Table 1.

Comparing gene-therapy strategies for neurodegenerative diseases

	ASOs	AAVs/other viruses	Small molecules	DNA/RNA editing
Risk/toxicity	• Intrathecal/invasive local CNS delivery is necessary.	• Hepatotoxicity and dorsal root ganglion pathology after systemic delivery (particularly with high doses). • May need intrathecal/invasive local CNS delivery, though intravenous route is feasible. • Insertional mutagenesis.	• Possible altered splicing/expression of off-target genes (e.g. high dose of SMN2 splicing modulator risdiplam affects FOXM1 splicing, leading to a protein product that blocks cell division).	• Irreversibility of DNA editing • Undesired on-target editing possible (large deletions and chromosomal rearrangements). • Possible immunogenicity from bacterial nucleases (Cas-proteins).
Off-target effects	Binding to off-target mRNA due to complete or partial complementarity.	Ectopic expression in peripheral tissues after systemic delivery.	Non-specific binding to off-target mRNA possible.	Binding to off-target site due to homologous sequence or mismatch tolerance.
Persistence of intervention	• Repeated administration necessary for persistent RNA modulation.	• Long-term transgene expression of AAV in postmitotic cells. • Long-term transgene expression of lentivirus in mitotically active and inactive cells. • Pre-existing neutralizing antibodies may reduce efficacy. • Immunogenicity of viral capsids and transgene products may affect long-term gene expression and repeated treatments.	• Repeated oral administration necessary, typically low brain availability.	• Persistent genome manipulation by DNA-editing tools.