and regional drug differences or adverse effects. Importantly, alternative splicing, as opposed to constitutive splicing, could be an untapped therapeutic approach in areas such as nociception and/or pain, and neuroprotection. Over the past 13 years, several strategies for the control of alternative splicing have been suggested, including targeted oligonucleotides against splice sites, or targeting splice factors, such as SR proteins. Chemically modified oligonucleotides resistant to degradation have proved effective at inducing either exon skipping or blocking splice sites in animal models and in some clinical trials, with the aim of repair of defective mRNAs. This approach can result in the restoration of functional protein in conditions such as Duchenne muscular dystrophy, where splicing events result in nonfunctional dystrophin. There has been some minor success in a few clinical trials using this approach. Alternatively, oligonucleotides can be targeted to block aberrant splicing events, restoring functional protein, such as in developing approaches to treat spinal muscular atrophy and beta-thalassemia. Theoretically, these approaches can also be used to control alternative splicing by blocking alternative splice sites to direct splice variant expression; there has been some reported success in this area in animal models. The SR family comprises around 40 proteins that can control multiple steps in RNA processing, including the recognition of splice sites, the binding of RNA polymerase II, mRNA export to the cytoplasm, and translation control. Targeting of CDC-like kinases and serine-arginine protein kinases with small-molecule inhibitors is emerging as a potential therapeutic strategy because these molecules might control limited downstream splicing events, reducing the possibility of off-target or other adverse effects. Proof-of-principle studies have shown efficacy in either blocking exon skipping and enhancing readthrough of full-length protein, or controlling alternate exon inclusion, showing that these strategies might be of use in control of, for example, congenital gain, or loss of function of sodium channels implicated in pain states. Unfortunately, our current understanding of the specific molecules controlling the alternative splicing of specific mRNAs, such as sodium channels, is limited. The power of controlling alternative splicing is obvious. Splicing directed towards truncated receptors that act as dominantnegative MRT-67307 web isoforms could be an alternative to antagonists and/or blockers that could reduce adverse effects. Favouring the expression of specific opioid receptor variants could potentiate the analgesic response to an agonist. If directed to ion channels that enhance opioid analgesia, it could improve efficacy of existing drugs. Where families of isoforms exist that have opposite functions, such as VEGF-A, control of splicing between families could shift the balance of isoforms to affect, for example angiogenesis in solid tumours or pain. To target alternative splicing therapeutically, without affecting constitutive splicing, we need a greater understanding of the specific mechanisms through which alternative PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19840865 splice site selection is controlled for key pre-mRNAs. There have been significant advances in this area, driven largely by the cancer field, but it is an area ripe for development for novel applications, such as the control of pain. Conflict of interest LFD is a co-inventor on patents protecting alternative RN
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