Methods and compositions for treating or preventing pruritis

Abstract

The invention features therapeutic compositions comprising agents useful for the treatment or prevention of pruritis, and methods useful for identifying such agents.

1 . A method of treating or preventing pruritis in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that inhibits the expression or biological activity of an human MrgX1 I or murine MrgA3 polypeptide or polynucleotide. 
     
     
         2 . The method of  claim 1 , wherein the agent is an inhibitory nucleic acid molecule that inhibits the expression of an MrgX1 polypeptide. 
     
     
         3 . The method of  claim 1 , wherein the agent is a 3-substituted-2-(diphenylmethy)-1-azabicyclo[2.2.2]octane or a compound of formula I that inhibits biological activity of MrgX1. 
     
     
         4 . A pharmaceutical composition labeled for the treatment or prevention of pruritis comprising an effective amount of an agent that inhibits the expression or biological activity of MrgX1. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the agent is a 3-substituted-2-(diphenylmethy)-1-azabicyclo[2.2.2]octane or a compound of formula I. 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein the agent is selected from the group consisting of compounds 1-16. 
     
     
         7 . The pharmaceutical composition of  claim 2 , wherein the agent is an inhibitory nucleic acid molecule that hybridizes to at least a portion of an MrgX1 polynucleotide and is capable of reducing MrgX1 polypeptide or polynucleotide expression. 
     
     
         8 . The pharmaceutical composition of  claim 4 , wherein the inhibitory nucleic acid molecule is an siRNA, antisense oligonucleotide, or shRNA. 
     
     
         9 . An inhibitory nucleic acid molecule comprising a nucleic acid sequence that hybridizes to at least a portion of an MrgX1 or MrgA3 polynucleotide and is capable of inhibiting MrgX1 polypeptide or polynucleotide expression. 
     
     
         10 . (canceled) 
     
     
         11 . A vector comprising the inhibitory nucleic acid molecule of  claim 9 . 
     
     
         12 . The vector of  claim 11 , wherein the inhibitory nucleic acid molecule is positioned for expression in a mammalian cell. 
     
     
         13 . A host cell comprising the vector of  claim 11 . 
     
     
         14 . A method of treating or preventing pruritis in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent of  claim 4 . 
     
     
         15 . The method of  claim 14 , wherein the subject has a histamine-independent itch or choroquine-induced itch. 
     
     
         16 . A method of treating or preventing pruritis in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that inhibits the expression or biological activity of an MrgX1 or MrgA3 polypeptide or polynucleotide in combination with an anti-histamine or a corticosteroid. 
     
     
         17 . The method of  claim 16 , wherein the agent is an inhibitory nucleic acid molecule that inhibits the expression of an MrgX1 polypeptide, a 3-substituted-2-(diphenylmethy)-1-azabicyclo[2.2.2]octane or a compound of formula I that inhibits biological activity of MrgX1. 
     
     
         18 . The method of  claim 16 , wherein the subject has histamine-independent itching or a condition selected from the group consisting of a dermatologic disorder, exposure to a surface irritant, chronic renal disease, liver disease, bacterial or viral infection, HIV, a parasitic infestation, chicken pox, opioid administration, multiple sclerosis, hyperparathyroidism; diabetes mellitus, iron deficiency anemia, allergic reactions to a drug, an adverse side effect associated with a vasoactive drug, CNS active agent or chloroquine, Hodgkin's disease, polycythemia rubra vera, leukemia, mycosis fungoides, Sézary syndrome, visceral neoplasia, carcinoid, multiple myeloma, and pregnancy. 
     
     
         19 . A pharmaceutical composition for the treatment or prevention of pruritis comprising an effective amount of an agent that inhibits the expression or biological activity of MrgX1 and an anti-histamine or corticosteroid. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the an inhibitory nucleic acid molecule that hybridizes to at least a portion of an MrgX1 polynucleotide and is capable of inhibiting MrgX1 polypeptide or polynucleotide expression, a 3-substituted-2-(diphenylmethy)-1-azabicyclo[2.2.2]octane or a compound of formula I. 
     
     
         21 . A method for identifying a candidate agent that reduces MrgA3 or MrgX1 expression, the method comprising:
 (a) contacting a cell expressing a MrgA3 or MrgX1 nucleic acid molecule with a candidate agent; and   (b) comparing MrgA3 or MrgX1 expression in the contacted cell with a reference level of expression, wherein a reduction in MrgA3 or MrgX1 expression identifies the agent as reducing MrgA3 or MrgX1 expression, or   A method for identifying a candidate agent that treats or prevents pruritis, the method comprising the steps of:   (a) contacting a cell expressing a MrgA3 or MrgX1 polypeptide with a candidate agent; and   (b) detecting a reduction in MrgA3 or MrgX1 polypeptide level or biological activity in the cell contacted with the candidate agent relative to a reference level, wherein a reduction in MrgA3 or MrgX1 polypeptide level or biological activity identifies a candidate agent that treats or prevents pruritis, or   A method for identifying a candidate agent useful for the treatment or prevention of pruritis, the method comprising the steps of:   (a) contacting a cell expressing a MrgA3 or MrgX1 polypeptide with a candidate agent; and   (b) detecting binding of the MrgA3 or MrgX1 polypeptide with the candidate agent, wherein a agent that binds a MrgA3 or MrgX1 polypeptide is useful for the treatment or prevention of pruritis, or   A transgenic mammal comprising a deletion in a Mas-related gene (Mrg), or   A transgenic mammal comprising detectable chloroquine sensitive neurons, the mouse comprising a MrgA3 or MrgX1 gene fused to a detectable reporter coding sequence, or   An isolated CQ-sensitive neuron derived from dorsal root ganglion having histamine- and capsaicin-sensitivity, or   A method for isolating a chloroquine activated cell, the method comprising identifying a MrgX1 or MrgprA3-expressing cell, and isolating the cell based on said expression.   
     
     
         22 - 44 . (canceled)