Annemieke Aartsma‐Rus

Leiden University Medical Center

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Co-Authors

Maaike van Putten

Leiden University Medical Center

Peter A.C. ‘t Hoen

Radboud University Nijmegen

Pietro Spitali

Leiden University Medical Center

Gert‐Jan B. van Ommen

Leiden University Medical Center

Jan J.G.M. Verschuuren

Leiden University Medical Center

Johan T. den Dunnen

Leiden University Medical Center

E. Niks

Leiden University Medical Center

J.C.T. van Deutekom

BioMarin (Netherlands)

Volker Straub

Newcastle upon Tyne Hospitals NHS Foundation Trust

Hanns Lochmüller

Children's Hospital of Eastern Ontario

Cooperative Institutions

Leiden University Medical Center

333

Leiden University

184

University College London

110

Newcastle University

Radboud University Nijmegen

Inserm

Great Ormond Street Hospital

Radboud University Medical Center

Erasmus MC

University of Amsterdam

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Association study of exome variants in the NF-κB and TGFβ pathways identifies CD40 as a modifier of Duchenne muscular dystrophy

Neuromuscular Disorders (2016)

Luca Bello Kevin M. Flanigan Robert B. Weiss Pietro Spitali Annemieke Aartsma‐Rus

Genome-wide Association Study

Minor allele frequency

Exome

10.1016/j.nmd.2016.06.049

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Citations (6)

From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of SOD1 Mutated Amyotrophic Lateral Sclerosis

Nucleic Acid Therapeutics (2023)

Willeke M. C. van Roon‐Mom Chantal Ferguson Annemieke Aartsma‐Rus

10.1089/nat.2023.0027

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Citations (22)

A Sequel to the Eteplirsen Saga: Eteplirsen Is Approved in the United States but Was Not Approved in Europe

Nucleic Acid Therapeutics (2018)

Annemieke Aartsma‐Rus Nathalie Goemans

Eteplirsen was approved for the treatment of eligible patients with Duchenne muscular dystrophy (DMD) in September 2016 in one of the most, if not the most, controversial approvals ever made by the Food and Drug Administration of the United States. Two years later, the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency gave a negative opinion for eteplirsen treatment. They had done so as well in May 2018, after which Sarepta (the company developing eteplirsen) appealed and a new evaluation was initiated, including a Scientific Advisory Group (SAG) meeting involving DMD experts and patient representatives. However, after reevaluation the opinion of the CHMP remained negative. In this commentary, we outline how differences in the perspective of FDA and EMA can lead to a DMD therapy being approved by FDA but not EMA, and vice versa.

Expert opinion

10.1089/nat.2018.0756

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Citations (54)

Consensus Guidelines for the Design and In Vitro Preclinical Efficacy Testing N-of-1 Exon Skipping Antisense Oligonucleotides

Nucleic Acid Therapeutics (2022)

Annemieke Aartsma‐Rus Alejandro Garanto Willeke M. C. van Roon‐Mom Erin M. McConnell Victoria Suslovitch

Antisense oligonucleotides (ASOs) can modulate pre-mRNA splicing. This offers therapeutic opportunities for numerous genetic diseases, often in a mutation-specific and sometimes even individual-specific manner. Developing therapeutic ASOs for as few as even a single patient has been shown feasible with the development of Milasen for an individual with Batten disease. Efforts to develop individualized ASOs for patients with different genetic diseases are ongoing globally. The N = 1 Collaborative (N1C) is an umbrella organization dedicated to supporting the nascent field of individualized medicine. N1C recently organized a workshop to discuss and advance standards for the rigorous design and testing of splice-switching ASOs. In this study, we present guidelines resulting from that meeting and the key recommendations: (1) dissemination of standardized experimental designs, (2) use of standardized reference ASOs, and (3) a commitment to data sharing and exchange.

Exon skipping

Preclinical testing

10.1089/nat.2022.0060

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Citations (27)

A dystrophic Duchenne mouse model for testing human antisense oligonucleotides

Neuromuscular Disorders (2016)

Marcel H. A. M. Veltrop L. van Vliet Margriet Hulsker Jill Claassens Conny Brouwers

Exon skipping

mdx mouse

10.1016/j.nmd.2016.06.157

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Citations (0)

Neuromuscular synapse characteristics of mice with low dystrophin levels

Neuromuscular Disorders (2015)

Erwin van der Pijl Maaike van Putten Jan J.G.M. Verschuuren Annemieke Aartsma‐Rus Jaap J. Plomp

mdx mouse

Utrophin

XIST

10.1016/j.nmd.2015.06.384

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Citations (0)

DMD – ANIMAL MODELS & PRECLINICAL TREATMENT

Neuromuscular Disorders (2020)

Alper Yavas Maaike van Putten E. Niks Annemieke Aartsma‐Rus

IGFBP3

10.1016/j.nmd.2020.08.219

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Citations (1)

Sensitive and reliable evaluation of single-cut sgRNAs to restore dystrophin by a GFP-reporter assay

PLoS ONE (2020)

Pin Lyu Kyung Whan Yoo Manish Kumar Yadav Anthony Atala Annemieke Aartsma‐Rus

Most Duchenne muscular dystrophy (DMD) cases are caused by deletions or duplications of one or more exons that disrupt the reading frame of DMD mRNA. Restoring the reading frame allows the production of partially functional dystrophin proteins, and result in less severe symptoms. Antisense oligonucleotide mediated exon skipping has been approved for DMD, but this strategy needs repeated treatment. CRISPR/Cas9 can also restore dystrophin reading frame. Although recent in vivo studies showed the efficacy of the single-cut reframing/exon skipping strategy, methods to find the most efficient single-cut sgRNAs for a specific mutation are lacking. Here we show that the insertion/deletion (INDEL) generating efficiency and the INDEL profiles both contribute to the reading frame restoring efficiency of a single-cut sgRNA, thus assays only examining INDEL frequency are not able to find the best sgRNAs. We therefore developed a GFP-reporter assay to evaluate single-cut reframing efficiency, reporting the combined effects of both aspects. We show that the GFP-reporter assay can reliably predict the performance of sgRNAs in myoblasts. This GFP-reporter assay makes it possible to efficiently and reliably find the most efficient single-cut sgRNA for restoring dystrophin expression.

Subgenomic mRNA

Exon skipping

Indel

10.1371/journal.pone.0239468

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Citations (9)

Prednisolone Treatment Does Not Interfere with 2′-O-Methyl Phosphorothioate Antisense-Mediated Exon Skipping in Duchenne Muscular Dystrophy

Human Gene Therapy (2011)

Ingrid E.C. Verhaart Hans Heemskerk Tatyana G. Karnaoukh Ingrid Kolfschoten Anne Vroon

In Duchenne muscular dystrophy (DMD), dystrophin deficiency leading to progressive muscular degeneration is caused by frame-shifting mutations in the DMD gene. Antisense oligonucleotides (AONs) aim to restore the reading frame by skipping of a specific exon(s), thereby allowing the production of a shorter, but semifunctional protein, as is found in the mostly more mildly affected patients with Becker muscular dystrophy. AONs are currently being investigated in phase 3 placebo-controlled clinical trials. Most of the participating patients are treated symptomatically with corticosteroids (mainly predniso[lo]ne) to stabilize the muscle fibers, which might affect the uptake and/or efficiency of AONs. Therefore the effect of prednisolone on 2'-O-methyl phosphorothioate AON efficacy in patient-derived cultured muscle cells and the mdx mouse model (after local and systemic AON treatment) was assessed in this study. Both in vitro and in vivo skip efficiency and biomarker expression were comparable between saline- and prednisolone-cotreated cells and mice. After systemic exon 23-specific AON (23AON) treatment for 8 weeks, dystrophin was detectable in all treated mice. Western blot analyses indicated slightly higher dystrophin levels in prednisolone-treated mice, which might be explained by better muscle condition and consequently more target dystrophin pre-mRNA. In addition, fibrotic and regeneration biomarkers were normalized to some extent in prednisolone- and/or 23AON-treated mice. Overall these results show that the use of prednisone forms no barrier to participation in clinical trials with AONs.

Prednisolone

Exon skipping

10.1089/hum.2011.127

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Citations (15)

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

Neuromuscular Disorders (2016)

Svitlana Pasteuning Joke Boertje-van der Meulen Maaike van Putten Maurice Overzier Peter ten Dijke

Myostatin

Muscle Atrophy

Follistatin

10.1016/j.nmd.2016.06.244

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Citations (2)