer. Message was analyzed by PCR as described (Nicolaides et al., 1995) and via Northern blot. Primers used to generate murine ICACC-1 message were; sense 5′-CCAGATCCACACCAAAACGAGAAG-3′ (SEQ ID NO:7) (nucleotides 689-712) and antisense 5′-CACTGTCAAAGGTCACCATCCCGA-3′ (SEQ ID NO:8) (nucleotides 1041-1064) which produce a gene product of 376 bp. DHFR was assayed as an internal control to measure for cDNA integrity using primers previously described Nicolaides et al., 1991). Amplification conditions used were 95° C. for 30 seconds, 58° C. for 1.5 minutes and 72° C. for 1.5 minutes for 35 cycles. For Northern blot analysis, total RNA derived from Tg5 or FVB lungs was electrophoresed on 1....

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Abstract

A new gene in the calcium-activated chloride channel family has been discovered that is induced by IL-9, thereby providing a therapeutic target in IL-9 mediated development of atopic allergy, asthma-related disorders and cystic fibrosis. A method for the identification and use of small molecule inhibitors of this gene and its products to treat these disorders has also been discovered. The invention also includes a method for diagnosing susceptibility to, and assessing treatment of atopic allergy, asthma-related disorders by measuring the level of gene expression in biologic samples using antibody specific for this protein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 076,815 which was filed Mar. 3, 1998 and which is herein incorporated by reference in its entirety. This invention is also related to the subject matter of U.S. patent application Ser. Nos. 08 / 697,419; 08 / 697,360; 08 / 697,473; 08 / 697,472; 08 / 697,471; 08 / 702,105; 08 / 702,110; 08 / 702,168; and 08 / 697,440, all of which were filed on Aug. 23, 1996 and are incorporated herein by reference. This application is also related to U.S. patent application Ser. No. 08 / 980,872 which was filed Dec. 1, 1997 and which is incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to modulating activities associated with the IL-9 pathway for the treatment of atopic allergies and related disorders such as asthma.BACKGROUND OF THE INVENTION[0003]Inflammation is a complex process in which the body's defense system combats foreign entities. While the bat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07H21/00A61K31/56A61P11/06A61K31/7052C07K14/00G01N33/53A61K31/7088A61K38/00A61K38/20A61K45/00A61P1/00A61P11/00A61P37/08A61P43/00C07H21/04C07K14/705C12N15/09C12N15/12C12P21/08G01N33/68
CPCC07K14/705G01N33/6872A61K38/00Y10S977/927Y10S977/914G01N2500/00A61P1/00A61P11/00A61P11/06A61P37/08A61P43/00
Inventor HOLROYD, KENNETH J.LEVITT, ROY C.MALOY, W. LEELOUAHED, JAMILAMCLANE, MIKENICOLAIDES, NICHOLAS C.ZHOU, YUHONGDONG, CHARLES QU
Owner HOLROYD KENNETH J
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