Compounds and methods for reducing the recruitment and/or migration of polymorphonuclear cells
Inventors
Admyre, Charlotte • Axelsson, Lars-Göran • Von Stein, Oliver • Zargari, Arezou
Assignees
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Publication Number
US-8877724-B2
Publication Date
2014-11-04
Expiration Date
Abstract
A therapeutically effective amount of an oligonucleotide is capable of influencing the properties and behavior of polymorphonuclear cells, e.g. suppressing endothelial adhesion and transmigration of said cells, and through this mechanism reduce the recruitment and/or migration of polymorphonuclear cells to a site of inflammation.
Core Innovation
The invention relates to anti-inflammatory oligonucleotide compounds comprising isolated oligonucleotide sequences including SEQ ID NO 8 (IDX9059), SEQ ID NO 1 (IDX9005), SEQ ID NO 9 (IDX9074), SEQ ID NO 2 (IDX9010), SEQ ID NO 4 (IDX9030), SEQ ID NO 10 (IDX9092), SEQ ID NO 11 (IDX9095), SEQ ID NO 12 (IDX9096), and SEQ ID NO 16 (IDX9134). The oligonucleotides include at least one nucleotide with a phosphate backbone modification.
The invention is described as reducing polymorphonuclear (PMN) cell recruitment and/or migration to inflammatory sites. It is associated with down-regulating neutrophil chemokine receptors CXCR1 and CXCR2 and leukotriene receptor BLT1, thereby reducing migration driven by IL-8 and LTB4.
The described examples provide support in multiple inflammation and ischemia-related models, including OVA airway inflammation, thioglycolate pleurisy, intravital microscopy of venules, rat focal cerebral ischemia with infarct/penumbra measures, isolated-perfused rat heart global ischemia, and mouse intestinal ischemia-reperfusion. Mechanistic studies in human PMN include flow-cytometry and chemotaxis readouts showing decreased receptor surface expression and reduced IL-8/LTB4-driven migration, including PMN from asthma and multiple sclerosis patients.
Claims Coverage
The provided independent claim set comprises 1 independent claim directed to specific isolated oligonucleotide sequences with phosphate backbone modification, with dependent claims further specifying the modification type and incorporating the oligonucleotide into a pharmaceutical composition.
Isolated oligonucleotide sequences with phosphate backbone modification
An isolated oligonucleotide sequence selected from SEQ ID NO: 8 (IDX9059), SEQ ID NO: 1 (IDX9005), SEQ ID NO: 9 (IDX9074), SEQ ID NO: 2 (IDX9010), SEQ ID NO: 4 (IDX9030), SEQ ID NO: 10 (IDX9092), SEQ ID NO: 11 (IDX9095), SEQ ID NO: 12 (IDX9096), or SEQ ID NO: 16 (IDX9134), wherein at least one nucleotide has a phosphate backbone modification.
Phosphate backbone modification specified as phosphorothioate or phosphorodithioate
The isolated oligonucleotide sequence wherein the phosphate backbone modification is selected from phosphorothioate or phosphorodithioate.
Pharmaceutical composition containing the oligonucleotide
A pharmaceutical composition including the oligonucleotide sequence as defined in the claim.
Overall, the claims focus on selected isolated oligonucleotide sequences (specific SEQ ID NOs) that include phosphate backbone modification, with dependent specification to phosphorothioate or phosphorodithioate, and optionally on pharmaceutical compositions containing the defined oligonucleotides.
Stated Advantages
Reduces polymorphonuclear (PMN) cell recruitment and/or migration to inflammatory sites.
Down-regulates neutrophil chemokine receptors CXCR1 and CXCR2.
Down-regulates leukotriene receptor BLT1.
Reduces IL-8/LTB4-driven PMN migration by decreasing receptor surface expression.
Documented Applications
Use in inflammatory settings described as OVA airway inflammation and thioglycolate pleurisy.
Use supported by intravital microscopy of venules to assess PMN recruitment and migration.
Use in rat focal cerebral ischemia with infarct/penumbra measures.
Use in isolated-perfused rat heart global ischemia.
Use in mouse intestinal ischemia-reperfusion.
Use involving transplantation conditioning, as described in the document.
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