TABLE 2.
Decrease α-synuclein expression
| Agent/Type of Therapy | Mechanism | Model | Delivery System | Findings | Reference |
|---|---|---|---|---|---|
| Clenbuterol and salbutamola: β2-adrenergic receptor agonists | Alter histone acetylation at the promoter and enhancer regions of SNCA DNA | Rat primary cortical neurons, mice | Intraperitoneal injection in mice | Reduced α-Syn mRNA and protein in the mouse substantia nigra | (Mittal et al., 2017) |
| SLS-004: biologic | Downregulates SNCA mRNA expression by editing SNCA gene methylation within intron 1 | Human induced pluripotent stem cells from patients with SNCA triplication | Lentiviral vector containing DNA-methyltransferase 3A | Decreased α-Syn mRNA and protein levels; reduced ROS; increased cell viability | (Kantor et al., 2018) |
| ST-502: biologic | Represses SNCA gene expression | AAV vector containing a zinc-finger transcription factor | Unpublished data | ||
| siRNA/shRNA | mRNA degradation | Rats injected with lentivirus containing human α-Syn in the striatum | Lentivirus injected into the striatum | Eliminated expression of human α-Syn | (Sapru et al., 2006) |
| Mice | Naked infusion into the hippocampus | Reduced expression of murine SNCA mRNA in the hippocampus | (Lewis et al., 2008) | ||
| Squirrel monkey | Naked infusion into the substantia nigra | Reduced expression of endogenous SNCA mRNA and α-Syn protein in the substantia nigra | (McCormack et al., 2010) | ||
| Rats treated with rotenone | AAV injected into the substantia nigra | Reduced α-Syn protein and protection against pathologic and motor changes | (Zharikov et al., 2015) | ||
| Fibroblasts from patients with SNCA triplication, and Drosophila expression human α-Syn | Direct transfection in cell cultures; BLOCK-iT Pol II miR RNAi Expression Vector in Drosophila | Normalized α-Syn protein levels in human fibroblasts; rescued motor impairments in Drosophila | (Takahashi et al., 2015) | ||
| Mice transgenic for S129D α-Syn | Peripheral injection of exosomes expressing rabies virus glycoprotein | Reduced α-Syn mRNA, protein, and aggregates | (Cooper et al., 2014) | ||
| Thy1-α-Syn overexpressing mice | Intraventricular infusion with polyethylenimine F25-LMW | Reduced SNCA mRNA and α-Syn protein expression in the striatum | (Helmschrodt et al., 2017) | ||
| Rats | AAV infusion into the substantia nigra | Dopaminergic cell degeneration | (Gorbatyuk et al., 2010) | ||
| Rats injected with AAV containing human α-Syn in the striatum | AAV injection into the substantia nigra | Dopaminergic cell degeneration but protection against motor deficits | (Khodr et al., 2011) | ||
| Mice | Intranasal delivery | Reduced α-Syn protein levels in monoaminergic neurons | (Alarcón-Arís et al., 2018) | ||
| Antisense oligonucleotides | mRNA degradation | Rats and mice given intrastriatal injection of α-Syn preformed fibrils and mice with AAV-mediated α-Syn overexpression; nonhuman primates | Intraventricular delivery | Reduced α-Syn expression and reduced phosphorylated α-Syn; in rodents, protection against the formation of α-Syn aggregates, TH cell loss, and motor deficits | (Cole et al., 2016, 2021; Alarcón-Arís et al., 2020) |
| A53T and WT α-Syn transgenic mice | Intraventricular delivery | Reduced α-Syn mRNA and protein, protection against behavioral deficits | (Uehara et al., 2019) | ||
| AAV-h-α-Syn mice | Intraventricular and intranasal delivery | Reduced α-Syn mRNA and protein, protection against formation of phosphorylated α-Syn and reductions in dopamine neurotransmission | (Alarcón-Arís et al., 2020) | ||
| microRNA | miRNA-7: downregulation of α-Syn expression through binding the 3′-UTR of SNCA mRNA; also promotes autophagic clearance of α-Syn | HEK293T cells | Direct transfection | Reduced α-Syn protein expression | (Junn et al., 2009) |
| HEK293 cells transfected with α-Syn expression vectors | Transduction with lentivirus | Reduced SNCA mRNA | (Doxakis, 2010) | ||
| ReNcell VM cells transduced with AAV2 containing α-Syn | Transduction with lentivirus | Accelerated degradation of monomeric and high molecular weight α-Syn | (Choi et al., 2018) | ||
| miRNA-153: downregulation of α-Syn expression through binding the 3′-UTR of SNCA mRNA | HEK293 cells transfected with α-Syn expression vectors | Transduction with lentivirus | Reduced SNCA mRNA | (Doxakis, 2010) | |
| miRNA-34b and miRNA-34c: unclear mechanism | SH-SY5Y cells | Transfection with miRNA containing plasmids | Reduced α-Syn expression | (Kabaria et al., 2015) | |
| Ribozymes | mRNA degradation | Rats treated with MPP+ | AAV injected into the substantia nigra | Reduced α-Syn expression | (Hayashita-Kinoh et al., 2006) |
| Synucleozid: small molecule | Reduced α-Syn translation by binding the IRE | SH-SY5Y cells treated with α-Syn preformed fibrils | Reduced cytotoxicity | (Zhang et al., 2020b) | |
| Posiphenb: small molecule | Reduce α-Syn translation through unclear mechanism | A53T and A30P transgenic mice | Intraperitoneal injection | Rescues colonic motility | (Kuo et al., 2019) |
aIn epidemiological studies, there was reduced risk of developing PD in patients taking salbutamol for asthma (Gronich et al., 2018; Mittal et al., 2017), but this association was not replicated after controlling for demographics, smoking status, and use of the medical system (Searles Nielsen et al., 2018).
bUndergoing phase 1 and 2 trial in AD and PD patients (NCT04524351).