Administration of NF- kappa B inhibitor into intervertebral disc to treat intervertebral disc degeneration, wherein NF- kappa B inhibitor is selected from decoy oligonucleotide capable of binding to and acting on DNA binding site of NF- kappa B, antisense NF- kappa B nucleic acid, and NF- kappa B siRNA
Inventors
Masuda, Koichi • Gemba, Takefumi
Assignees
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Publication Number
US-7585848-B2
Publication Date
2009-09-08
Expiration Date
Abstract
Described herein are methods and compositions for inhibiting, treating and reversing intervertebral disc disorders using transcription factor inhibitors. In certain embodiments, the transcription factor inhibitor targets the transcription factor NF-κB. Also described are methods and compositions where intervertebral disc disorder is reversed using a decoy oligodeoxy-nucleotide that blocks NF-κB.
Core Innovation
The invention relates to treating intervertebral disc degeneration and intervertebral disc disorders by locally administering a transcription factor inhibitor, specifically an NF-κB inhibitor, into pathological intervertebral discs. The NF-κB inhibitor is configured to act directly on NF-κB or directly on NF-κB mRNA as part of the treatment.
The NF-κB inhibition is provided using NF-κB decoy oligonucleotides, including sequence-defined NF-κB decoy oligonucleotide sequences such as SEQ ID NO.: 1 and SEQ ID NO.: 2, NF-κB antisense nucleic acids, or NF-κB siRNA. The document describes the approach as reversing prior disc damage by restoring disc integrity through NF-κB inhibition within the intervertebral disc.
The description further supports that NF-κB inhibition reduces catabolic mediator expression and promotes proteoglycan accumulation in AF/NP cell cultures, including reduction of IL-1β-stimulated MMPs, ADAMTS4, TIMP-1, IL-6, and nitric oxide (NO), and increased proteoglycan accumulation. The document also references in vivo disc height recovery, including partial disc height recovery measured by disc height indices following an intra-discal injection of a naked NF-κB decoy in rabbit annular puncture studies.
Claims Coverage
The independent claims (two) cover a treatment method for intervertebral disc degeneration that administers an NF-κB inhibitor directly into an intervertebral disc to treat the degeneration, with the inhibitor acting directly on NF-κB or on NF-κB mRNA. Across the independent claims, the main inventive features are the specified local target-site administration and the selection/definition of the NF-κB inhibitor type, including a sequence-defined decoy.
Intradiscal NF-κB inhibitor for treating intervertebral disc degeneration
Administration of an NF-κB inhibitor into an intervertebral disc, wherein administration treats an intervertebral disc degeneration.
NF-κB inhibitor acting directly on NF-κB or NF-κB mRNA
Selection of the NF-κB inhibitor from a decoy oligonucleotide capable of binding to the DNA binding site of NF-κB, an antisense NF-κB nucleic acid, or an NF-κB siRNA, wherein the NF-κB inhibitor acts directly on NF-κB, or directly on NF-κB mRNA.
Sequence-defined NF-κB decoy administered into an intervertebral disc
Administration of an NF-κB inhibitor into an intervertebral disc, wherein the NF-κB inhibitor is a NF-κB decoy having the sequence of SEQ ID NO.: 1, and wherein administration treats an intervertebral disc degeneration.
Overall, the claim coverage centers on a method of treating intervertebral disc degeneration using intradiscal administration of an NF-κB inhibitor, with coverage extending to inhibitor types that act directly on NF-κB or NF-κB mRNA, and specifically to a decoy oligonucleotide sequence of SEQ ID NO.: 1.
Stated Advantages
Restores disc integrity by reversing prior disc damage, as described in the document.
Reduces IL-1β-stimulated catabolic mediator expression including MMPs, ADAMTS4, TIMP-1, IL-6, and NO in AF/NP cell cultures.
Increases proteoglycan accumulation in AF/NP cell cultures.
Shows partial disc height recovery after intra-discal naked NF-κB decoy injection in rabbit annular puncture studies.
Documented Applications
Treatment of intervertebral disc degeneration and intervertebral disc disorders by locally administering NF-κB inhibitors into pathological intervertebral discs.
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