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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression
Eman M Zaghloul1,2, Olof Gissberg1, Pedro M D Moreno1,3,4
1Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, SE-141 86 Huddinge, Stockholm, Sweden.
Insights
Researchers developed a novel oligonucleotide therapy targeting the Huntington gene (HTT) to reduce toxic mutant HTT. This approach successfully lowered HTT mRNA and protein levels, offering a potential new treatment for Huntington's disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by motor, cognitive, and psychological impairments.
- Current HD treatments are purely symptomatic and do not affect disease progression or lifespan.
- HD pathogenesis involves the expansion of CAG trinucleotide repeats in the Huntingtin gene (HTT), producing toxic mutant HTT (muHTT) mRNA and protein.
Purpose of the Study:
- To develop a novel therapeutic strategy for Huntington's disease by targeting the expanded CAG trinucleotide repeat DNA in the HTT gene.
- To investigate the efficacy of oligonucleotides (ONs) in reducing both mutant HTT mRNA and protein levels.
- To explore the impact of different ON backbone chemistries and delivery methods for potential in vivo applications.
Main Methods:
- Oligonucleotides (ONs) were designed to directly target the CAG trinucleotide repeat region in the Huntingtin (HTT) gene DNA.
- The study assessed the knockdown efficiency of both HTT mRNA and protein levels.
- Researchers examined the phosphorylation of HTT gene-associated RNA-polymerase II and evaluated various ON backbone chemistries and delivery vehicles.
Main Results:
- A significant and potentially long-term reduction in both HTT mRNA and protein levels was achieved using the novel ON strategy.
- Diminished phosphorylation of HTT gene-associated RNA-polymerase II suggests reduced transcription downstream of the targeted repeat.
- Different ON backbone chemistries significantly influenced therapeutic efficiency, and successful delivery was demonstrated using various vehicles and naked uptake.
Conclusions:
- This novel oligonucleotide-based approach effectively reduces mutant Huntingtin (muHTT) mRNA and protein, representing a promising therapeutic strategy for Huntington's disease.
- The findings highlight the importance of ON backbone chemistry and delivery methods for therapeutic efficacy.
- The study provides a foundation for developing in vivo applications of this targeted gene-silencing strategy for Huntington's disease.
Abstract:
Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion of the CAG trinucleotide repeat region in exon 1 of the Huntingtin gene (HTT), leading to the formation of mutant HTT transcripts (muHTT). The toxic gain-of-function of muHTT protein is a major cause of the disease. In addition, it has been suggested that the muHTT transcript contributes to the toxicity. Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT knock-down of both mRNA and protein was successfully achieved. Diminished phosphorylation of HTT gene-associated RNA-polymerase II is demonstrated, suggestive of reduced transcription downstream the ON-targeted repeat. Different backbone chemistries were found to have a strong impact on the ON efficiency. We also successfully use different delivery vehicles as well as naked uptake of the ONs, demonstrating versatility and possibly providing insights for in vivo applications.
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