Synthetic nucleic acids and treatment of neurological diseases

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.