Therapies targeting DNA and RNA in Huntington's disease
Edward J Wild1, Sarah J Tabrizi1
1Huntington's Disease Centre, University College London Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
Insights
Huntington's disease therapies targeting the HTT gene are advancing rapidly. Gene-silencing strategies like antisense oligonucleotides are entering clinical trials, offering new hope for patients.
Area of Science:
- Neurogenetics
- Molecular Medicine
- Therapeutic Development
Background:
- Huntington's disease (HD) is a monogenic neurodegenerative disorder.
- It stems from CAG repeat expansions in the HTT gene, leading to toxic huntingtin protein accumulation.
- Currently, no treatments can slow or halt HD progression.
Purpose of the Study:
- To review the current landscape of Huntington's disease therapeutic strategies.
- To highlight the progress in developing gene-silencing therapies targeting HTT.
- To discuss the potential of these novel approaches in clinical settings.
Main Methods:
- Review of current research and clinical trial data for HD therapies.
- Focus on huntingtin-lowering strategies including antisense oligonucleotides (ASOs) and RNA interference (RNAi) targeting mRNA.
- Exploration of DNA-targeting methods like zinc finger transcriptional repressors and CRISPR-Cas9.
Main Results:
- An intrathecally delivered ASO targeting huntingtin is in its first human clinical trial.
- Multiple ASO therapies are anticipated to enter clinical trials within 1-2 years.
- RNAi and zinc finger transcriptional repressors are in advanced preclinical development in animal models.
Conclusions:
- Advances in HTT RNA and DNA targeting therapies show promise for improved efficacy and safety.
- Gene-silencing strategies represent a significant therapeutic avenue for Huntington's disease.
- Ongoing research and clinical trials are paving the way for potential disease-modifying treatments.
Abstract:
No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.
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