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

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 Center for RNA Therapeutics aims to develop bespoke AONs for these individuals in an academic setting and provide them to patients at cost.