Refinement of antisense oligonucleotide mediated exon skipping as therapy for Duchenne muscular dystrophy

Heemskerk, J.A.

In recent years, modulation of mRNA has emerged as a promising therapeutic tool. For instance, in the field of neuromuscular disorders therapeutic strategies are being developed for several diseases, including antisense oligonucleotide (AON) mediated exon skipping for Duchenne Muscular Dystrophy (DMD). DMD patients have no functional dystrophin protein and as a result muscle fibres are damaged upon contraction. Because of the extent and chronicity of the damage this leads to a detrimental inflammatory reaction and eventually to the replacement of muscle fibres by fibro-fatty tissue. With AON mediated exon skipping, a targeted exon is skipped during the pre-mRNA splicing process, resulting in a shorter but partially functional protein. In this thesis we describe studies comparing different AON backbone chemistries and different routes of administration, we describe a reliable method to measure exon skipping, as well as pre-clinical pharmacokinetic and pharmacodynamic studies. These...Show moreIn recent years, modulation of mRNA has emerged as a promising therapeutic tool. For instance, in the field of neuromuscular disorders therapeutic strategies are being developed for several diseases, including antisense oligonucleotide (AON) mediated exon skipping for Duchenne Muscular Dystrophy (DMD). DMD patients have no functional dystrophin protein and as a result muscle fibres are damaged upon contraction. Because of the extent and chronicity of the damage this leads to a detrimental inflammatory reaction and eventually to the replacement of muscle fibres by fibro-fatty tissue. With AON mediated exon skipping, a targeted exon is skipped during the pre-mRNA splicing process, resulting in a shorter but partially functional protein. In this thesis we describe studies comparing different AON backbone chemistries and different routes of administration, we describe a reliable method to measure exon skipping, as well as pre-clinical pharmacokinetic and pharmacodynamic studies. These studies have provided valuable data for the development of AON exon skipping, which is already in clinical trials. Finally, we describe a peptide that potentially homes to muscle tissue and a method to find such peptides. These peptides could increase the amount of AON delivered to the muscle and possible further improve exon skipping in the future.Show less

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Refinement of antisense oligonucleotide mediated exon skipping as therapy for Duchenne muscular dystrophy

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