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Clinical Implications of Basic Neuroscience Research |

Synthetic Nucleic Acids and Treatment of Neurological Diseases ONLINE FIRST

David R. Corey, PhD1,2
[+] Author Affiliations
1Department of Pharmacology, University of Texas Southwestern, Dallas
2Department of Biochemistry, University of Texas Southwestern, Dallas
JAMA Neurol. Published online August 01, 2016. doi:10.1001/jamaneurol.2016.2089
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Importance  The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease.

Objective  To review the use of ASOs for the treatment of neurological disorders.

Evidence Review  Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich’s ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy).

Findings  Many neurological diseases are caused by inappropriate expression of a protein. Mutations may reduce expression of a wild-type protein, and strategies to activate expression may provide therapeutic benefit. For other diseases, a mutant protein may be expressed too highly and methods that reduce mutant protein expression might form the basis for drug development. Synthetic ASOs can recognize cellular RNA and control gene expression. Antisense oligonucleotides are not a new concept, but successful clinical development has proceeded at a slow pace. Advances in ASO chemistry, biological understanding, and clinical design are making successful applications more likely.

Conclusions and Relevance  Both laboratory and clinical studies are demonstrating the potential of ASOs as a source of drugs to treat neurological disease.

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Figure.
Activation of FXN Expression by Antisense Oligonucleotides

A, Mechanism of transcriptional regulation by expanded AAG trinucleotide repeat within intron 1 of FXN messenger RNA (mRNA). The expanded RNA binds to chromosomal DNA to form an R-loop. This R-loop induces histone modifications and reduces transcription. B, Action of antisense oligonucleotides that target the expanded repeat within intron 1 of FXN mRNA. The antisense oligonucleotide binds the expanded repeat, prevents the RNA from binding to the DNA, and releases the break on transcription. The expression of FXN increases to normal levels.

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