Gene therapy for epilepsy targeting neuropeptide Y and its Y2 receptor to dentate gyrus granule cells

被引:0
|
作者
Cattaneo, Stefano [1 ,2 ]
Bettegazzi, Barbara [1 ,2 ]
Crippa, Lucia [1 ,2 ]
Asth, Laila [3 ]
Regoni, Maria [1 ,2 ]
Soukupova, Marie [3 ]
Zucchini, Silvia [3 ]
Cantore, Alessio [1 ,4 ]
Codazzi, Franca [1 ,2 ]
Valtorta, Flavia [1 ,2 ]
Simonato, Michele [2 ,3 ]
机构
[1] Univ Vita Salute San Raffaele, I-20132 Milan, Italy
[2] IRCCS San Raffaele Sci Inst, Div Neurosci, I-20132 Milan, Italy
[3] Univ Ferrara, Dept Neurosci & Rehabil, I-44121 Ferrara, Italy
[4] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy, I-20123 Milan, Italy
关键词
Glutamate; Hippocampus; Mouse; Synapsin; PROTEIN EXPRESSION; OVEREXPRESSION; VECTOR; SEIZURES; BRAIN; MOUSE; MODEL; IRES; NPY; BIOSYNTHESIS;
D O I
10.1038/s44319-024-00244-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Gene therapy is emerging as an alternative option for individuals with drug-resistant focal epilepsy. Here, we explore the potential of a novel gene therapy based on Neuropeptide Y (NPY), a well-known endogenous anticonvulsant. We develop a lentiviral vector co-expressing NPY with its inhibitory receptor Y2 in which, for the first time, both transgenes are placed under the control of the minimal CamKIIa(0.4) promoter, biasing expression toward excitatory neurons and allowing autoregulation of neuronal excitability by Y2 receptor-mediated inhibition. Vector-induced NPY and Y2 expression and safety are first assessed in cultures of hippocampal neurons. In vivo experiments demonstrate efficient and nearly selective overexpression of both genes in granule cell mossy fiber terminals following vector administration in the dentate gyrus. Telemetry video-EEG monitoring reveals a reduction in the frequency and duration of seizures in the synapsin triple KO model. This study shows that targeting a small subset of neurons (hippocampal granule cells) with a combined overexpression of NPY and Y2 receptor is sufficient to reduce the occurrence of spontaneous seizures. Co-expressing NPY and its inhibitory receptor Y2 in excitatory hippocampal cells allows inhibitory autoregulation of glutamate release. Expression of both genes in granule cell mossy fiber terminals reduces the frequency and duration of seizures in the synapsin triple KO model of epilepsy.We develop a LV vector with minimal CamKinaseII promoter driving expression of NPY and its receptor Y2.Vector administration in the dentate gyrus allows for efficient and nearly selective in vivo overexpression of NPY and Y2 receptor in granule cell mossy fiber terminals.This reduces the frequency and duration of seizures in the synapsin triple KO model of epilepsy. Co-expressing NPY and its inhibitory receptor Y2 in excitatory hippocampal cells allows inhibitory autoregulation of glutamate release. Expression of both genes in granule cell mossy fiber terminals reduces the frequency and duration of seizures in the synapsin triple KO model of epilepsy.
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页数:23
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