TABLE 2

Decrease α-synuclein expression

Agent/Type of TherapyMechanismModelDelivery SystemFindingsReference
Clenbuterol and salbutamola: β2-adrenergic receptor agonistsAlter histone acetylation at the promoter and enhancer regions of SNCA DNARat primary cortical neurons, miceIntraperitoneal injection in miceReduced α-Syn mRNA and protein in the mouse substantia nigra(Mittal et al., 2017)
SLS-004: biologicDownregulates SNCA mRNA expression by editing SNCA gene methylation within intron 1Human induced pluripotent stem cells from patients with SNCA triplicationLentiviral vector containing DNA-methyltransferase 3ADecreased α-Syn mRNA and protein levels; reduced ROS; increased cell viability(Kantor et al., 2018)
ST-502: biologicRepresses SNCA gene expressionAAV vector containing a zinc-finger transcription factorUnpublished data
siRNA/shRNAmRNA degradationRats injected with lentivirus containing human α-Syn in the striatumLentivirus injected into the striatumEliminated expression of human α-Syn(Sapru et al., 2006)
MiceNaked infusion into the hippocampusReduced expression of murine SNCA mRNA in the hippocampus(Lewis et al., 2008)
Squirrel monkeyNaked infusion into the substantia nigraReduced expression of endogenous SNCA mRNA and α-Syn protein in the substantia nigra(McCormack et al., 2010)
Rats treated with rotenoneAAV injected into the substantia nigraReduced 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-SynDirect transfection in cell cultures; BLOCK-iT Pol II miR RNAi Expression Vector in DrosophilaNormalized α-Syn protein levels in human fibroblasts; rescued motor impairments in Drosophila(Takahashi et al., 2015)
Mice transgenic for S129D α-SynPeripheral injection of exosomes expressing rabies virus glycoproteinReduced α-Syn mRNA, protein, and aggregates(Cooper et al., 2014)
Thy1-α-Syn overexpressing miceIntraventricular infusion with polyethylenimine F25-LMWReduced SNCA mRNA and α-Syn protein expression in the striatum(Helmschrodt et al., 2017)
RatsAAV infusion into the substantia nigraDopaminergic cell degeneration(Gorbatyuk et al., 2010)
Rats injected with AAV containing human α-Syn in the striatumAAV injection into the substantia nigraDopaminergic cell degeneration but protection against motor deficits(Khodr et al., 2011)
MiceIntranasal deliveryReduced α-Syn protein levels in monoaminergic neurons(Alarcón-Arís et al., 2018)
Antisense oligonucleotidesmRNA degradationRats and mice given intrastriatal injection of α-Syn preformed fibrils and mice with AAV-mediated α-Syn overexpression; nonhuman primatesIntraventricular deliveryReduced 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 miceIntraventricular deliveryReduced α-Syn mRNA and protein, protection against behavioral deficits(Uehara et al., 2019)
AAV-h-α-Syn miceIntraventricular and intranasal deliveryReduced α-Syn mRNA and protein, protection against formation of phosphorylated α-Syn and reductions in dopamine neurotransmission(Alarcón-Arís et al., 2020)
microRNAmiRNA-7: downregulation of α-Syn expression through binding the 3′-UTR of SNCA mRNA; also promotes autophagic clearance of α-SynHEK293T cellsDirect transfectionReduced α-Syn protein expression(Junn et al., 2009)
HEK293 cells transfected with α-Syn expression vectorsTransduction with lentivirusReduced SNCA mRNA(Doxakis, 2010)
ReNcell VM cells transduced with AAV2 containing α-SynTransduction with lentivirusAccelerated 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 mRNAHEK293 cells transfected with α-Syn expression vectorsTransduction with lentivirusReduced SNCA mRNA(Doxakis, 2010)
miRNA-34b and miRNA-34c: unclear mechanismSH-SY5Y cellsTransfection with miRNA containing plasmidsReduced α-Syn expression(Kabaria et al., 2015)
RibozymesmRNA degradationRats treated with MPP+AAV injected into the substantia nigraReduced α-Syn expression(Hayashita-Kinoh et al., 2006)
Synucleozid: small moleculeReduced α-Syn translation by binding the IRESH-SY5Y cells treated with α-Syn preformed fibrilsReduced cytotoxicity(Zhang et al., 2020b)
Posiphenb: small moleculeReduce α-Syn translation through unclear mechanismA53T and A30P transgenic miceIntraperitoneal injectionRescues 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).