None approved; Tominersen Phase 3 halted; WVE-003 (allele-selective) in Phase 1/2
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in exon 1 of the HTT gene. Normal individuals have 10–35 CAG repeats; individuals with 36 or more develop Huntington’s disease, typically with onset in the 30s–50s. The expanded repeat produces a mutant huntingtin protein with an abnormally long polyglutamine tract, which misfolds, aggregates, and is toxic to neurons, particularly in the striatum and cortex.
The disease manifests as a triad of motor symptoms (chorea, dystonia, impaired coordination), cognitive decline, and psychiatric disturbances. It is relentlessly progressive and uniformly fatal, with death typically occurring 15–20 years after onset. There is currently no approved disease-modifying treatment.
Because Huntington’s disease is caused by a toxic gain-of-function protein, gene silencing is a rational therapeutic strategy. ASOs designed to reduce HTT mRNA levels can decrease production of the toxic mutant huntingtin protein. The approach is conceptually similar to the gene-silencing strategy used in hATTR (Tegsedi) and ALS (Qalsody).
Tominersen (formerly IONIS-HTTRx/RG6042), developed by Ionis Pharmaceuticals and Roche, was the first HTT-lowering ASO to reach Phase 3 clinical trials. Tominersen is a non-selective ASO that reduces both mutant and wild-type HTT mRNA. While the Phase 1/2 trial showed dose-dependent reduction of mutant huntingtin in cerebrospinal fluid, the Phase 3 GENERATION HD1 trial was halted in 2021 after an independent monitoring committee found that treated patients fared worse than controls in some dosing regimens. This setback highlighted the potential importance of allele selectivity — reducing the mutant HTT while preserving the normal copy.
Wave Life Sciences is developing WVE-003, an allele-selective ASO that targets a single nucleotide polymorphism (SNP) linked to the expanded CAG repeat on the mutant allele. By designing the ASO to discriminate between the mutant and wild-type alleles based on this SNP, WVE-003 aims to reduce mutant huntingtin while leaving wild-type huntingtin intact. This allele-selective approach is in Phase 1/2 trials.
The Huntington’s disease experience illustrates why personalized ASO design matters even for well-studied diseases. Different patients carry different SNP haplotypes linked to their expanded allele, and an allele-selective ASO must be designed to match the patient’s specific genetic context. Pequliar designs gene-silencing ASO candidates for Huntington’s disease, with the ability to target specific SNPs for allele-selective approaches. The platform identifies optimal binding sites, scores candidates for binding affinity and off-target safety, and provides synthesis-ready sequences with full chemistry assignment.
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Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.