Antisense Oligonucleotides: Insights from Preclinical Studies and Clinical Trials

Kunze, Doreen; Kraemer, Kai; Fuessel, Susanne

doi:10.1007/978-3-642-12168-5_13

Cited by 3 publications

(1 citation statement)

References 65 publications

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“…One ASO has been approved by the FDA and at least 22 oligonucleotide drugs are in Phase II or III clinical trials (Table 2). Many more are earlier in the process of clinical development [91,158,160,161]. …”

Section: Clinical Progressmentioning

confidence: 99%

Silencing disease genes in the laboratory and the clinic

Watts

Corey

2011

The Journal of Pathology

391

309

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Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past twenty years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology.

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Section: Clinical Progressmentioning

confidence: 99%

Silencing disease genes in the laboratory and the clinic

Watts

Corey

2011

The Journal of Pathology

391

309

View full text Add to dashboard Cite

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Recent advances in chemical modifications of guide RNA, mRNA and donor template for CRISPR-mediated genome editing

Chen

Zhang

Yin

2021

Advanced Drug Delivery Reviews

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RNA therapy for polyglutamine neurodegenerative diseases

Watson

Wood

2012

Expert Rev. Mol. Med.

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Polyglutamine neurodegenerative diseases result from the expansion of a trinucleotide CAG repeat, encoding a polyglutamine tract in the disease-causing protein. The process by which each polyglutamine protein exerts its toxicity is complex, involving a variety of mechanisms including transcriptional dysregulation, proteasome impairment and mitochondrial dysfunction. Thus, the most effective and widely applicable therapies are likely to be those designed to eliminate production of the mutant protein upstream of these deleterious effects. RNA-based approaches represent promising therapeutic strategies for polyglutamine diseases, offering the potential to suppress gene expression in a sequence-specific manner at the transcriptional and post-transcriptional levels. In particular, gene silencing therapies capable of discrimination between mutant and wildtype alleles, based on disease-linked polymorphisms or CAG repeat length, might prove crucial in cases where a loss of wild type function is deleterious. Novel methods, such as gene knockdown and replacement, seek to eliminate the technical difficulties associated with allele-specific silencing by avoiding the need to target specific mutations. With a variety of RNA technologies currently being developed to target multiple facets of polyglutamine pathogenesis, the emergence of an effective therapy seems imminent. However, numerous technical obstacles associated with design, discrimination and delivery must be overcome before RNA therapy can be effectively applied in the clinical setting.

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Antisense Oligonucleotides: Insights from Preclinical Studies and Clinical Trials

Cited by 3 publications

References 65 publications

Silencing disease genes in the laboratory and the clinic

Silencing disease genes in the laboratory and the clinic

Recent advances in chemical modifications of guide RNA, mRNA and donor template for CRISPR-mediated genome editing

RNA therapy for polyglutamine neurodegenerative diseases

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