Abstract
Antisense oligonucleotides (ASOs) are short, modified pieces of DNA that are chemically
modified. They can be used to induce exon skipping and treat Duchenne muscular dystrophy
(DMD) patients by interfering with the splicing process so mutated dystrophin transcripts
become readable allowing production of partially functional dystrophin proteins, rather
than nonfunctional dystrophins. After over 2 decades of research, 4 ASOs are FDA approved
for DMD, but clinical effects are suboptimal due to limited delivery to skeletal muscle.
At the same time, ASOs for brain diseases result in much more functional impact, because
local delivery allows higher exposure to the target tissue at a low dose and infrequent
treatment regimen. This has opened the way to develop ASOs in an individualized setting,
as was exemplified by the development of Milasen to treat a patient with CLN7 Batten
disease.
In this perspective paper I will share my personal journey as one of the pioneers
of ASO-mediated exon skipping development for DMD, currently applying expertise gained
and lessons learned along the way to develop exon skipping ASOs for eligible patients
with genetic brain diseases in a national and international setting.
1 Duchenne and Antisense-Mediated Exon Skipping
2 Opportunities for Treating Central Nervous System Diseases and Developing Individualized
ASOs for Central Nervous System Diseases
3 Collaborative Spirit to Develop Individualized Treatments Globally
4 Global Implementation
5 Concluding Remarks
Key words antisense oligonucleotide - exon skipping - N-of-1 treatment - rare disease - therapy
