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H2020Individual fellowship2016–2017

DYS_FUNCTION · Novel use of exon skipping technology to study structure-function relationship of dystrophin

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-01-01 → 2017-12-31
EU contribution
€195,455
Participants
1
Scheme
MSCA-IF-EF-RI

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Results in brief

Novel use of exon skipping technology to study structure-function relationship of dystrophin

Patients with Duchenne or Becker muscular dystrophy either lack dystrophin or produce a non-functional version of dystrophin, leading to progressive skeletal muscle and heart disease. Heart disease is currently poorly managed with cardiac medications and has become a major cause of death in these patient populations. Very promising new treatment approaches (gene therapy and exon skipping) that lead to expression of a shorter but functional form of dystrophin are currently effective in skeletal muscles but sub-optimal for preventing heart failure. One primary obstacle to their optimization is the lack of information on specific regions of dystrophin that are important for cardiac function and need to be preserved by these new treatment strategies. Therefore, the primary objective of this fellowship was to establish whether a specific region of dystrophin (Hinge 3) that is often absent in shorter dystrophins produced by exon skipping and gene therapy approaches plays a role in heart disease. Our studies have identified a new region adjacent to Hinge 3 that is important for preventing heart disease. We have further determined why this region is important for heart function and have gained important insights into the mechanisms underlying heart disease in Duchenne and Becker muscular dystrophies. This new knowledge will enable the future development of optimized gene therapy and exon skipping strategies that can more effectively protect patients from heart failure. In addition, this knowledge can help identify patients that are at higher risk of early onset heart disease and of heart failure based on genetic testing.

Data: CORDIS, © European Union

Project objective

Duchenne muscular dystrophy (DMD) stems from loss of dystrophin in skeletal and cardiac muscles, which leads to loss of ambulation and cardio-respiratory failure. The most promising treatment that could be applicable to 83% of DMD patients is exon skipping, a technology where the EU is a world leader. Antisense oligonucleotide mediated exon skipping targets DMD pre-mRNA to induce skipping of specific exons and restore the open reading frame. This allows expression of shorter dystrophin proteins that lack domains encoded by the skipped exon(s). A crucial question is how to predict which short dystrophins will be stable and functional. This knowledge is fundamental to select DMD patients that would most benefit from this treatment and identify exons worth targeting via exon skipping. The goal of this proposal is to develop a new use of exon skipping technology to rapidly generate mouse models to screen short dystrophins for in vivo stability and functionality in both skeletal and cardiac muscles. This is made possible by a new exon skipping chemistry developed in the UK with unparalleled skipping efficiency in vivo and capable of targeting the heart. I will use this technology to create mouse models for two short dystrophins generated in DMD patients undergoing exon 51 skipping in the current UK clinical trial. I will then biochemically assess their stability and functionality in limb, cardiac and respiratory muscles. Parallel histological studies will assess the presence of muscle pathology with a focus on heart and diaphragm that cannot be sampled in DMD patients. This project will serve as a trampoline for future studies to identify dystrophin exons that when skipped will produce functional proteins with clinical benefits. In addition, this research will generate new fundamental knowledge on dystrophin domains critical for muscle function and may help in the prognosis of DMD patients currently undergoing exon 51 skipping.

Original text from CORDIS.

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Data: CORDIS, © European Union