Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model

被引:66
作者
Li, Melody [1 ]
Jancovski, Nikola [1 ]
Jafar-Nejad, Paymaan [2 ]
Burbano, Lisseth E. [1 ]
Rollo, Ben [1 ]
Richards, Kay [1 ]
Drew, Lisa [1 ]
Sedo, Alicia [1 ]
Heighway, Jacqueline [1 ]
Pachernegg, Svenja [1 ]
Soriano, Armand [2 ]
Jia, Linghan [1 ]
Blackburn, Todd [1 ,3 ]
Roberts, Blaine [1 ,5 ]
Nemiroff, Alex [3 ,4 ]
Dalby, Kelley [3 ,4 ]
Maljevic, Snezana [1 ]
Reid, Christopher A. [1 ]
Rigo, Frank [2 ]
Petrou, Steven [1 ,3 ,4 ]
机构
[1] Florey Inst Neurosci & Mental Hlth, 30 Royal Parade, Parkville, Vic 3052, Australia
[2] Ionis Pharmaceut, Carlsbad, CA USA
[3] RogCon Biosci, Miami Beach, FL USA
[4] Praxis Precis Med, Boston, MA USA
[5] Monash Univ, Clayton, Vic, Australia
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
DE-NOVO MUTATIONS; BRAIN-DEVELOPMENT; NUSINERSEN; PHARMACOLOGY; MECHANISMS; DISEASE; INJURY;
D O I
10.1172/JCI152079
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function in SCN2A is seen in some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction in SCN2A expression could substantially improve clinical outcomes. We tested this theory by central administration of a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA in a mouse model of Scn2a early seizure onset DEE (Q/+ mice). Untreated Q/+ mice presented with spontaneous seizures at P1 and did not survive beyond P30. Administration of the ASO to Q/+ mice reduced spontaneous seizures and significantly extended life span. Across a range of behavioral tests, Scn2a ASO-treated Q/+ mice were largely indistinguishable from WT mice, suggesting treatment is well tolerated. A human SCN2A gapmer ASO could likewise impact the lives of patients with SCN2A gain-of-function DEE.
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页数:14
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