Antisense RNA Therapeutics: A Brief Overview

Arechavala‐Gomeza, Virginia; Garanto, Alejandro

doi:10.1007/978-1-0716-2010-6_2

Cited by 6 publications

(6 citation statements)

References 80 publications

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“…The procedure for preclinical development of a therapeutic molecule usually involves an initial step with a series of assays performed in cellular model systems, which also applies to NATs. Once the nucleic acid sequences are designed using in silico predictions [ 35–37 ], they are subsequently assessed on efficacy in cellular models [ 33 ]. Thereby, having a suitable cellular model system is crucial not only at initial development stages, but also for lead candidate selection and optimization.…”

Section: Discussionmentioning

confidence: 99%

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Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics

Zhou

Arechavala‐Gomeza

Garanto

2023

Nucleic Acid Therapeutics

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Preclinical evaluation of nucleic acid therapeutics (NATs) in relevant experimental model systems is essential for NAT drug development. As part of COST Action “DARTER” (Delivery of Antisense RNA ThERapeutics), a network of researchers in the field of RNA therapeutics, we have conducted a survey on the experimental model systems routinely used by our members in preclinical NAT development. The questionnaire focused on both cellular and animal models. Our survey results suggest that skin fibroblast cultures derived from patients is the most commonly used cellular model, while induced pluripotent stem cell-derived models are also highly reported, highlighting the increasing potential of this technology. Splice-switching antisense oligonucleotide is the most frequently investigated RNA molecule, followed by small interfering RNA. Animal models are less prevalent but also widely used among groups in the network, with transgenic mouse models ranking the top. Concerning the research fields represented in our survey, the mostly studied disease area is neuromuscular disorders, followed by neurometabolic diseases and cancers. Brain, skeletal muscle, heart, and liver are the top four tissues of interest reported. We expect that this snapshot of the current preclinical models will facilitate decision making and the share of resources between academics and industry worldwide to facilitate the development of NATs.

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Section: Discussionmentioning

confidence: 99%

“…Model system is one of the key topics that the DARTER network has been focused on. In the last 4 years, this working group has shared among its members their individual experiences in using different models at DARTER seminars and through shared protocols [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics

Zhou

Arechavala‐Gomeza

Garanto

2023

Nucleic Acid Therapeutics

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“…For example, the development of proper models to assess the sequence-dependent efficacy and safety of ASOs is still a pending issue [ 54 ]. This is particularly relevant for the splicing modulation approaches designed to correct specific disease-causing mutations that affect the normal splicing process, the so-called splicing mutations.…”

Section: Splicing: How It Work and How It Can Be Modulatedmentioning

confidence: 99%

“…The alternative would be to generate humanized animal models, an approach that is both time- and resource-consuming and may contribute to a substantial increase in the drug development time while requiring additional funding. Furthermore, the generation of a humanized animal model for every mutation that needs to be targeted is neither feasible nor ethical and may not always recapitulate the human molecular and/or physiological phenotypes [ 54 , 55 ].…”

Section: Splicing: How It Work and How It Can Be Modulatedmentioning

confidence: 99%

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

Santos

Gonçalves

Matos

et al. 2022

Life

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Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled. Quite remarkably, this explosion of novel RNA classes has increased the possibility for new therapeutic strategies that tap into RNA biology. Most of these drugs use nucleic acid analogues and take advantage of complementary base pairing to either mimic or antagonize the function of RNAs. Among the most successful RNA-based drugs are those that act at the pre-mRNA level to modulate or correct aberrant splicing patterns, which are caused by specific pathogenic variants. This approach is particularly tempting for monogenic disorders with associated splicing defects, especially when they are highly frequent among affected patients worldwide or within a specific population. With more than 600 mutations that cause disease affecting the pre-mRNA splicing process, we consider lysosomal storage diseases (LSDs) to be perfect candidates for this type of approach. Here, we introduce the overall rationale and general mechanisms of splicing modulation approaches and highlight the currently marketed formulations, which have been developed for non-lysosomal genetic disorders. We also extensively reviewed the existing preclinical studies on the potential of this sort of therapeutic strategy to recover aberrant splicing and increase enzyme activity in our diseases of interest: the LSDs. Special attention was paid to a particular subgroup of LSDs: the mucopolysaccharidoses (MPSs). By doing this, we hoped to unveil the unique therapeutic potential of the use of this sort of approach for LSDs as a whole.

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“…Broadly speaking, ONDs can be used to inhibit or restore the expression of some target genes by diverse mechanisms, including degrading messenger RNA (mRNA) transcripts causing gene silencing/knockdown or altering the splicing of pre-mRNAs [ 2 ]. For example, transcript degradation of mRNA can be achieved by antisense oligonucleotides (ASOs) recruiting RNase H1 cleaving DNA-RNA hybrids; by small interfering RNAs (siRNAs) that mediate target RNA degradation through RNA-induced silencing complex (RISC); or by splice-switching OND, which may be designed to skip regular exons in the pre-mRNA and thus create mRNA isoforms that encode nonfunctional proteins or trigger degradation of the mRNA by nonsense-mediated decay [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides

Goyenvalle

Jiménez-Mallebrera

Roon-Mom

et al. 2023

Nucleic Acid Therapeutics

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The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network “DARTER,” a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity in vitro or ex vivo to filter out potential toxic candidates before moving to in vivo phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human in vitro systems. Yet, small preliminary in vivo studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.

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Antisense RNA Therapeutics: A Brief Overview

Cited by 6 publications

References 80 publications

Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics

Experimental Model Systems Used in the Preclinical Development of Nucleic Acid Therapeutics

Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides

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