TRPV1 modulatory gene product that affects TRPV1-specific pain behavioral responses identified in a functional screen of an HSV-based cDNA library
The invention provides a method for ameliorating chronic pain signaling involving transient receptor potential cation channel subfamily V member 1 (TRPV1) by expressing PP1α in neurons. The invention also provides HSV vectors for expressing PP1α within neurons and compositions comprising such vectors.
1. A herpes simplex virus (HSV) vector comprising an expression cassette, which expression cassette comprises a nucleic acid sequence encoding PP1α, wherein the nucleic acid sequence encoding PP1α is operably linked to the transient receptor potential cation channel subfamily V member 1 (TRPV1) promoter.
2. The HSV vector of claim 1 , which is replication deficient in vivo.
3. The HSV vector of claim 2 , which lacks functioning genes encoding ICP4 and ICP27.
4. The HSV vector of claim 3 which contains at least one other mutation.
5. The HSV vector of claim 1 , which is targeted to specifically infect C-fibers within a mammal.
6. The HSV vector of claim 5 , wherein the mammal is human.
7. The HSV vector of claim 1 , wherein the nucleic acid sequence encoding PP1α encodes the human form of PP1α.
8. The HSV vector of claim 1 , wherein the TRPV1 promoter is a human TRPV1 promoter.
9. A viral stock comprising a defined titer of HSV vectors according to claim 1 .
10. A pharmaceutical composition comprising HSV vectors of claim 1 and a pharmaceutically-acceptable carrier.
11. The pharmaceutical composition of claim 10 , which is formulated as a liquid suitable for administration by skin prick, or via subdermal, intramuscular, or parenteral injection.
12. The pharmaceutical composition of claim 10 , which is formulated for transdermal administration.
13. A method of treating pain within a mammal in need thereof, the method comprising administering the pharmaceutical composition of claim 10 to the mammal in an amount and at a location sufficient to result in HSV vectors within the composition to infect peripheral neurons associated with the sensation of pain, such that the nucleic acid sequences encoding PP1α within said vectors are transcribed within the neurons of the mammal to produce PP1α within the neurons of the mammal.
14. The method of claim 13 , which mitigates the sensation of pain caused by exposure to capsaicin or Resiniferatoxin (RTx).
15. The method of claim 13 , wherein the mammal is human.