Current approaches for repeat expansion diseases

Therapeutic approachDescriptionDiseases targetedReferences
Gene silencing therapies
Antisense oligonucleotides (ASOs)Synthetic strands of nucleic acids targeting specific RNA to degrade or prevent translation.HD, SCA3, C9ORF72 mediated ALS/FTD, SBMA, DM1[4–20]
RNA interference by siRNAUses siRNA to degrade mRNA encoding toxic proteins.DM1, HD, C9ORF72 mediated ALS/FTD[21–29]
RNA interference by miRNAUses miRNA to degrade mRNA encoding toxic proteins.HD, SBMA[15, 30–34]
CRISPR/Cas9 gene editing
Direct repeat excisionExcises expanded repeat sequences using CRISPR/Cas9.HD, SCA, DM1[35–40]
Base editingAlters specific nucleotides in expanded repeats without creating double-stranded breaks.HD[41–43]
Small molecule therapies
RNA repeats or transcription factor binding moleculesSmall molecules bind expanded RNA repeats or transcription factors to prevent toxic RNA foci formation.DM, HD[44–46]
Proteostasis regulatorsEnhance degradation of toxic proteins via the proteasome or autophagy pathways.HD[47–53]
Gene therapy
Gene replacementIntroduces functional copies of affected genes.SBMA, DM[54–56]
Regulatory element modificationModifies regulatory elements to upregulate normal alleles or downregulate mutant ones.FXS[57]
Modulating toxic protein aggregation
Heat shock proteins (HSPs)Enhance protein folding and clearance of misfolded proteins.HD[58]
Chemical chaperonesStabilize protein structures to prevent toxic aggregation.HD[59–63]

HD: Huntington’s disease; SCA3: spinocerebellar ataxia type 3; ALS/FTD: amyotrophic lateral sclerosis/frontotemporal dementia; SBMA: spinal and bulbar muscular atrophy; DM1: myotonic dystrophy type 1; FXS: fragile X syndrome