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• W2056635622 abstract "Engineered zinc finger protein transcription factors (ZFP TFs) can be designed to regulate virtually any endogenous gene with high specificity. Acting at the DNA level, these proteins offer a novel way of tackling disease targets that are not easily “druggable” by conventional methodologies. To test the potential of ZFP TFs in treating chronic pain, we designed ZFP repressors that target the promoters of (i) the high affinity nerve growth factor receptor (TrkA) gene and, (ii) the voltage-gated sodium channel PN3 (Nav1.8, SCN10a) gene. Although TrkA and PN3 are well validated nociceptive molecules, specific and targeted inhibition of their activities in sensory neurons has been difficult with approaches such as small molecule inhibitors or antibodies. Designed ZFP repressors efficiently inhibited the expression of TrkA and PN3 in cultured dorsal root ganglia (DRG) neurons; their in vivo efficacies were then tested in a rat spinal nerve ligation (SNL) model of neuropathic pain. For delivery of the ZFP TFs to the DRG we took advantage of the natural tropism of Herpes Simplex virus (HSV) for sensory neurons. Six weeks post SNL surgery, the ipsilateral lumbar DRGs were transduced by subcutaneous inoculation into the footpad with non-replicating HSV vectors that express either the ZFP-TrkA-repressor, the ZFP-PN3-repressor, or green fluorescent protein (GFP). Mechanical allodynia (MA) was measured using electronic Von Frey filament weekly for 8 weeks. Starting at 1 week after HSV delivery, rats inoculated with either the TrkA repressor or the PN3 repressor had significantly reduced MA compared to GFP and uninjected controls. This improvement was maintained for at least 4 weeks following a single HSV injection. These results demonstrate the efficacy of engineered ZFP TFs in vivo and highlight the potential of this technology to expand the universe of potential drug targets in complex disease such as neuropathic pain. Engineered zinc finger protein transcription factors (ZFP TFs) can be designed to regulate virtually any endogenous gene with high specificity. Acting at the DNA level, these proteins offer a novel way of tackling disease targets that are not easily “druggable” by conventional methodologies. To test the potential of ZFP TFs in treating chronic pain, we designed ZFP repressors that target the promoters of (i) the high affinity nerve growth factor receptor (TrkA) gene and, (ii) the voltage-gated sodium channel PN3 (Nav1.8, SCN10a) gene. Although TrkA and PN3 are well validated nociceptive molecules, specific and targeted inhibition of their activities in sensory neurons has been difficult with approaches such as small molecule inhibitors or antibodies. Designed ZFP repressors efficiently inhibited the expression of TrkA and PN3 in cultured dorsal root ganglia (DRG) neurons; their in vivo efficacies were then tested in a rat spinal nerve ligation (SNL) model of neuropathic pain. For delivery of the ZFP TFs to the DRG we took advantage of the natural tropism of Herpes Simplex virus (HSV) for sensory neurons. Six weeks post SNL surgery, the ipsilateral lumbar DRGs were transduced by subcutaneous inoculation into the footpad with non-replicating HSV vectors that express either the ZFP-TrkA-repressor, the ZFP-PN3-repressor, or green fluorescent protein (GFP). Mechanical allodynia (MA) was measured using electronic Von Frey filament weekly for 8 weeks. Starting at 1 week after HSV delivery, rats inoculated with either the TrkA repressor or the PN3 repressor had significantly reduced MA compared to GFP and uninjected controls. This improvement was maintained for at least 4 weeks following a single HSV injection. These results demonstrate the efficacy of engineered ZFP TFs in vivo and highlight the potential of this technology to expand the universe of potential drug targets in complex disease such as neuropathic pain." @default.
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• W2056635622 date "2008-04-01" @default.
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• W2056635622 title "(108) Engineered zinc finger protein transcription factors as a potential therapy for neuropathic pain" @default.
• W2056635622 doi "https://doi.org/10.1016/j.jpain.2008.01.027" @default.
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