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CN-122012619-A - Pharmaceutical composition for treating KCNQ2 developmental epileptic encephalopathy, nucleic acid construct and application

CN122012619ACN 122012619 ACN122012619 ACN 122012619ACN-122012619-A

Abstract

The invention discloses a pharmaceutical composition for treating KCNQ2 developmental epileptic encephalopathy, a nucleic acid construct and application thereof. The invention verifies the effectiveness of the nucleic acid construct carrying hKCNQ gene in improving the expression level of KCNQ2 and improving the related neuropathological mechanism by introducing the nucleic acid construct carrying hKCNQ gene into a KCNQ2 A294V/+ developmental epileptic encephalopathy animal model and a human forebrain neuron model. The method not only provides new hope for KCNQ2 related development epileptic encephalopathy treatment, but also opens up new direction for application of gene therapy in the neural development diseases.

Inventors

  • CHENG YONG
  • HE QIANG
  • FU QIANG
  • DU YANG
  • LI QIBIN

Assignees

  • 深圳瑞恩康成生物技术有限公司

Dates

Publication Date
20260512
Application Date
20260209
Priority Date
20250411

Claims (10)

  1. 1. A pharmaceutical composition for treating or ameliorating KCNQ 2-associated developmental epileptic brain disease, comprising a nucleic acid construct comprising or capable of producing a polynucleotide of (1) and/or (2) below: (1) A polynucleotide with a sequence shown as SEQ ID No. 2; (2) The polynucleotide (1) having the same function as the nucleotide modified polynucleotide.
  2. 2. The pharmaceutical composition for treating or ameliorating KCNQ 2-associated developmental epileptic brain diseases according to claim 1, further comprising pharmaceutically acceptable excipients.
  3. 3. The pharmaceutical composition for treating or ameliorating KCNQ 2-associated developmental epileptic brain diseases according to claim 1, wherein the pharmaceutical composition is an injection.
  4. 4. A pharmaceutical composition for treating or ameliorating KCNQ 2-associated developmental epileptic brain diseases according to claim 1, wherein the mode of administration of the pharmaceutical composition comprises an intra-brain injection.
  5. 5. A nucleic acid construct for use in the treatment or amelioration of KCNQ 2-associated developmental epileptic brain disease, wherein the nucleic acid construct comprises or is capable of producing a polynucleotide of (1) and/or (2) below: (1) A polynucleotide with a sequence shown as SEQ ID No. 2; (2) The polynucleotide (1) having the same function as the nucleotide modified polynucleotide.
  6. 6. The pharmaceutical composition of any one of claims 1-4, or the nucleic acid construct of claim 5, wherein the KCNQ 2-associated developmental epileptic brain disease is a subject diagnosed with a missense mutation of KCNQ2 A294V/+ .
  7. 7. Use of the nucleic acid construct of claim 5 for the preparation of a medicament for treating or ameliorating KCNQ2 developmental epileptic encephalopathy.
  8. 8. A method for determining the effectiveness of a drug to be tested for treating or ameliorating KCNQ2 developmental epileptic encephalopathy, comprising the steps of: (1) Providing a cell model or an animal model, and detecting related indexes comprising the expression level of KCNQ2 protein and a neuropathological index to obtain a first parameter, wherein the cell model or the animal model has KCNQ2 A294V/+ missense mutation; (2) Applying the drug to be tested to the cell model or the animal model, and then detecting related indexes comprising KCNQ2 protein expression level and neuropathological indexes to obtain a second parameter; (3) Comparing the first parameter with the second parameter.
  9. 9. The method of determining the effectiveness of a test drug for treating or ameliorating KCNQ2 developmental epileptic brain disorders of claim 8, wherein the neuropathological index comprises at least one of social ability, anxiety index, cognitive ability, seizure frequency or duration of spontaneous epilepsy, dendritic spine density.
  10. 10. The method of determining the effectiveness of a test agent for treating or ameliorating KCNQ2 developmental epileptic brain diseases according to claim 8 wherein said animal model is administered said test agent for 3 weeks and said cell model is administered said test agent for 1 week.

Description

Pharmaceutical composition for treating KCNQ2 developmental epileptic encephalopathy, nucleic acid construct and application Technical Field The invention relates to the field of medical technology and gene therapy, in particular to a pharmaceutical composition for treating KCNQ2 developmental epileptic encephalopathy, a nucleic acid construct and application thereof. Background Epilepsy is a chronic disease that causes a transient brain dysfunction due to highly synchronized abnormal discharges of brain neurons for a variety of reasons. According to the data issued by WHO, more than 5000 people suffer from epilepsy worldwide, about 1000 ten thousand people suffer from epilepsy in China, and the speed of 60 ten thousand people per year is continuously increased, and the annual economic burden is more than 200 hundred million RMB. While Developmental Epileptic Encephalopathy (DEE) is one of the most severe disease types of epileptic disorders, which is a severe neurological disorder characterized by frequent seizures and significant Developmental retardation or mental dysfunction. DEE can occur at any age, but is most common and severe during infancy. Infant stage is the key period for the maturation and perfection of brain morphology, nerve connection and synaptic plasticity of children. DEE has not only a fundamental etiology leading to a developmental delay, but also progressive functional impairment from seizures that are difficult to control. Unlike the sequelae caused by the simple status epilepticus and the transient damage caused by the occasional epileptic seizure, the brain development of the infant is irreversibly affected, the development of the existing functions and age-related new functions of the infant is aggravated, and the movement, language, intelligence development and social functions of the infant are seriously affected. For KCNQ2-DEE (developmental epileptic encephalopathy caused by pathogenic variation of KCNQ 2), symptomatic therapeutic agents are preferred, including, for example, sodium channel blockers. Common sodium channel blockers are oxcarbazepine, carbamazepine, phenytoin sodium, lamotrigine, and the like. Despite their therapeutic effect in controlling seizures, their neurological improvement and long-term prognosis for KCNQ2-DEE remains limited. And some patients may have drug resistance to conventional antiepileptic drugs, resulting in poor therapeutic effects. Thus, there is a need for a drug that can be used to treat or ameliorate KCNQ2 developmental epileptic encephalopathy, thereby reversing the irreversible effects of KCNQ 2-induced brain development with a long-acting improvement mechanism. The information in the background section is only for the purpose of illustrating the general background of the invention and is not to be construed as an admission or any form of suggestion that such information forms the prior art that is well known to those of ordinary skill in the art. Disclosure of Invention In order to solve at least part of the technical problems in the prior art, the invention provides a gene therapy scheme for remedying the development epileptic encephalopathy caused by KCNQ2 mutation. In certain embodiments, recombinant vectors (pFD-rAAV-ITR-hSyn-hKCNQ 2-WPRE-BGHpA) are used to correct neurological dysfunction due to KCNQ2 mutations with KCNQ2 gene expression. The recombinant vector developed by the invention has high transduction efficiency in a central nervous system, and the adopted hSyn neuron-specific promoter can realize better treatment effect. The invention fundamentally improves the cognitive dysfunction of the developmental epileptic encephalopathy by regulating the synaptic plasticity of the brain. Specifically, the present invention includes the following. In a first aspect of the invention, there is provided a nucleic acid construct for use in the treatment of KCNQ 2-associated developmental epileptic brain disease, wherein the nucleic acid construct comprises or is capable of producing a polynucleotide of (1) and/or (2) below: (1) A polynucleotide with a sequence shown as SEQ ID No. 2; (2) The polynucleotide (1) having the same function as the nucleotide modified polynucleotide. In a second aspect of the invention, there is provided a pharmaceutical composition for the treatment of KCNQ 2-associated developmental epileptic brain disease, wherein the pharmaceutical composition comprises a nucleic acid construct according to the first aspect. In certain embodiments, the pharmaceutical composition for treating KCNQ 2-associated developmental epileptic brain disease according to the present invention, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant. In certain embodiments, the pharmaceutical composition for treating KCNQ 2-associated developmental epileptic brain diseases according to the present invention, wherein the pharmaceutical composition is an injection. In certain embodiments, a pharmace