Table 3. Comparison of chemical and genetic approaches for ON delivery.

	Chemically modified ONs (AONs and siRNA)	Genetic vectors (viral)
Design	• Variety of chemical modifications available	• Expression level can be determined by the choice of the promoter
	• The chemical modification pattern must be carefully optimized for high stability, efficiency and lack of toxicity	• Heterogeneous cleavage of pri- or pre-miRNA-based constructs generates isomiRs, which is considered a drawback
Neuronal tissue specificity	• Can be obtained by specific ligands or adaptors	• Can be obtained by vector tropism
Distribution in brain	• Free uptake by neuronal cells when delivered intra-CNS	• Brain transduction observed for some vectors in rodents and non-human primates but still less dispersed compared to synthetic ONs
Lifespan after delivery	• Much higher than for unmodified ONs but still transient	• Possibly long-term
	• Require repetitive administration	• Appropriate for permanent treatment
Safety	• Transient activity may be regarded as an advantage concerning the safety	• Dosage control is more problematic
	• Direct control of dosage	• Possible mutagenesis and immunogenicity
Other	• Requires large-scale chemical synthesis	• Difficulties in large-scale manufacturing