Methods and compositions for decreasing chronic pain

Abstract

The present invention provides compositions and methods for the selective silencing of neurons in pain pathway by using a combination of inhibitory light-sensitive protein gene transfer and wavelength specific illumination.

What is claimed is: 
     
         1 . A recombinant nucleic acid, comprising:
 a nucleic acid fragment encoding a light-sensitive protein; and   a regulatory nucleic acid fragment that is capable of directing selective expression of said light-sensitive protein in a cell of the central nervous system (CNS).   
     
     
         2 . The recombinant nucleic acid of  claim 1 , wherein said light-sensitive protein is sensitive to a light that is a visible light. 
     
     
         3 . The recombinant nucleic acid of  claim 1 , wherein said light-sensitive protein is capable of modulate the neuronal activity of said cell. 
     
     
         4 . The recombinant nucleic acid of  claim 3 , wherein said the neuronal activity of said cell is associated with pain transmission or generation. 
     
     
         5 . The recombinant nucleic acid of  claim 1 , wherein said light-sensitive protein is a membrane bound microbial opsin. 
     
     
         6 . The recombinant nucleic acid of  claim 5 , wherein said microbial opsin is a photosensitive ion channel or pump. 
     
     
         7 . The recombinant nucleic acid of  claim 1 , wherein said light-sensitive protein is selected from the group consisting of: halorhodopsin (NpHR), enhanced halorhopopsin (eNpHR), archaerhodopsin-3 (Arch), leptosphaeria maculans (Mac), and functional variants thereof. 
     
     
         8 . The recombinant nucleic acid of  claim 1 , wherein said cell is associated with pain neurotransmission or generation. 
     
     
         9 . The recombinant nucleic acid of  claim 1 , wherein said cell is a Wide Dynamic Range (WDR) cell, a cell of dorsal root ganglia (DRG), or a cell of NK-1 Expressing Afferent Fibers. 
     
     
         10 . The recombinant nucleic acid of  claim 9 , wherein said cell is a nociceptive neuron of the DRG. 
     
     
         11 . The recombinant nucleic acid of  claim 1 , wherein said regulatory nucleic acid fragment has the sequence of a promoter that is specific to said cell of the CNS. 
     
     
         12 . The recombinant nucleic acid of  claim 11 , wherein said promoter is preprotachykinin-A (PPT) promoter, voltage-gated sodium channel subunit alpha (Scn10a) promoter. 
     
     
         13 . A recombinant virus, comprising the recombinant nucleic acid of  claim 1 . 
     
     
         14 . The recombinant virus of  claim 13 , wherein said virus is selected from the group consisting of: recombinant adeno-associated virus (AAV), recombinant retrovirus, recombinant lentivirus, and recombinant poxvirus. 
     
     
         15 . The recombinant virus of  claim 14 , wherein said virus is an AAV virus of a serotype selected from the group consisting of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, and hybrids thereof. 
     
     
         16 . The recombinant virus of  claim 15 , wherein said virus is sc-rAAV1 or sc-rAAV8. 
     
     
         17 . A host cell, derived from a cell transfected with the recombinant virus of  claim 13 . 
     
     
         18 . A vector, comprising the recombinant nucleic acid of  claim 1 . 
     
     
         19 . A host cell, derived from a cell transfected with the vector of  claim 18 . 
     
     
         20 . A host cell, comprising the recombinant nucleic acid of  claim 1 . 
     
     
         21 . A method to relieve neuropathic pain, comprising: optically silencing pain-associated neurotransmission or generation in a mammalian subject in need of such relief. 
     
     
         22 . The method of  claim 21 , comprising:
 expressing in a cell of said subject the recombinant nucleic acid of  claim 1 ; and   controlling the neural activity of said cell with a light beam to modulate the expression of said light-sensitive protein, thereby relieve the neuropathic pain in said subject.   
     
     
         23 . The method of  claim 22 , wherein said controlling is carried out with high spatial and temporal precision using a specifically positioned device where the light emission is controlled over time. 
     
     
         24 . The method of  claim 22 , wherein said method provides significant analgesia for chronic neuropathic pain without off-target effects. 
     
     
         25 . The method of  claim 24 , wherein said off-target effects comprise general central nervous system depression. 
     
     
         26 . The method of  claim 24 , wherein such analgesia results in greater than 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 percent reduction in said neuropathic pain. 
     
     
         27 . The method of  claim 21 , wherein, the extent of said silencing is dynamically controlled via a variable intensity optical source with temporal control. 
     
     
         28 . The method of  claim 27 , wherein said optical source comprises an implantable 1- or 2- or 3-dimensional fiber optic device. 
     
     
         29 . A method of optically controlling neural activity in a cell, comprising:
 expressing in a cell the recombinant nucleic acid of  claim 1 ; and   controlling the neural activity of said cell with a light beam to modulate the expression of said light-sensitive protein.   
     
     
         30 . A method of optically controlling neural activity in a subject, comprising:
 expressing in a cell of a subject the recombinant nucleic acid of  claim 1 ; and   controlling the neural activity of said cell with a light beam to modulate the expression of said light-sensitive protein.   
     
     
         31 . A pharmaceutical composition, comprising the recombinant nucleic acid of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         32 . A kit, comprising the recombinant nucleic acid of  claim 1 . 
     
     
         33 . A kit, comprising the recombinant virus of  claim 13 . 
     
     
         34 . The method of  claim 22 , wherein said light beam is delivered intradermally. 
     
     
         35 . The method of  claim 22 , wherein said light sensitive protein is directly exposed to said light beam. 
     
     
         36 . The method of  claim 29 , wherein said light beam is delivered intradermally. 
     
     
         37 . The method of  claim 30 , wherein said light beam is delivered intradermally. 
     
     
         38 . The method of  claim 29 , wherein said light sensitive protein is directly exposed to said light beam. 
     
     
         39 . The method of  claim 30 , wherein said light sensitive protein is directly exposed to said light beam.