Table 5 Gene silencing targeting α-syn in animal models

Lentiviral-mediated RNAi

Striatum

Rat

Effective silencing of α-syn

Potential immune response to lentivirus, limited long-term data

[133]

AAV vector-derived RNAi

Substantia nigra

Rat

Long-term knockdown of α-syn without causing neurodegeneration

Possible off-target effects, variability in RNAi efficiency

[135]

AAV vector-derived RNAi

Substantia nigra

Thy1-hSNCA mice and viral hSNCA mice

Reduced α-syn levels and amelioration of behavioral deficits without adverse effects on neurons or glial cells

Limited to specific brain regions, potential off-target effects, long-term efficacy not established

[134]

Polyethylenimine F25-LMW mediated siRNA delivery

Cerebrospinal fluid

Thy1-asyn mice

Reduced SNCA mRNA and protein expression

Concerns about insufficient nucleic acid delivery

[137]

Indatraline-conjugated antisense oligonucleotide

Cerebrospinal fluid

Human WT α-syn overexpression in dopamine neurons mouse

Decreased levels of endogenous α-syn

Select delivery to neuronal populations

[142]

Exosome-mediated delivery of antisense oligonucleotides

Cerebrospinal fluid

α-syn A53T mice

Attenuated α-syn aggregation and decreased degeneration of dopaminergic neurons

Complexity in exosome production and delivery, potential immune response

[143]

Amido-bridged nucleic acids modified antisense oligonucleotide

Cerebrospinal fluid

Human WT α-syn overexpressing PD mice

Downregulated SNCA mRNA and protein, ameliorated neurological defects

Further safety evaluation, controlling for a modest reduction rather than total reduction

[144]

Antisense oligonucleotides

Striatum

Wild-type mice

Local reduction of endogenous α-syn, preventing fibril-induced propagation of pathology

Localized delivery limitations and short duration of observation

[145]