Targeted Augmentation of Nuclear Gene Output (TANGO)

Excerpt

Most development and epileptic encephalopathies (DEEs) are genetic in origin. Drug-resistant epilepsy is often the most notable feature of the DEEs, although numerous other symptoms are present that have significant impact on patients’ quality of life. Despite novel, third-generation antiseizure drug treatment options becoming available over the last several years, seizure freedom is often not attained and nonseizure symptoms remain. Therapeutic approaches such as antisense oligonucleotides and adeno-associated virus delivered gene modulation offers realistic hope for seizure freedom in some DEEs with an underlying genetic etiology, with several approaches demonstrating preclinical success and now transitioning to clinical trials. Several of these therapeutic strategies risk the exacerbation of gain-of-function variants and may not be reversible, thus emphasizing the need for functional testing of variants and more reliable prediction tools for pathogenicity. Dravet syndrome, Rett syndrome, and Angelman syndrome are presented here as examples of how these techniques are being applied and the nuances and challenges of each unique genetic disorder. Additionally, with so many gene regulatory therapeutic options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.