Composition and method for the prevention, treatment and/or alleviation of an inflammatory disease
Inventors
Von Stein, Oliver • Hellström, Karin
Assignees
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Publication Number
US-8895522-B2
Publication Date
2014-11-25
Expiration Date
Abstract
A method for enhancing the clinical responsiveness to an anti-inflammatory therapy in a patient afflicted with an inflammatory condition, comprising administering an oligonucleotide having the sequence 5′-Xm-CG-Yn-3′ in an effective amount to said patient, and wherein X is A, T, C or G; Y is A, T, C or G; m=1-40; n=1-40 and wherein at least one CG dinucleotide is unmethylated. The invention also encompasses the use of such an oligonucleotide for the manufacture of a medicament for enhancing steroid efficacy in the treatment of a patient afflicted with an inflammatory condition.
Core Innovation
A method is provided for enhancing steroid efficacy in a steroid refractory patient afflicted with an airway inflammatory condition who is currently on steroid anti-inflammatory treatment but does not respond, responds poorly, or responds inadequately, or in a steroid dependent patient afflicted with an airway inflammatory condition who is currently on steroid anti-inflammatory treatment and responds adequately but is unable to be weaned off systemically or topically administered steroid treatment without increasing the severity of the airway inflammatory condition. The method comprises administering to the patient an oligonucleotide that alone does not provide effective treatment for the airway inflammatory condition in a patient that is not steroid refractory.
The oligonucleotide has the sequence 5′-X^m-CG-Y^n-3′, where X is A, T, C or G, Y is A, T, C or G, m=1-30, n=1-30, and the total length is 8-40 nucleotides. At least one CG dinucleotide is unmethylated. The oligonucleotide is administered in an amount effective to improve sensitivity of the patient to the steroid anti-inflammatory treatment and thereby induce a clinical response to the steroid anti-inflammatory treatment.
The described approach is directed to steroid enhancement for patients with airway inflammatory conditions, including asthma and COPD. Experimental results described include dose-dependent suppression of LPS-induced airway inflammation in murine systems and induction of IL-10 and interferons (IFN-γ and IFN-α) by CG-oligonucleotides, with loss of activity in CG-motif controls. The document also reports that IL-10 induction can be boosted after dexamethasone pre-treatment, and reduced cytokine responses are described in steroid-resistant asthmatics.
Claims Coverage
The independent claim describes a method with a core of administering an unmethylated CG-containing oligonucleotide that alone is not effective in non-steroid-refractory patients, to improve sensitivity to steroid anti-inflammatory treatment and induce a clinical response. The claim includes both the patient-treatment framework and the sequence/structure constraints with an unmethylated CG dinucleotide, and it is directed to steroid-refractory or steroid-dependent airway inflammatory conditions.
Enhancing steroid efficacy by improving steroid sensitivity with an unmethylated CG-containing oligonucleotide
Administering to a steroid refractory or steroid dependent patient with an airway inflammatory condition an oligonucleotide that alone does not provide effective treatment in a patient that is not steroid refractory, where the oligonucleotide is administered in an amount effective to improve sensitivity to steroid anti-inflammatory treatment and thereby induce a clinical response to the steroid anti-inflammatory treatment.
Sequence-constrained oligonucleotide 5′-X^m-CG-Y^n-3′ with at least one unmethylated CG dinucleotide
Using an oligonucleotide having the sequence 5′-X^m-CG-Y^n-3′ where X and Y are each A, T, C or G, m=1-30, n=1-30, total length is 8-40 nucleotides, and wherein at least one CG dinucleotide is unmethylated.
Across the independent claim, steroid efficacy is enhanced by giving an unmethylated CG-containing oligonucleotide that alone is not effective in non-steroid-refractory patients, with effectiveness defined by improved sensitivity to steroid anti-inflammatory treatment and induction of a clinical response, using a specific 5′-X^m-CG-Y^n-3′ sequence/length constraint and at least one unmethylated CG dinucleotide.
Stated Advantages
Improves sensitivity of the patient to steroid anti-inflammatory treatment and thereby induces a clinical response to steroid anti-inflammatory treatment.
Enhances steroid efficacy in steroid refractory or steroid dependent patients with an airway inflammatory condition.
Dose-dependent suppression of LPS-induced airway inflammation is described.
Induces IL-10 and interferons (IFN-γ and IFN-α) is described.
Boosts IL-10 induction after dexamethasone pre-treatment is described.
Reduced cytokine responses in steroid-resistant asthmatics is described.
Documented Applications
Enhancing steroid efficacy for steroid refractory or steroid dependent patients afflicted with an airway inflammatory condition, including asthma and COPD.
Treating an inflammatory condition selected from Addison's disease, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), allergy, and asthma is described.
The document reports a pilot human proof-of-concept study in ulcerative colitis and Crohn’s disease and a larger Phase II ulcerative colitis study after rectal dosing of SEQ ID NO:1 is described.
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