The Use of Tricyclo-DNA Oligomers for the Treatment of Genetic Disorders

Aupy, Philippine; Echevarría, Lucía; Relizani, Karima; Goyenvalle, Aurélie

doi:10.3390/biomedicines6010002

Cited by 11 publications

(11 citation statements)

References 95 publications

(110 reference statements)

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“…A ntisense strategies are based on the use of antisense oligonucleotides (ASOs) to modify mRNA by increasing or decreasing gene expression or via splicing modulation [1]. ASO-based therapeutics are currently one of the most promising therapeutic solutions for the treatment of many yet-uncured genetic diseases, in particular Duchene muscular dystrophy (DMD) for which ASO-exon skipping represents one of the most advanced therapeutic strategies [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Impact of Variable Phosphorothioate Content in Tricyclo-DNA Antisense Oligonucleotides in a Duchenne Muscular Dystrophy Mouse Model

Echevarría

Aupy

Relizani

et al. 2019

Nucleic Acid Therapeutics

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Antisense oligonucleotides (ASOs) hold promise for therapeutic splice switching correction for genetic diseases, in particular for Duchenne muscular dystrophy (DMD), for which ASO-exon skipping represents one of the most advanced therapeutic strategies. We have previously reported the therapeutic potential of tricyclo-DNA (tcDNA) in mouse models of DMD, highlighting the unique pharmaceutical properties and unprecedented uptake in many tissues after systemic delivery, including the heart and central nervous system. TcDNA-ASOs demonstrate an encouraging safety profile and no particular class-related toxicity, however, when administered in high doses for several months, mild renal toxicity is observed secondary to predictable phosphorothioate (PS)-ASO accumulation in kidneys. In this study, we investigate the influence of the relative content of PS linkages in tcDNA-ASOs on exon skipping efficacy. Mdx mice were injected intravenously once weekly for 4 weeks with tcDNA carrying various amounts of PS linkages (0%, 25%, 33%, 50%, 67%, 83%, and 100%). The results indicate that levels of exon-23 skipping and dystrophin rescue increase with the number of PS linkages in most skeletal muscles except in the heart. As expected, plasma coagulation times are shortened with decreasing PS content, and tcDNA-protein binding in serum directly correlates with the number of PS linkages on the tcDNA backbone. Altogether, these data contribute in establishing the appropriate sulfur content within the tcDNA backbone for maximal efficacy and minimal toxicity of the oligonucleotide.

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Section: Introductionmentioning

confidence: 99%

Evaluating the Impact of Variable Phosphorothioate Content in Tricyclo-DNA Antisense Oligonucleotides in a Duchenne Muscular Dystrophy Mouse Model

Echevarría

Aupy

Relizani

et al. 2019

Nucleic Acid Therapeutics

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“…They are very effective antisense agents. They have high serum stability and are unable to activate RNAse H [ 92 , 93 ]. Except for the poly-A and poly-T sequences, tricyclo-DNA prefers Watson-Crick pairing [ 94 ].…”

Section: Artificial Nucleic Acidsmentioning

confidence: 99%

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

Bege

Borbás

2022

Pharmaceuticals

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Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.

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“…tcDNA deviates from natural DNA by the presence of three additional carbon atoms between c5′ and c3′, to which a cyclopropane unit is attached to further enhance structural stability [ 41 , 42 ]. tcDNA chemistry displays interesting properties for neuromuscular disorder therapy due to its quick uptake in cardiac and respiratory muscles [ 43 ]. This chemistry also has the unique property of being capable of crossing the blood-brain barrier at low levels after systemic uptake [ 38 , 39 , 40 ].…”

Section: Chemical Modificationsmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation

Raguraman

Akilandeswari

Chen

et al. 2021

Cancers

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Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer.

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The Use of Tricyclo-DNA Oligomers for the Treatment of Genetic Disorders

Cited by 11 publications

References 95 publications

Evaluating the Impact of Variable Phosphorothioate Content in Tricyclo-DNA Antisense Oligonucleotides in a Duchenne Muscular Dystrophy Mouse Model

Evaluating the Impact of Variable Phosphorothioate Content in Tricyclo-DNA Antisense Oligonucleotides in a Duchenne Muscular Dystrophy Mouse Model

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation

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