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Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
Published on: May 7, 2020
Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic
Morgan E Rook1, Amber L Southwell2
1Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, 32827, USA. amber.southwell@ucf.edu.
Insights
Huntington disease (HD) treatments using antisense oligonucleotides (ASOs) to lower huntingtin (HTT) protein showed promise but faced setbacks in clinical trials. Further research is needed to understand and overcome these challenges for effective HD therapy.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington disease (HD) is a fatal neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene.
- HTT lowering strategies, particularly antisense oligonucleotides (ASOs), show therapeutic potential for HD.
- ASOs are suitable for central nervous system (CNS) delivery and neuronal uptake.
Purpose of the Study:
- To review the differences in chemistry, targeting, and specificity of HTT ASOs used in recent HD clinical trials.
- To explore preliminary clinical findings from these trials.
- To discuss potential reasons for and implications of the early halting of these trials.
Main Methods:
- Review of preclinical studies and clinical trial data for HTT ASOs in Huntington disease.
- Comparative analysis of ASO chemistry, targeting mechanisms, and specificity.
- Examination of clinical outcomes and safety profiles.
Main Results:
- Two distinct types of HTT ASOs were evaluated in human clinical trials for HD.
- Both clinical trials involving these HTT ASOs were terminated prematurely.
- The review will detail the specific characteristics and findings related to these halted trials.
Conclusions:
- Despite preclinical promise, recent ASO therapies for HD have encountered significant challenges in clinical settings.
- Understanding the differences in ASO design and their clinical performance is crucial for future HD therapeutic development.
- Further investigation is required to optimize ASO strategies for effective Huntington disease treatment.
Abstract:
Huntington disease (HD) is a fatal progressive neurodegenerative disorder caused by an inherited mutation in the huntingtin (HTT) gene, which encodes mutant HTT protein. Though HD remains incurable, various preclinical studies have reported a favorable response to HTT suppression, emphasizing HTT lowering strategies as prospective disease-modifying treatments. Antisense oligonucleotides (ASOs) lower HTT by targeting transcripts and are well suited for treating neurodegenerative disorders as they distribute broadly throughout the central nervous system (CNS) and are freely taken up by neurons, glia, and ependymal cells. With the FDA approval of an ASO therapy for another disease of the CNS, spinal muscular atrophy, ASOs have become a particularly attractive therapeutic option for HD. However, two types of ASOs were recently assessed in human clinical trials for the treatment of HD, and both were halted early. In this review, we will explore the differences in chemistry, targeting, and specificity of these HTT ASOs as well as preliminary clinical findings and potential reasons for and implications of these halted trials.
