Oligonucleotide therapies are currently experiencing a resurgence driven by 
advances in backbone chemistry and discoveries of novel therapeutic pathways 
that can be uniquely and efficiently modulated by the oligonucleotide drugs. A 
quarter of a century has passed since oligonucleotides were first applied in 
living mammalian brain to modulate gene expression. Despite challenges in 
delivery to the brain, multiple oligonucleotide-based compounds are now being 
developed for treatment of human brain disorders by direct delivery inside the 
blood brain barrier (BBB). Notably, the first new central nervous system 
(CNS)-targeted oligonucleotide-based drug (nusinersen/Spinraza) was approved by 
US Food and Drug Administration (FDA) in late 2016 and several other compounds 
are in advanced clinical trials. Human testing of brain-targeted 
oligonucleotides has highlighted unusual pharmacokinetic and pharmacodynamic 
properties of these compounds, including complex active uptake mechanisms, low 
systemic exposure, extremely long half-lives, accumulation and gradual release 
from subcellular depots. Further work on oligonucleotide uptake, development of 
formulations for delivery across the BBB and relevant disease biology studies 
are required for further optimization of the oligonucleotide drug development 
process for brain applications.