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J Pharmacol Exp Ther. 2019 Jun;369(3):364-374. doi: 10.1124/jpet.118.255695. Epub 2019 Mar 27.

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson's Disease.

Author information

1
Atuka Inc., Toronto, Ontario, Canada (T.H.J., P.R., M.P.H., J.S., J.M.B., J.B.K.); Junaxo Inc., Toronto, Ontario, Canada (P.A.H.); and Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (P.A.H., T.H.J., P.R., M.P.H., J.M.B., J.B.K.) p.howson@junaxo.com.
2
Atuka Inc., Toronto, Ontario, Canada (T.H.J., P.R., M.P.H., J.S., J.M.B., J.B.K.); Junaxo Inc., Toronto, Ontario, Canada (P.A.H.); and Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (P.A.H., T.H.J., P.R., M.P.H., J.M.B., J.B.K.).

Abstract

Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T α-synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.67 g/kg per day, by mouth) for 6 weeks had less forelimb asymmetry (93% reduction) and higher striatal dopamine (54% increase) compared with rats receiving vehicle. In a pharmacokinetic study, we determined that efficacy was associated with plasma C max of 8900 ng/ml and area under the curve from time 0 to infinity (AUC0-inf) of 11,136 hour⋅ng/ml. We then showed, in macaques, that oral administration of trehalose (2.67 g/kg per day) produced plasma exposures of similar magnitude, with plasma C max of 10,918 ng/ml and AUC0-inf of 27,445 hour⋅ng/ml. In a macaque model of PD, also based on delivery of AAV1/2-hourA53T-aSyn to the SN, trehalose (2.67 g/kg per day, by mouth), administered for 142 days, produced higher striatal dopamine (by 39%) and dopamine transporter levels (by 50%), compared with macaques receiving vehicle. In neither model did trehalose treatment prevent loss of tyrosine hydroxylase (TH) positive (TH+ve) cells in the SN or alter α-synuclein levels in the striatum. These studies demonstrated that trehalose reduces striatal dopaminergic deficits in a rodent and macaque model of synucleinopathy in PD. Furthermore, we have determined the pharmacokinetic parameters associated with efficacy, and thus defined exposures to target in future clinical trials.

PMID:
30918068
DOI:
10.1124/jpet.118.255695

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