Compounds and methods for the treatment of inflammatory diseases of the CNS
Inventors
Bandholtz, Lisa C. • Gielen, Alexander • Zargari, Arezou • Von Stein, Oliver • AXELSSON LARS-GOERAN, null • Axelsson, Lars-Göran
Assignees
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Publication Number
US-8637479-B2
Publication Date
2014-01-28
Expiration Date
Abstract
Inflammatory diseases in the CNS can be treated or alleviated by the administration of an oligonucleotide in an amount sufficient to reduce the influx of mononuclear cells to the central nervous system by down-regulating the expression of at least one cell surface marker. For example multiple sclerosis can be treated or at least alleviated, by the administration of an oligonucleotide in a dose effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system. The oligonucleotide can be used alone, or in combination with other treatment strategies.
Core Innovation
The invention relates to the treatment and/or alleviation of inflammatory diseases of the central nervous system, especially multiple sclerosis, using an isolated and substantially purified oligonucleotide selected from the group of SEQ ID NO: 1–8. The oligonucleotide is used to modulate immune cell behavior in relation to CNS inflammation and is linked to reduction of mononuclear and/or autoaggressive cell influx into the CNS.
A central feature of the invention is inhibition or reduction of cell influx into the CNS by down-regulating the expression of at least one specific cell surface marker. The description specifically identifies cell-surface markers including CD49d, CXCR3, CCR2, and CCR5, and frames the oligonucleotide as acting through marker expression down-regulation. An alternative or additional mechanism is reducing VEGF production.
The document also supports pharmaceutical composition embodiments and administration routes for the oligonucleotide. The described administration routes include mucosal, subcutaneous, intramuscular, intravenous, intraperitoneal, and multiple mucosal subtypes, and experimental evidence is presented showing immunomodulatory changes in cytokine/chemokine mRNA expression, changes in CD49d expression, reduced incidence/severity/mortality in MOG-induced EAE, and patient PBMC-associated down-regulation and chemotaxis/VEGF/IFN-beta-related effects.
Claims Coverage
The patent includes three independent claims covering sequence-defined isolated and substantially purified oligonucleotides, a treatment/alleviation method based on down-regulating cell surface marker expression to reduce mononuclear and/or autoaggressive cell influx, and a treatment/alleviation method based on reducing VEGF production to reduce such influx. Across the independent claims, the main inventive features relate to specific SEQ ID NOs and two mechanistic pathways for reducing CNS inflammatory cell influx.
Sequence-defined isolated and substantially purified oligonucleotides
An isolated and substantially purified oligonucleotide selected from the group consisting of SEQ ID NO: 1 (IDX9045), SEQ ID NO: 2 (IDX9054), SEQ ID NO: 4 (IDX9004), and SEQ ID NO: 8 (IDX9060).
Down-regulating cell surface marker expression to reduce influx for multiple sclerosis treatment
A method for the treatment and/or alleviation of multiple sclerosis comprising administering an oligonucleotide to a patient in need thereof in an amount effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system by down-regulating the expression of at least one specific cell surface marker, wherein the oligonucleotide is selected from the group consisting of SEQ ID NO: 1, 2, 3, 7, 6, 4, 8, and 5.
Reducing VEGF production to reduce influx for multiple sclerosis treatment
A method for the treatment and/or alleviation of multiple sclerosis, wherein an oligonucleotide is administered to a patient in need thereof in an amount effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system by reducing the production of VEGF, wherein the oligonucleotide is selected from the group consisting of SEQ ID NO: 1, 2, 3, 7, 6, 4, 8, and 5.
Overall, the claim coverage centers on isolated and substantially purified, sequence-defined oligonucleotides used to treat multiple sclerosis by reducing CNS inflammatory cell influx either through down-regulating expression of specific cell surface markers or through reducing VEGF production.
Stated Advantages
Inhibits or reduces the influx of mononuclear and/or autoaggressive cells to the central nervous system.
Down-regulates expression of specific cell surface markers, including CD49d, CXCR3, CCR2, and CCR5.
Reduces the production of VEGF.
Provides treatment and/or alleviation of multiple sclerosis.
Documented Applications
Treatment and/or alleviation of multiple sclerosis by administering an isolated and substantially purified oligonucleotide to a patient in need thereof.
Use of the oligonucleotide for treatment and/or alleviation of inflammatory diseases of the central nervous system, especially multiple sclerosis.
Experimental autoimmune encephalomyelitis (EAE) model, including MOG-induced EAE in DA rats, with reported reduced incidence, severity, and mortality.
Patient peripheral blood mononuclear cell (PBMC) data showing down-regulation of CD49d and decreased chemokine receptor expression and reduced chemotaxis toward MCP-1 and RANTES.
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