Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

Abstract

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.Key Words Chromatin . DNA repair . fragile X syndrome . locked nucleic acid . spinal and bulbar muscular atrophy . non-canonical DNA structure Neurotherapeutics (2019) 16:248-262 https://doi.

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

“…Moreover, the ACAP3 gene, in which UPS29 is located, may play a role in the development of this disease and other neurological pathologies under environmental influences. The structural and epigenetic changes of intra-intronic minisatellite observed in this work upon epilepsy and perhaps for other neurological disease points to possible usage of nucleic acid (in particular non-coding tandem repeats) therapies as was suggested in [108][109][110]. All these statements concerning the molecular mechanisms of action of UPS29 and ACAP3 in the etiopathogenesis of epilepsy require further research.…”

Genomic analysis of patients in a South Indian Community with autosomal dominant cortical tremor, myoclonus and epilepsy suggests a founder repeat expansion mutation in theSAMD12gene

“…The RP-PCR can serve as a sensitive and cost-effective technique to do community level genetic screening. Screening for such repeat expansions associated with epileptic disorders across diverse communities in India will provide further understanding of the molecular basis of the disease and help in bridging the gap for developing therapeutic strategies ( Batra et al , 2017 ; Zain and Smith, 2019 ).…”

Pharmacokinetics and Proceedings in Clinical Application of Nucleic Acid Therapeutics

“…For such gain-offunction disorders, therapeutic oligonucleotides can be used to target either transcripts or duplex DNA. 111…”