siRNA relieves chronic neuropathic pain.
Double stranded, short interfering RNAs (siRNA) of 21-22 nt length initiate a sequence-specific, post-trancriptional gene silencing in animals and plants known as RNA interference (RNAi). Here we show that RNAi can block a pathophysiological pain response and provide relief from neuropathic pain in a rat disease model by down regulating an endogenous, neuronally expressed gene. Rats, intrathecally infused with a 21 nt siRNA perfectly complementary to the pain-related cation-channel P2X3, showed diminished pain responses compared to missense (MS) siRNA-treated and untreated controls in models of both agonist-evoked pain and chronic neuropathic pain. This form of delivery caused no adverse effects in any of the animals receiving P2X3 siRNA, MS siRNA or vehicle. Molecular analysis of tissues revealed that P2X3 mRNA expressed in dorsal root ganglia, and P2X3 protein translocated into the dorsal horn of the spinal cord, were significantly diminished. These observations open a path toward use of siRNA as a genetic tool for drug target validation in the mammalian central nervous system, as well as for proof of concept studies and as therapeutic agents in man.
Dorn
Gabriele
G
Functional Genomics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland.
Patel
Sadhana
S
Wotherspoon
Glen
G
Hemmings-Mieszczak
Maja
M
Barclay
Jane
J
Natt
Francois J C
FJ
Martin
Pierre
P
Bevan
Stuart
S
Fox
Alyson
A
Ganju
Pam
P
Wishart
William
W
Hall
Jonathan
J
D000818:Animals; D002908:Chronic Disease; D006930:Hyperalgesia / Q000628:therapy; D009437:Neuralgia / Q000378:metabolism / Q000628:therapy*; D058919:Purinergic P2 Receptor Antagonists; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058477:Receptors, Purinergic P2X3
C546410:P2rx3 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3