Online Seminar: Optimizing antisense mediated exon skipping for Duchenne muscular dystrophy and ultrarare diseases

This seminar is intended for the personnel and students at the University of Oxford and the Oxford University Hospitals Foundation Trust.

Online Seminar – please register for the Zoom event

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disease caused by mutations in the dystrophin gene. The dystrophin protein provides muscle fibres with stability during contraction. In DMD patients, mutations disrupt the reading frame, resulting in prematurely truncated, non-functional dystrophins. By contrast, mutations maintaining the reading frame allow production of internally deleted, partially functional dystrophins. These dystrophins are found in the later onset and less severe Becker muscular dystrophy. The rationale of the exon skipping approach is to modulate splicing of dystrophin pre-mRNA to restore the reading frame so DMD patients can produce Becker-like dystrophins. This can be achieved with antisense oligonucleotides (AON). Exon skipping is a mutation specific approach, since different exons have to be skipped to restore the reading frame depending on the location and size of the mutation. Each AON has to be developed separately as an individual drug.

Currently 4 AONs are approved for DMD by the FDA. However, approvals are based on small increases in dystrophin levels in skeletal muscles. Evidence that treatment results in a slower disease progression still needs to be gathered in currently ongoing clinical trials.

With very low dystrophin levels achieved, it is clear there is room for improvement. There are several ways to achieve this. Here I will touch on a humanized mouse model, and present preclinical studies to try and improve chemistry, dosing and delivery to skeletal muscles.

The exon skipping approach also provides a unique opportunity to treat patients with brain and eye diseases caused by cryptic splicing mutations. Here, local, infrequent treatment is feasible. However, such mutations are rare and therefore these ultimate personalized medicines are not developed. The Dutch Centre for RNA Therapeutics aims to develop bespoke AONs for these individuals in an academic setting and provide them to patients at cost.

Prof. Dr. Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. She played an important role in the development of antisense mediated exon skipping for Duchenne muscular dystrophy during her PhD research (2000-2004) at the Leiden University Medical Center (the Netherlands). As of December 2007 she became leader of the “DMD exon skip group”. Since 2013 she has a visiting professorship at the Institute of Genetic Medicine of Newcastle University (UK). In 2020 she co-founded the Dutch Center for RNA Therapeutics (DCRT), a non-for-profit academic collaboration aiming to develop clinical treatment with exon skipping therapies for eligible patients with unique mutations.

Her work currently focuses on developing antisense-mediated exon skipping as a therapy for Duchenne muscular dystrophy and other rare diseases. This involves work in cell and animal models to improve efficiency of exon skipping, studies in muscle pathology, the identification of biomarkers, studying the basics of pre-mRNA splicing and transcript processing and the generation and detailed analysis of mouse models. Finally, she aims to bridge the gap between stakeholders (patients, academics, regulators and industry) involved in drug development for rare diseases.

In 2011 she received the Duchenne Award from the Dutch Duchenne Parent Project in recognition of this work and her dedication to the Duchenne field. In 2020 she received the Black Pearl Science Award from Eurordis for her work in educating patients in the Duchenne field and other rare disease fields. In 2021 she received the Ammodo Science Award for her contribution to developing exon skipping therapies for Duchenne and the Lifetime achievement award from the Dutch Society of Gene and Cell Therapy for her work on antisense oligonucleotide mediated exon skipping. She has been selected as most influential scientist in Duchenne muscular dystrophy in the past 10 years by Expertscape based on contributions to the understanding and treatment of Duchenne muscular dystrophy annually since 2015.

She is President of the Oligonucleotide Therapeutics Society (2019-2021), is vice-chair of COST Action CA17103 (Delivery of antisense RNA therapies), chair of the TREAT-NMD Advisory Committee for Therapeutics (TACT) and was Chair of the TREAT-NMD executive committee (2013-2016 and 2019-2020). She was a junior member of the Dutch Royal Academy of Sciences (DJA), consisting of the top 50 scientists in the Netherlands under 45, from 2014-2019. She is one of the coordinators of the Oligonucleotide Therapeutics Society Taskforce for the development of N-of-1 oligonucleotide treatments and part of the core group of the N-of-1 collaborative.

For more information about Prof. Dr. Annemieke Aartsma-Rus, visit her group website