Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: Investigate the long-term neuroprotective effect of a single bilateral injection of human ENGRAILED1 (hEN1) in a rat α-synuclein model of Parkinson Disease (PD).
Background: EN1 homeoprotein plays a key role during development of mesencephalic dopaminergic (mDA) neurons and contributes to their maintenance/survival in the adult. Nigral injection of hEN1 was shown to partially protect against nigrostriatal DA neuron death and motor deficits in neurotoxin models of PD in mice and monkeys based on intoxication by 6-OHDA and MPTP.These pharmacological animal models typically use acute dosage regimens of neurotoxins to induce nigrostriatal neuron degeneration, after which the neurotoxin is cleared allowing for surviving neurons recovery, thus questioning the neurorestorative effect an experimental agent in a disease-evolving context.In the present experiment, an AAV-A53T vector expressing mutated human α-synuclein is injected, covering 40-50% of Substantia Nigra pars compacta (SNc) 1 wk after injection. Maximum expression level is observed at 4-8 weeks post-injection in both SNc and striatum, and then remains stable at this high level making it an interesting model for neuroprotection/neurorestoration evaluation.
Method: 40 Sprague-Dawley rats were randomized into 2 groups and injected bilaterally in the SNc with AAV-A53T or control AAV-GFP on day 1. hEN1 or vehicle was administered bilaterally into the SNc of half of each group in a second surgery on day 8. Behavioral assessment was performed every 4th week for 16 weeks post-vector injection. Expression of TH and α-synuclein in the SNc and monoamine content in striatum were quantified post-mortem.
Results: The significant decrease in locomotor activity in the vehicle AAV-A53T group, compared to AAV-GFP, was antagonized by a single hEN1 injection. hEN1 protective activity was maintained over 8 weeks. Post-mortem data supporting these behavioral observations will be presented.
Conclusion: A single nigral injection of hEN1 early after injection of the AAV-A53T into the SNc was well tolerated and produced long-lasting behavioral benefits in rats, despite continuous expression of the toxic protein. This confirms the interest of the EN1 pathway in preclinical models of PD, and support hEN1 further evaluation as a therapeutic candidate for PD.
To cite this abstract in AMA style:A. Prochiantz, G. Porras, A. Simonnet, E. Pioli, C. Friedel, E. Bézard, A. Bousseau. Evaluation of neuroprotection by human ENGRAILED-1 in a chronic AAV-hα-synuclein-A53T (AAV-A53T) rat model of Parkinson Disease [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/evaluation-of-neuroprotection-by-human-engrailed-1-in-a-chronic-aav-h%ce%b1-synuclein-a53t-aav-a53t-rat-model-of-parkinson-disease/. Accessed December 7, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-neuroprotection-by-human-engrailed-1-in-a-chronic-aav-h%ce%b1-synuclein-a53t-aav-a53t-rat-model-of-parkinson-disease/