Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Nucleotide repeat disorders comprise over 30 dominant and recessive diseases, including Huntington's disease and Friedreich's ataxia.
• A commonality is the presence of DNA tandem repeats within disease-associated genes, prone to expansion in germ and somatic cells, leading to neurological and neuromuscular defects.

Purpose of the Study:

• To explore novel therapeutic strategies for nucleotide repeat disorders, focusing on DNA-targeting oligonucleotides.
• To discuss the mechanisms and structural aspects of repeat sequences influencing oligonucleotide binding and efficacy.

Main Methods:

• Review of current literature on nucleotide repeat disorders and oligonucleotide-based therapies.
• Analysis of DNA tandem repeat structures, including non-B-DNA conformations (hairpins, cruciforms, triplexes/H-DNA).

Main Results:

• Repeat expansion is the most frequent pathogenic event, though contractions, deletions, and mutations also occur.
• Nucleotide repeat sequences can form non-B-DNA structures, impacting therapeutic targeting.
• Oligonucleotides can target transcripts or DNA, with emerging DNA-directed therapies showing promise.

Conclusions:

• Oligonucleotide-based therapies targeting DNA represent a promising frontier for treating nucleotide repeat disorders.
• Understanding the structural properties of repeat sequences is crucial for optimizing the design and efficiency of these novel therapies.