Oligonucleotide-mediated gene editing for neuromuscular disorders.
In the last decade, outstanding progress has been made in the development of new approaches to treat neuromuscular disorders and in particular Duchenne muscular dystrophy (DMD). The use of oligonucleotides to induce single base pair alterations in the dystrophin gene and restore gene expression in skeletal muscle has proven to be a feasible alternative approach to dystrophin gene replacement. Oligonucleotide-mediated gene editing for dystrophin has the potential to treat the disorder permanently and effectively. Many hurdles however still need to be overcome before this technology can enter into a clinical setting. Understanding the mechanisms of the repair process is a key for the design of oligonucleotides capable to induce gene repair more efficiently and precisely. The future of this technology will depend, ultimately, on the development of safe delivery systems capable to target a large number of muscles. Furthermore, before using oligonucleotides into a clinical setting, we will need to evaluate issues of toxicity, which will have to be balanced with the severity of the disease and the prognosis of the patient. Finally, the rapid progress that has been made to scale up the production of synthetic oligonucleotides will enable the synthesis from micrograms to milligrams quantities allowing this field to move from the bench to the bedside. This review will describe the basic mechanisms of oligonucleotide-mediated gene editing and will explain the potential, hurdles and substantial results obtained using this technology in the treatment of muscular dystrophies.
Bertoni
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Department of Neurology and Neurological Sciences, Stanford University Medical Center, Room A-343, Stanford, CA 94305-5235, USA. cbertoni@stanford.edu
D004260:DNA Repair; D016189:Dystrophin / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy*; D009841:Oligonucleotides; D017393:RNA Editing
D016189:Dystrophin; D009841:Oligonucleotides