ABSTRACT
Pain is one of the primitive behaviors that is highly conserved among species and is critical for survival when facing environmental stresses. In an extremely rare
6.1 Introduction .................................................................................................. 139 6.2 Challenges Associated with Gene Transfer to Neuronal Cells in Vitro ....... 140
6.2.1 Challenge 1: Gene Delivery to Non-Dividing Neuronal Cells ......... 141 6.2.1.1 Non-Viral Vectors .............................................................. 141 6.2.1.2 Viral Vectors ...................................................................... 143
6.2.2 Challenge 2: DRG Neurons and Cell Membrane Activity ............... 144 6.3 Administration Routes for in Vivo Gene Transfer to Primary
Sensory Neurons ........................................................................................... 147 6.3.1 Challenge 1: Gene Transfer to DRG ................................................. 148 6.3.2 Challenge 2: Retrograde Gene Transfer through Neurons Using
Viral Vectors ..................................................................................... 149 6.3.3 Challenge 3: Non-Viral Vector Gene Transfer to the PNS
in Vivo ............................................................................................... 150 6.4 “Loss-or Gain-of-Function” Experiments in Peripheral Neuropathy
Animal Models ............................................................................................. 150 6.4.1 Challenge 1: Post-Transcriptional Regulation .................................. 151 6.4.2 Challenge 2: Post-Translational Regulation ...................................... 153
6.5 Conclusions ................................................................................................... 154 Acknowledgments .................................................................................................. 154 References .............................................................................................................. 154
occurrence, families in a remote village of Pakistan were discovered to completely lack the capability for nociception (Cox et al. 2006). The resulting lack of pain appeared to manifest with frequent injuries ranging from bone fractures and extensive burns to accidental death. Whole genome linkage analysis revealed candidate single nucleotide polymorphisms (SNPs) in the SCN9A allele, which encodes the tetrodotoxin-sensitive voltage-gated sodium channel NaV1.7. SNPs in these families (Cox et al. 2006), as well as in other families from Canada exhibiting a similar phenotype (Goldberg et al. 2007; Ahmad et al. 2007), result in truncation of the NaV1.7 molecule that leads to loss of function. Furthermore, SNPs causing protein substitutions in the SCN9A allele have been found to lead to gain of function mutations in patients with primary erythermalgia (Drenth et al. 2005; Han et al. 2006; Yang et al. 2004) and paroxysmal extreme pain disorder (Fertleman et al. 2006; Yiangou et al. 2007), both of which manifest with localized severe pain episodes. The information gained from patients has been particularly valuable for understanding the role of NaV1.7 in inheritable disorders with inammation-mediated pain.
