PMID- 32075941
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20210623
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 12
IP  - 531
DP  - 2020 Feb 19
TI  - Filamin A inhibition reduces seizure activity in a mouse model of focal cortical 
      malformations.
LID - eaay0289 [pii]
LID - 10.1126/scitranslmed.aay0289 [doi]
AB  - Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) 
      disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia 
      type II (FCDII), are urgently needed. In these patients, the presence of focal 
      cortical malformations is associated with the occurrence of lifelong epilepsy, 
      leading to severe neurological comorbidities. Here, we show that the expression 
      of the actin cross-linking protein filamin A (FLNA) is increased in resected 
      cortical tissue that is responsible for seizures in patients with FCDII and in 
      mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase 
      (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA 
      expression in these mice through genetic knockdown limited cell misplacement and 
      neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In 
      addition, Flna knockdown reduced seizure frequency independently of mTOR 
      signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before 
      the onset of seizures alleviated neuronal abnormalities and reduced seizure 
      frequency compared to vehicle-treated mice. In addition, the treatment was also 
      effective when injected after seizure onset in juvenile and adult mice. These 
      data suggest that targeting FLNA with either short hairpin RNAs or the small 
      molecule PTI-125 might be effective in reducing seizures in patients with TSC and 
      FCDII bearing mutations in PI3K-Rheb pathway genes.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Zhang, Longbo
AU  - Zhang L
AUID- ORCID: 0000-0002-9077-3239
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA.
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, 87 
      Xiangya Street, Changsha, Hunan 410008, China.
FAU - Huang, Tianxiang
AU  - Huang T
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA.
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, 87 
      Xiangya Street, Changsha, Hunan 410008, China.
FAU - Teaw, Shannon
AU  - Teaw S
AUID- ORCID: 0000-0001-7409-8731
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA.
FAU - Nguyen, Lena H
AU  - Nguyen LH
AUID- ORCID: 0000-0002-4463-7164
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA.
FAU - Hsieh, Lawrence S
AU  - Hsieh LS
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA.
FAU - Gong, Xuan
AU  - Gong X
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA.
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, 87 
      Xiangya Street, Changsha, Hunan 410008, China.
FAU - Burns, Lindsay H
AU  - Burns LH
AUID- ORCID: 0000-0002-4303-3174
AD  - Cassava Sciences Inc., Austin, TX 78731, USA.
FAU - Bordey, Angelique
AU  - Bordey A
AUID- ORCID: 0000-0003-3496-3385
AD  - Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University 
      School of Medicine, New Haven, CT 06520-8082, USA. angelique.bordey@yale.edu.
LA  - eng
GR  - R01 NS093704/NS/NINDS NIH HHS/United States
GR  - R61 NS111074/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Filamins)
SB  - IM
CIN - Nat Rev Drug Discov. 2020 Apr;19(4):238. PMID: 32161370
CIN - Epilepsy Curr. 2020 Dec 3;21(1):51-53. PMID: 34025274
MH  - Animals
MH  - *Epilepsy
MH  - Filamins
MH  - Humans
MH  - *Malformations of Cortical Development, Group I
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases
MH  - Seizures/drug therapy
EDAT- 2020/02/23 06:00
MHDA- 2021/06/24 06:00
CRDT- 2020/02/21 06:00
PHST- 2019/05/14 00:00 [received]
PHST- 2019/10/28 00:00 [revised]
PHST- 2019/12/28 00:00 [accepted]
PHST- 2020/02/21 06:00 [entrez]
PHST- 2020/02/23 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
AID - 12/531/eaay0289 [pii]
AID - 10.1126/scitranslmed.aay0289 [doi]
PST - ppublish
SO  - Sci Transl Med. 2020 Feb 19;12(531):eaay0289. doi: 10.1126/scitranslmed.aay0289.