Session Information
Date: Monday, September 23, 2019
Session Title: Clinical Trials, Pharmacology and Treatment
Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: Evaluate the efficacy of a single nigral injection of human ENGRAILED-1 (hEN1) in a recognized chronic MPTP macaque model.
Background: EN1 homeoprotein has been shown to play a key role in the development of midbrain DA (mDA) neurons during embryogenesis, but also in their maintenance/survival in the adult. Indeed, nigral injection or infusion of hEN1 in mice partially protect against 6-OHDA-, MPTP- and a-synuclein-induced mDA neuron death and motor deficits. This protection involves different hEN1 functions both at mitochondrial (translational regulation) and nuclear (transcriptional and epigenetic regulation) levels.
Method: Sixteen macaques received MPTP for 12 days. On D6, animals were injected bilaterally with either vehicle (n=8) or hEN1 (n=8) in the Substantia Nigra. Half of the animals in each treatment group received an additional hEN1 injection on wk 10, leading to 4 groups: vehicle, early hEN1 injection, late hEN1 injection, and two early/late hEN1 injections. Behavior was assessed every third week for 18 weeks by an observer blinded to treatment. Post-mortem analyses of the nigrostriatal system were performed at week 23.
Results: At week 10, compared to vehicle, hEN1-treated monkeys showed a significant improvement of their Parkinson Disability scores. From week 12 to week 18, all monkeys receiving hEN1, regardless of time of injection (early or late) showed significant higher locomotor activity compared to control. Comparison of early (D6) vs late (week10) hEN1 injection showed statistical difference at all times, suggesting that treating early (pre-symptomatic phase) is more effective than treating late (symptomatic phase). There was no additional benefit of a repeated injection at week 10. At autopsy at week 23, a trend towards a higher number of TH-expressing neurons and an increase in TH-containing fibers in the putamen was observed in all hEN1-treated groups.
Conclusion: A single nigral injection of hEN1 early after the MPTP chronic injury initiation was well tolerated and produced long-lasting behavioral benefits in macaques. This data makes EN1 a new pathway worth exploring in PD, and support hEN1 further evaluation as a therapeutic candidate for PD.
To cite this abstract in AMA style:
A. Prochiantz, E. Pioli, C. Friedel, K. Moya, E. Bézard, A. Bousseau. A single nigral injection of human ENGRAILED-1 induces long-lasting behavior benefit in an experimental primate model of Parkinson Disease [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/a-single-nigral-injection-of-human-engrailed-1-induces-long-lasting-behavior-benefit-in-an-experimental-primate-model-of-parkinson-disease/. Accessed November 24, 2024.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/a-single-nigral-injection-of-human-engrailed-1-induces-long-lasting-behavior-benefit-in-an-experimental-primate-model-of-parkinson-disease/