Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

Nucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington’s disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich’s ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, with ensuing neurological and frequently also neuromuscular defects. Repeat expansion is the most frequent event in these diseases; however, sequence contractions, deletions, and mutations have also been reported. Nucleotide repeat sequences are predisposed to adopt non-B-DNA conformations, such as hairpins, cruciform, and intramolecular triple-helix structures (triplexes), also known as H-DNA. For gain-of-function disorders, oligonucleotides can be used to target either transcripts or duplex DNA and in diseases with recessive inheritance oligonucleotides may be used to alter repressive DNA or RNA conformations. Most current treatment strategies are aimed at altering transcript levels, but therapies directed against DNA are also emerging, and novel strategies targeting DNA, instead of RNA, are described. Different mechanisms using modified oligonucleotides are discussed along with the structural aspects of repeat sequences, which can influence binding modes and efficiencies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00712-9) contains supplementary material, which is available to authorized users.