Antisense-Mediated Exon Skipping: Networking to Meet Opportunities and to Overcome Challenges

Aartsma‐Rus, Annemieke

doi:10.1089/nat.2014.1500

Cited by 13 publications

(5 citation statements)

References 10 publications

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“…A substantial proportion of diseases are caused by missplicing of the pre-mRNA. Oligonucleotides are increasingly applied for splicing correction as reviewed [88,89]. These oligonucleotides are not aimed at cleaving the target RNA; rather, they prevent incorrect splicing or redirect splicing.…”

Section: No Target Cleavagementioning

confidence: 99%

Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

Eckstein

2014

Nucleic Acid Therapeutics

498

385

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Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined.

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Section: No Target Cleavagementioning

confidence: 99%

Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

Eckstein

2014

Nucleic Acid Therapeutics

498

385

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“…However, numerous specific and early biomarkers of toxicity can now be evaluated in mice (treated with high doses of AONs) to predict toxicity in pre-clinical development 20 . These delivery challenges were recognized by experts from the COST Action BM1207 “Networking towards clinical implementation of antisense-mediated exon skipping for rare diseases” 21 (http://exonskipping.eu), and it is becoming clear that these toxicological challenges should be addressed in the very early stages of new AON development to ensure the clinical translation of these studies 22 . Because tcDNA chemistry has never been used in the clinic, as opposed to other naked chemistries, which have been evaluated for other applications before DMD, we believe it is of importance to evaluate its toxicological profile in mice before undertaking expensive and lengthy reglementary toxicological studies.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety Profile of Tricyclo-DNA Antisense Oligonucleotides in Duchenne Muscular Dystrophy Mouse Model

Relizani

Griffith

Echevarría

et al. 2017

Molecular Therapy - Nucleic Acids

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Antisense oligonucleotides (AONs) hold promise for therapeutic splice-switching correction in many genetic diseases. However, despite advances in AON chemistry and design, systemic use of AONs is limited due to poor tissue uptake and sufficient therapeutic efficacy is still difficult to achieve. A novel class of AONs made of tricyclo-DNA (tcDNA) is considered very promising for the treatment of Duchenne muscular dystrophy (DMD), a neuromuscular disease typically caused by frameshifting deletions or nonsense mutations in the gene-encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, and respiratory failure in addition to cognitive impairment. Herein, we report the efficacy and toxicology profile of a 13-mer tcDNA in mdx mice. We show that systemic delivery of 13-mer tcDNA allows restoration of dystrophin in skeletal muscles and to a lower extent in the brain, leading to muscle function improvement and correction of behavioral features linked to the emotional/cognitive deficiency. More importantly, tcDNA treatment was generally limited to minimal glomerular changes and few cell necroses in proximal tubules, with only slight variation in serum and urinary kidney toxicity biomarker levels. These results demonstrate an encouraging safety profile for tcDNA, albeit typical of phosphorothiate AONs, and confirm its therapeutic potential for the systemic treatment of DMD patients.

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“…Regulatory agencies have a process in place to qualify biomarkers for a specific purpose (‘context of use’) [2,3]. Multiple interactions coordinated by patient organisations, the TREAT-NMD [7] alliance and a cooperation of science and technology (COST) Action (BM1207) [8] have taken place between the DMD field (academics, patient organisations and industry) and the regulators to discuss the specific challenges of DMD therapy development, including biomarkers where the focus thus far mostly has been on dystrophin quantification and magnetic resonance imaging (MRI) [4,9].…”

Section: Session 1: Setting the Stagementioning

confidence: 99%