Table 3 Comparative framework of JEV-ASO, molecular carriers, and pharmacological strategies for CNS-targeted ALS therapy

Platform type and representative examples

Self-replicating flavivirus (i.e., JEV)

Viral capsids, certain components of virions or VLPs (e.g., AAV9, AAVrh.10, RABV, VSV, MV)

Liposomes (e.g., phosphatidylinositol), polymersomes, niosomes, inorganic nanoparticles, exosomes, nanoligomers, and AOCs

Riluzole, edaravone, PB-TURSO, and investigational therapies (e.g., arimoclomol, tideglusib, pridopidine, and zilucoplan)

Genome content and self-replicative nature

Full-length engineered JEV genome enabling replication and ASO expression

No viral genome; contain capsid/glycoproteins only (e.g., AAV shell, RABV/VSV-G); replication defective

No viral-associated components; synthetic or biologically derived

N/A

Mechanism of action

ASO-mediated degradation or steric inhibition of mutant SOD1 mRNA via RNAi instead of RNase H

Gene silencing or gene replacement via transgene expression (e.g., shRNA, miRNA, CRISPR, ASO)

Delivery of therapeutic oligonucleotides or proteins to target cells (e.g., splicing modulation, inflammasome inhibition)

Activators or inhibitors targeting a specific intracellular component(s) (e.g., transmembrane receptors, cytoplasmic enzymes, cofactors, regulators)

CNS tropism/specificity

High (Innate neurotropism with preferential targeting of hippocampal and cortical neurons via receptor-mediated entry)212

Moderate to high [Depends on viral serotype or glycoprotein (e.g., AAV9, RABV-G) with engineered tropism toward CNS cells]104,108,118,213,214,215,216

Low to moderate [CNS targeting achievable through ligand functionalization (e.g., RVG peptides, transferrin), but inherently passive]217,218,219

Low (Limited passive diffusion across the BBB)220

Immunogenicity

Moderate to high (Potential innate and adaptive immune activation due to viral replication, mitigated by miRNA-mediated attenuation and rational engineering)144,149

Moderate (Immunogenicity arises from viral capsid proteins and pre-existing antibodies, especially for AAVs221, though VLP lack replicative components)222

Low [Generally well-tolerated, although immunogenicity may arise from carrier surface chemistry, antibody components (in AOCs), or impurities in bioproduction]223,224

Variable (Some compounds elicit systemic inflammatory responses or idiosyncratic immune toxicity, though most are considered non-immunogenic under standard doses)

Bioavailability

High (Viral encapsulation protects the ASO from degradation, enables efficient intracellular delivery, and facilitates sustained distribution within the CNS via replication)131,225

Moderate [Capsid shielding improves stability and circulation time, but vector clearance by neutralizing antibodies or liver uptake (e.g., via Kupffer cells) can reduce effective dose]99,222

Variable (Exosomes exhibit moderate stability but are prone to macrophage clearance, while nanoligomers and AOCs may show improved stability with PEGylation or optimized linkers)218,226,227,228,229

Low (Rapid renal clearance and metabolic degradation result in short half-lives, often requiring frequent dosing or formulation enhancement to improve CNS penetration)220

Cargo versatility

High [Compatible with RNA-based ASO integrated into the viral genome, and potentially adaptable to other small RNA species (e.g., miRNA, siRNA) within replication limits]

High (Capable of delivering diverse genetic payloads including shRNA, miRNA, CRISPR/Cas components, and therapeutic transgenes, constrained by packaging size and vector compatibility)

High (Supports a wide range of cargos, including ASO, siRNAs, mRNAs, peptides, and proteins; versatility depends on conjugation chemistry and carrier structure)

Low to none (Constrained to chemically stable, low molecular weight compounds that can cross biological barriers; unsuitable for macromolecular or nucleic acid delivery)

Disease versatility

High (Platform can be retargeted to other neurodegenerative or CNS diseases by modifying the ASO sequence and miRNA attenuation elements, provided target mRNAs and cell specificity are known)

High (Modular design allows broad adaptation to various genetic or protein-coding payloads for treating diverse diseases, including neurological, muscular, hepatic, and oncologic conditions)

High (Applicable to multiple disease types by tailoring cargo and targeting ligands, including neurological, inflammatory, metabolic, and genetic disorders)

Low to none (Typically target single biochemical pathways or receptor types, requiring separate development and optimization for each disease context)