Enhance α-synuclein degradation
| Agent | Sponsor | Mechanism of Action | Phase of Development | Status/Findings |
|---|---|---|---|---|
| Rapamycin | Enhances autophagic activity by inhibiting mTOR | Preclinical | Protective in mice treated with MPTP and in WT α-Syn transgenic mice (Crews et al., 2010; Dehay et al., 2010; Malagelada et al., 2010) | |
| MSDC-0160 | Metabolic Solutions Development Company | Enhances autophagic activity by inhibiting mTOR | Preclinical in PD, but Phase 2 in AD | Good safety and tolerability (NCT01374438)(Shah et al., 2014) |
| RTB-101 | resTORbio | Enhances autophagic activity by inhibiting TORC1 | Phase 1/2 trials initiated but not completed | No longer actively being investigated for neurodegeneration |
| Nilotinib | Georgetown University and Northwestern University | c-Abl tyrosine kinase inhibitor: activates autophagy by decreasing activation of the PI3K-AKT-mTOR pathway | Phase 1 | NCT02281474: good safety and tolerability (Pagan et al., 2016) |
| Phase 2 | NCT02954978: reduced plasma α-Syn, reduced CSF oligomeric α-Syn, and increased level of 3,4-dihydroxyphenylacetic acid and homovanillic acid in CSF (Pagan et al., 2019) | |||
| Phase 2 | NCT03205488: poor CSF penetration and no clinical improvement relative to placebo (Simuni et al., 2020) | |||
| K0706/SCC-138 | Sun Pharma Advanced Research | c-Abl tyrosine kinase inhibitor: activates autophagy by decreasing activation of the PI3K-AKT-mTOR pathway | Phase 1 | NCT03316820, NCT03445338, and NCT02970019: preliminary reports suggest good safety and tolerability |
| Phase 2 | NCT03655236 and NCT03996460: recruiting | |||
| Radotinib | Il-Yang Pharm. Co., Ltd. | c-Abl tyrosine kinase inhibitor: activates autophagy by decreasing activation of the PI3K-AKT-mTOR pathway | Phase 2 | NCT04691661: not yet recruiting |
| FB101 | 1ST Biotherapeutics, Inc. | c-Abl tyrosine kinase inhibitor: activates autophagy by decreasing activation of the PI3K-AKT-mTOR pathway | Phase 1 | NCT04165837: recruiting |
| ikT-148009 | Inhibikase Therapeutics, Inc. | c-Abl tyrosine kinase inhibitor: activates autophagy by decreasing activation of the PI3K-AKT-mTOR pathway | Phase 1 | NCT04350177: enrolling by invitation |
| Bosutinib | Georgetown University | Tyrosine kinase inhibitor: activates autophagy by decreasing activation of the PI3K-AKT-mTOR pathway | Phase 2 | NCT03888222: active, not recruiting |
| Trehalose | Mashhad University of Medical Sciences and National University of Malaysia | Enhances autophagic activity by activating transcription factor EB | Preclinical in PD; Phase 1 in AD and spinocerebellar ataxia | NCT04663854 and NCT04399265: recruiting NCT04426149: completed, results pending |
| Autophagy activation through lentivirus mediated overexpression of Beclin-1 | Preclinical | Over-expression of Beclin01 using a lentiviral vector was protective in and α-Syn transgenic mouse (Spencer et al., 2009) | ||
| miRNA-7 | Autophagy activation | Preclinical | Accelerates clearance of α-Syn in ReNcell VM cells (Choi et al., 2018) | |
| IU1 | Enhances proteosomal function by inhibiting USP14 | Preclinical | Inhibition of USP14 is protective in a Drosophila model of PD (Chakraborty et al., 2018) | |
| VH4PEST and NbSyn87PEST | Targets the NAC domain of α-Syn to interfere with aggregation and target α-Syn to the proteosome | Preclinical | Rats 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) |
TORC1, target of rapamycin kinase complex 1.