RESUMO
Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 µg or 300/300/300 µg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 µg and 300/300/300 µg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov: NCT04075318 .
RESUMO
Parkinson's disease (PD) is a neurodegenerative disease with a hallmark motor defect caused by the death of dopaminergic neurons in the substantia nigra. Intranasal drug administration may be useful for Parkinson's treatment because this route avoids first-pass metabolism and increases bioavailability in the brain. In this study, we investigated the neuroprotection/neurorestoration effect of dopamine D3 receptor (D3R) agonists administered via both intranasal and subcutaneous routes in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD mouse model. Furthermore, we employed D3R knock-out mice to validate the dependence on D3R signaling. We found that in wild-type mice, but not D3 receptor knockout mice, both intranasal and subcutaneous administration of D3R agonists rescue dopamine (DA) depletion in the striatum as well as DA neuronal death in the substantia nigra after MPTP treatment. Moreover, subcutaneous 7-OH-DPAT administration significantly improved gait performance (stride length and overall running speed) of MPTP-lesioned mice after 7 and 14 days of recovery. In addition, the distribution of D3 agonist 7-OH-DPAT was measured in designated brain areas by mass spectrometry analysis after subcutaneous and intranasal administration. Our data suggest that intranasal administration of D3R agonist would be a practical approach to treat PD.
