Present developments in Parkinson’s disease preclinical gene therapy.
| Animal models | Targeted genes and vectors | Administration process | Safety/Toxicity | Outcome measures | Follow-up and monitoring | Reference(s) |
|---|---|---|---|---|---|---|
| Adult male Sprague Dawley rats | SNCA, AAV-shRNA | Bilateral injection into the SN | Not safe: loss of striatal projecting dopamine neurons was evident in the vector injection site | Reduced behavioral deficiencies in rats and silenced ectopically expressed SNCA | Followed up on [35] | [36] |
| Adult male Lewis rats | SNCA, AAV-shRNA | Unilateral injection into the SN | No neurodegeneration or cell death | Protected the SN against the neurotoxic mitochondrial rotenone and lowered SNCA protein levels by about 35% | [35] | |
| Rhesus monkeys | GDNF, AAV2-GDNF | Bilateral injection of AAV2-GDNF in the putamen after MPTP-lesioning | There was no adverse effect | Bilaterally increased striatal metabolism, indicating increased dopaminergic activity in the nigrostriatal pathway | [37] | |
| MPTP-lesioned macaque monkey | Aromatic AADC, AAV2-hAADC | Unilateral injection into the striatum | Safe, minimal, or no side effects | Positron emission tomography-verified increase in AADC activity after 2 years. Consistently higher L-DOPA sensitivity in the treatment group | Followed up for 8 years | [38, 39] |
| Mice | GBA1, AAV-GFP-micro RNA-GBA | Intracerebroventricular administration | Safe | Slower progression of neurological complications and an increased lifespan | [40] | |
| Mice | GBA1, AAV-PhP.B-GBA1 | Tail vein injection | It did not lead to evident dysfunction in the integrity and permeability of the BBB | Decreased SNCA pathology and attenuated behavioral deficits | [41] | |
| Macaque monkeys (n = 4) | GDNF, AAV5-GDNF | Unilateral administration into the putamen | No adverse effect | At higher dosages, striatal and SN GDNF expression levels are greater | [32] | |
| Unilaterally MPTP-treated macaques (n = 15) | GDNF, AAV2-GDNF | Bilateral delivery to the putamen following a lesion | The persistent high level of GDNF in the basal ganglia after AAV2-GDNF delivery to the putamen is well tolerated | Motor behavior significantly improved at 24 months. Impact was proportionate to the lesion’s severity. A threefold rise in striatal dopamine | [42] |
SNCA: synuclein alpha; AAV: adeno-associated virus; shRNA: short hairpin RNA; GDNF: growth-derived neurotrophic factor; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; AADC: L-amino acid decarboxylase; L-DOPA: levodopa; hAADC: human AADC; GBA1: glucocerebrosidase 1; GFP: green fluorescent protein; SN: substantia nigra; BBB: blood-brain barrier.
AOA: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. GOO: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. GAF: Validation, Writing—review & editing. All authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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