Figure 3. Delivery of oligonucleotides to the brain and eye.

(A) ONs are prevented from passive diffusion into the central nervous system (CNS) by the vascular BBB. (B) ONs without a delivery reagent require direct administration into the brain or spinal cord. The most frequently used CNS administration route in humans is intrathecal (IT) administration, where ONs are administered into the subarachnoid space of the spinal cord to pass the pia mater and enter the parenchyma. This results in an immediate high ON concentration in the cerebral spinal fluid, meaning that a lower dose can be used, which reduces side effects. Also, the BBB prevents transport of ONs into the peripheral circulation resulting in long‐lasting high ON concentrations. (C) The eye is a contained and immune‐privileged organ of the CNS that allows local delivery. ONs are effective and well tolerated when administered directly by intravitreal injection. Subretinal delivery is also possible, but the treated area will be reduced. (D) Certain macromolecules can cross the vascular barriers via receptor‐mediated endocytosis after systemic administration (Pardridge, 2007). The transferrin transport pathway has been exploited in several rodent studies to carry ONs into the brain parenchyma (Lee et al, 2002; Kozlu et al, 2014). Systemically delivered ONs covalently conjugated to arginine‐rich CPPs have been shown to cross the BBB in mice (Du et al, 2011) and have been used for ON delivery in mouse models of SMA (Hammond et al, 2016). Several studies have shown exosome‐mediated delivery of small RNAs across the vascular barriers into the CNS (Alvarez‐Erviti et al, 2011; Yang et al, 2017). (E) Drugs dosed by intranasal administration can be transported into the brain along the olfactory, trigeminal nerve and rostral migratory stream (Curtis et al, 2007).