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Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT
Naoki Iwamoto1, Yuanjing Liu1, Maria Frank-Kamenetsky1
1Wave Life Sciences, Cambridge, MA 02138, USA.
Insights
Researchers developed allele-selective oligonucleotides to lower mutant huntingtin protein (mHTT) in Huntington's disease (HD). These compounds selectively target mHTT, sparing beneficial wild-type HTT (wtHTT), showing promise for safer HD treatments.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Drug Discovery
Background:
- Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the HTT gene.
- Mutant HTT (mHTT) leads to toxic protein aggregation, while wild-type HTT (wtHTT) has essential functions in the central nervous system.
- Selective lowering of mHTT while preserving wtHTT is a therapeutic strategy to mitigate HD pathology and preserve neurological function.
Purpose of the Study:
- To investigate the potential of stereopure phosphorothioate (PS) and phosphoryl guanidine (PN) oligonucleotides for allele-selective lowering of mHTT.
- To target the rs362273 single-nucleotide polymorphism (SNP3) for differentiating between mutant and wild-type HTT alleles.
- To evaluate the potency, durability, and selectivity of SNP3-targeting oligonucleotides in vitro and in vivo.
Main Methods:
- Design and synthesis of stereopure PS- and PN-containing oligonucleotides targeting the rs362273 (SNP3) polymorphism.
- In vitro assays to assess the allele selectivity and potency of the oligonucleotides against mHTT and wtHTT.
- In vivo studies in mouse models of Huntington's disease to evaluate the efficacy, durability, and safety profile of the lead candidate.
Main Results:
- SNP3-targeting oligonucleotides demonstrated potent and durable allele-selective lowering of mHTT in both in vitro and in vivo models.
- The developed molecules effectively spared wtHTT, preserving its essential functions.
- Comparison with a nonselective agent showed equivalent mHTT lowering with improved durability and wtHTT sparing, supporting the therapeutic advantage of allele-selective approaches.
Conclusions:
- Stereopure oligonucleotides targeting SNP3 offer a promising strategy for allele-selective mHTT lowering in Huntington's disease.
- These findings support the advancement of WVE-003, an investigational therapy for HD, into clinical trials.
- Allele-selective lowering represents a potentially safer and more effective therapeutic approach for Huntington's disease compared to nonselective methods.
Abstract:
Huntington's disease (HD) is an autosomal dominant disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in one copy of the HTT gene (mutant HTT, mHTT). The unaffected HTT gene encodes wild-type HTT (wtHTT) protein, which supports processes important for the health and function of the central nervous system. Selective lowering of mHTT for the treatment of HD may provide a benefit over nonselective HTT-lowering approaches, as it aims to preserve the beneficial activities of wtHTT. Targeting a heterozygous single-nucleotide polymorphism (SNP) where the targeted variant is on the mHTT gene is one strategy for achieving allele-selective activity. Herein, we investigated whether stereopure phosphorothioate (PS)- and phosphoryl guanidine (PN)-containing oligonucleotides can direct allele-selective mHTT lowering by targeting rs362273 (SNP3). We demonstrate that our SNP3-targeting molecules are potent, durable, and selective for mHTT in vitro and in vivo in mouse models. Through comparisons with a surrogate for the nonselective investigational compound tominersen, we also demonstrate that allele-selective molecules display equivalent potency toward mHTT with improved durability while sparing wtHTT. Our preclinical findings support the advancement of WVE-003, an investigational allele-selective compound currently in clinical testing (NCT05032196) for the treatment of patients with HD.
