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COMPOSITION FOR PREVENTION OR TREATMENT OF INTRACTABLE EPILEPSY COMPRISING mTOR INHIBITOR

a technology of intractable epilepsy and inhibitors, which is applied in the field of prevention or treatment of intractable epilepsy, can solve the problems of inability to develop novel and more effective fcd therapies, inability to identify such mutations, and poor understanding of the molecular genetic etiology of fcdii, and achieve the effect of reducing the frequency of ons

Inactive Publication Date: 2018-08-02
KOREA ADVANCED INST OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes the use of mTOR inhibitors to treat brain somatic mutation-related FCD. These inhibitors can reduce the frequency of seizures and the number of abnormal neurons in the brain. The patent also provides a biomarker panel for the diagnosis of intractable epilepsy and a technique for diagnosis using the biomarker panel. Furthermore, the patent describes inducing intractable epilepsy in animal models to study genetic functions and molecular mechanisms of epilepsy, as well as new anti-epileptic drugs.

Problems solved by technology

FCD is an important cause of epilepsy that is difficult to control with available antiepileptic drugs, and this condition accounts for as much as 50% of juvenile patients undergoing epilepsy surgery.
Due to the lack of understanding of the molecular genetic etiology, the development of novel and more effective FCD therapies remains elusive.
However, no such mutations have been identified.
Although an association between human papilloma virus and FCDII has been reported, the molecular genetic etiology of FCDII remains poorly understood.
These radiological and histopathological findings suggest that only a small fraction of cells containing somatic mutations exist in surgically resected tissue, and that these mutations might not be efficiently detected through capillary Sanger sequencing or typical whole exome sequencing (WES) with an average read depth of 100-150×.

Method used

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  • COMPOSITION FOR PREVENTION OR TREATMENT OF INTRACTABLE EPILEPSY COMPRISING mTOR INHIBITOR
  • COMPOSITION FOR PREVENTION OR TREATMENT OF INTRACTABLE EPILEPSY COMPRISING mTOR INHIBITOR
  • COMPOSITION FOR PREVENTION OR TREATMENT OF INTRACTABLE EPILEPSY COMPRISING mTOR INHIBITOR

Examples

Experimental program
Comparison scheme
Effect test

example 1

ation of Gene by Whole Exome Sequencing, and Confirmation

example 1-1

ion of 3 Candidate mTOR Mutations from 4 Patients Through Whole Exome Sequencing

[0183]Deep whole exome sequencing (read depth 412-668×) was performed on brain tissue samples from four FCDII patients (designated FCD3, FCD4, FCD6, and FCD23, respectively). Selection was made of three candidate genetic mutations that were found simultaneously using the two algorithms Virmid and Mutect.

[0184]To obtain data of the whole exome sequencing, libraries of sequences were prepared using the Agilent library preparation protocols (Agilent Human All Exon 50 Mb kit) according to the manufacturer's instructions. The libraries were subjected to sequencing on Hiseq2000 (Ilumina). For more accurate analysis, sequencing was carried out with a read depth of about 500×, five-times higher than the general sequencing depth. The sequencing data was prepared into a file that can be analyzed using the Best Practices Pipeline suggested by Broad Institute (https: / / www.broadinstitute.org / gatk / ).

example 1-2

n of 3 Gene Mutant Candidates by Site-Specific Amplicon Sequencing and Identification of One Genetic Mutation (L2427P)

[0185]Site-specific amplicon was performed for the candidate mutations—(read depth, 100-347, 499×). The samples were obtained from the same brain tissue block through biological replication, thereby minimizing any unexpected sequencing artifacts or erroneous calls that can mimic low-frequency somatic mutations. For the site-specific amplicon sequencing, the samples were determined to have a mutation when the percentage of mutated reads exceeded 1%.

[0186]Site-Specific Amplicon Sequencing

[0187]Two pairs of primers carrying two target regions of mTOR target gene codon sites (amino acids Cys1483 and Leu2427) were designed (Table 2).

TABLE 2SEQIDTarget regionprimerNOChr1:11174301~Forward5′-TAGGTTACAGGCCTGGATGG-11Chr1:111745133′Reverse5′-CTTGGCCTCCCAAAATGTTA-123′Chr1:11217133~Forward5′-TCCAGGCTACCTGGTATGAGA-13Chr1:112173443′reverse5′-GCCTTCCTTTCAAATCCAAA-143′

[0188]Each prim...

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Abstract

Provided is a use of the prophylaxis, amelioration or therapy of intractable epilepsy, for example, Focal Cortical Dysplasia (FCD).

Description

TECHNICAL FIELD[0001]The present invention relates to the prophylaxis, amelioration or therapy of intractable epilepsy, for example, Focal Cortical Dysplasia (FCD). Also, the present invention relates to a biomarker panel for diagnosing intractable epilepsy, especially pediatric intractable epilepsy, and a method for diagnosing intractable epilepsy using the same.BACKGROUND ART[0002]Epilepsy is a group of chronic neurological diseases characterized by repetitive seizures induced by excessive electric activity in some neurons within a short time, with the consequent incurrence of neurobiological, mental, perceptual, and social changes.[0003]Epilepsy that is insensitive to anti-epileptic drugs developed thus far is called intractable epilepsy, and accounts for about 20% of all epilepsy cases diagnosed each year. Malformations of cortical developments (MCD) such as Focal Cortical Dysplasia (FCD), Hemimegalencephaly (HME) and Tuberous Sclerosis Complex (TSC), Hippocampal Sclerosis (HS),...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61K31/4375A61K31/519A61K31/436A61P25/08
CPCA61K31/5377A61K31/4375A61K31/519A61K31/436A61P25/08A01K67/0276C12Q1/6883C12N15/907A01K2217/075A01K2227/105A01K2267/0356C12Q2600/156A61K31/501A61K31/711G01N33/6872G01N2333/4704G01N2800/2857C12N9/12G01N33/68A01K67/027C12N15/85
Inventor LEE, JEONG HOLIM, JAE SEOKKIM, WOO-IIKIM, DONG SEOKKANG, HOON CHULKIM, SE HOON
Owner KOREA ADVANCED INST OF SCI & TECH
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