Advantages of different approaches to post-transcriptional gene suppression
• siRNAs do not cross the BBB and if introduced into CSF cannot achieve widespread distribution in the CNS parenchyma. However, siRNA effector sequences can be constitutively delivered through miRNA expression systems expressed from a viral vector.
• siRNAs can lead to very high levels of translational suppression and lowering of target protein, if this is desired.
• siRNAs have prolonged effects in terms of gene suppression and so there is potentially minimal or no need for repetitive administration. However, this is a type of gene therapy, which is irreversible, and there are no antidotes.
• Through peripheral administration in neonates or very early infancy, global or larger CNS areas can be targeted.
• ASOs do not cross an intact BBB. However, ASOs are soluble in artificial CSF and can be delivered directly into the CSF space. Once introduced into the CSF, modified ASOs achieve widespread distribution in the CNS parenchyma and enter neuronal and glial cells.
• ASOs have predictable, dose-dependent pharmacokinetics, enabling modulation of dose to achieve the desired level of pharmacological activity; with intrathecal bolus dosing every few months in symptomatic patients and potentially less frequently in pre-symptomatic patients.
• ASO pharmacological effects are reversible and gene suppression reverses when treatment is stopped.
• In addition to exonic regions, ASOs are able to target intronic regions as they bind to pre-mRNA rather than only mature transcripts. Thus they have more mRNA “real estate” from which to find the ideal ASO drug candidate, and can be used to treat a wider range of diseases.
• Avoids saturation of RNAi pathways which can lead to liver toxicity.
• No need for viral vector delivery, and therefore avoids the generation of an immune response.