Treatment of pain

摘要

Use of a therapeutic molecule, for the treatment of specific pain conditions, wherein the therapeutic molecule is a single chain, polypeptide fusion protein, comprising: a non-cytotoxic protease, or a fragment thereof, which protease or protease fragment can cleave a protein of the exocytic fusion apparatus of a nociceptive sensory afferent; a Targeting Moiety that can bind to a Binding Site on the nociceptive sensory afferent, which Binding Site can undergo endocytosis to be incorporated into an endosome within the nociceptive sensory afferent; a protease cleavage site at which site the fusion protein is cleavable by a protease, wherein the protease cleavage site is located between the non-cytotoxic protease or fragment thereof and the Targeting Moiety; and a translation domain that can translocate the protease or protease fragment from within an endosome, across the endosomal membrane and into the cytosol of the nociceptive sensory afferent.

主权项

1. A method of preventing or suppressing a specific pain condition in a subject, wherein said pain condition is selected from the group consisting of: neuropathic pain, inflammatory pain, headache pain, somatic pain, visceral pain and referred pain, said method comprising administering to said subject a therapeutically effective amount of a polypeptide fusion protein, comprising:
a) a clostridial neurotoxin protease or an IgA protease that cleaves a protein of the exocytic fusion apparatus in a nociceptive sensory afferent; b) a Targeting Moiety that binds to a Binding Site present on the nociceptive sensory afferent; c) a protease cleavage site located between the clostridial neurotoxin protease or the IgA protease and the Targeting Moiety; and d) a translocation domain that translocates the protease from within an endosome, across an endosomal membrane and into the cytosol of the nociceptive sensory afferent; wherein the Targeting Moiety is located between the protease cleavage site and the translocation domain and wherein,
I. the clostridial neurotoxin protease or the IgA protease forms a disulphide bond with the translocation domain and,wherein the amino acid residue of the clostridial neurotoxin protease or the IgA protease that forms the first part of the disulphide bond is located within the last 20 C-terminal amino acid residues of the clostridial neurotoxin protease or the IgA protease, and the amino acid residue within the translocation domain that forms the second part of the disulphide bond is located within the first 20 N-terminal amino acid residues of the translocation domain; orII. the clostridial neurotoxin protease or the IgA protease forms a disulphide bond with the Targeting Moiety component of the polypeptide fusion protein,wherein the amino acid residue of the clostridial neurotoxin protease or the IgA protease that forms the first part of the disulphide bond is located within the last 20 C-terminal amino acid residues of the clostridial neurotoxin protease or the IgA protease, and the amino acid residue within the Targeting Moiety that forms the second part of the disulphide bond is located within the last 20 C-terminal amino acid residues of the Targeting Moiety.