Target α-synuclein aggregation

AgentSponsorMechanism of ActionType of TherapyPhase of DevelopmentStatus/Findings
Anle138bMODAG GmbHInhibits α-Syn oligomer formationSmall moleculePhase 1NCT04208152: completed, results pending
NCT04685265: recruiting
NPT200-11Neuropore Therapies Inc.Interferes with α-Syn aggregation by displacing α-Syn from membranesSmall moleculePhase 1NCT02606682: completed, results pending
ENT-01Enterin, IncInterferes with α-Syn aggregation by displacing α-Syn from membranesSmall moleculePhase 2NCT03047629: improvement in constipation (Hauser et al., 2019)
Phase 2NCT04483479: recruiting
Phase 2NCT03781791: recruiting
Phase 1 in PD dementiaNCT03938922: active, not recruiting
TrodusquemineInterferes with α-Syn aggregation by displacing α-Syn from membranesSmall moleculePreclinicalProtects against α-Syn aggregation and paralysis in C. elegans overexpressing α-Syn (Perni et al., 2018)
NPT088Proclara BiosciencesBinds aggregated proteins and disrupts the amyloid conformationSmall moleculePreclinical in PD, but phase 1 in ADGood safety and tolerability in patients with AD but no effect on markers of clinical progression (Michelson et al., 2019)
VH14Targets the NAC domain of α-Syn to interfere with aggregation and target α-Syn to the proteosomeIntrabody/nanobodyPreclinicalRats injected with VH14 into the striatum had protection against injection of AAV-α-Syn into the striatum on measures of phosphorylated α-Syn and dopaminergic cell health (Chatterjee et al., 2018)
SLS-007 peptides, S62 and S71Seelos TherapeuticsInterfere with α-Syn aggregation by targeting the NAC domainPeptidesPreclinicalPrevent aggregation of α-Syn in cell culture (Sangwan et al., 2020) and are now being testing in animal models using an AAV delivery system
EHT ± caffeineIncreases activity of PP2A by inhibiting PME1Small moleculesPreclinicalProtective in transgenic α-Syn, MPTP treated and α-Syn preformed fibril treated mice on measures of dopaminergic cell integrity, neuroinflammation, and motor behavior (Lee et al., 2011, 2013; Yan et al., 2018)
DeferiproneUniversity Hospital, Lille; ApoPharma; Imperial College LondonIron chelationSmall moleculePilot clinical studyImproved motor performance on the UPDRS (Devos et al., 2014)
Phase 2/3Improved motor performance on the UPDRS (NCT00943748) (Grolez et al., 2015)
Phase 2Trend in improvement in motor scores (NCT01539837)(Martin-Bastida et al., 2017)
Phase 2NCT02728843: completed, results pending
Phase 2NCT02655315: active, not recruiting
PBT434Alterity TherapeuticsIron attenuationSmall moleculePhase 1Completed, results not yet published
YTX-7739Yumanity TherapeuticsInhibits stearoyl-CoA desaturaseSmall moleculePhase 1Active
CystamineDecreased α-Syn aggregation through blocking TG2 activitySmall moleculePreclinicalProtective in mice treated with MPTP or 6-OHDA on measures of dopaminergic cell loss and generation of reactive oxygen species (Tremblay et al., 2006; Stack et al., 2008; Sun et al., 2010); in addition, overexpression of TG2 exacerbates α-Syn toxicity, whereas knockout of TG2 is protective against α-Syn toxicity in α-Syn transgenic mice, on measures of α-Syn aggregation, neuroinflammation, and motor performance (Grosso et al., 2014; Zhang et al., 2020a)