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Clinical Implications of Basic Neuroscience Research
October 2016

Synthetic Nucleic Acids and Treatment of Neurological Diseases

Author Affiliations
  • 1Department of Pharmacology, University of Texas Southwestern, Dallas
  • 2Department of Biochemistry, University of Texas Southwestern, Dallas
JAMA Neurol. 2016;73(10):1238-1242. doi:10.1001/jamaneurol.2016.2089
Key Points

Question  What is the status of using oligonucleotides to modulate gene expression for the treatment of neurological diseases?

Findings  Work using oligonucleotides to modulate expression of frataxin and survival motor neuron proteins demonstrates progress in both the basic and clinical science.

Meaning  The significance of oligonucleotides as a treatment strategy for neurological diseases is likely to increase.


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.