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CN-122012620-A - Pharmaceutical composition for long-acting treatment STXBP of nervous system diseases related to STXBP of nervous system diseases, nucleic acid construct and application of nucleic acid construct

CN122012620ACN 122012620 ACN122012620 ACN 122012620ACN-122012620-A

Abstract

The invention discloses a pharmaceutical composition for treating STXBP related neurological diseases, a nucleic acid construct and application thereof. Aiming at the defects of poor targeting, unstable expression, insufficient safety verification, incomplete improvement on nerve functions and the like in the existing gene therapy, the invention realizes targeted intervention on the abnormal nervous system caused by STXBP gene function deficiency or mutation by precisely regulating and controlling the sequence composition, the packaging system and the dosing scheme of a nucleic acid construct, thereby effectively recovering STXBP1 protein expression and improving synaptic transmission dysfunction and related behavioral abnormal phenotypes for a long time.

Inventors

  • CHENG YONG
  • FU QIANG
  • LIU HUA
  • LI XIAODONG
  • 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 the long-acting treatment or amelioration of STXBP a neurological disorder associated with STXBP a 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 the long-acting treatment or amelioration of STXBP a related neurological disorder of claim 1 further comprising a pharmaceutically acceptable adjuvant.
  3. 3. The pharmaceutical composition for the long-acting treatment or amelioration of STXBP a related neurological disease according to claim 1, wherein the pharmaceutical composition is an injection.
  4. 4. The pharmaceutical composition for the long-acting treatment or amelioration of STXBP a related neurological disorder of 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 long-term treatment or amelioration of STXBP a neurological disorder associated with, said nucleic acid construct comprising or being capable of producing a polynucleotide of (1) and/or (2) as follows: (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 STXBP-related neurological disorder is a subject diagnosed with a STXBP1 E549V/- mutation.
  7. 7. Use of the nucleic acid construct of claim 5 in the manufacture of a medicament for treating or ameliorating STXBP-related neurological disorders.
  8. 8. A method of determining the effectiveness of a test agent for treating or ameliorating STXBP-related neurological conditions, comprising the steps of: (1) Providing a cell model or an animal model, and detecting a related indicator comprising STXBP a protein expression level to obtain a first parameter, wherein the cell model or animal model has a STXBP a E549V/- mutation; (2) Administering the drug to be tested to the cell model or animal model, and then detecting a related index containing STXBP protein expression level 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 STXBP a related neurological disorder of claim 8, wherein the indicators further comprise neuropathological indicators comprising at least one of expression of a synaptic function related protein, number of neurons, activation state of a neurological cell, level of oxidative stress, total length of dendrites, number of dendrites, density of dendrites; Preferably, when an animal model is selected, the neuropathological index further comprises at least one of cognitive function, social response, anxiety phenotype.
  10. 10. The method of determining the effectiveness of a test agent for treating or ameliorating STXBP a related neurological disorder of claim 8 wherein said indicator is measured at least 1.5 months after administration of said test agent to said animal model.

Description

Pharmaceutical composition for long-acting treatment STXBP of nervous system diseases related to STXBP of nervous system diseases, nucleic acid construct and application of nucleic acid construct Technical Field The invention relates to the technical field of biological medicine and genetic engineering, in particular to a pharmaceutical composition for long-acting treatment of STXBP related neurological diseases, a nucleic acid construct and application thereof. Background STXBP1 (Syntaxin Binding Protein) gene mutation is a known causative factor of a group of nervous system dysplasia diseases, and is manifested by electroencephalogram abnormality, epilepsy, language disorder, bradykinesia, cognitive deficit and the like. The prior art is not provided with effective intervention means aiming at STXBP gene function defects, only a small number of reports at early animal research stages have the following problems or defects that (1) target selection is limited, most of the prior art focuses on symptomatic regulation of epilepsy or dyskinesia and lacks direct intervention on STXBP as a core pathogenic mechanism, (2) an expression system is unstable, partial research does not optimize a promoter aiming at specific expression requirements of STXBP in neurons, which is easy to cause non-specific expression or insufficient expression level, (3) virus titer control and biosafety verification are insufficient, systematic long-term research is not provided to evaluate long-term safety of different doses of viruses in behaviours, electroencephalograms, neurotoxicity and liver and kidney functions, and (4) the prior research is not comprehensive in overall functional recovery evaluation of a nervous system is limited to protein expression or local behavior test, and lacks systematic mechanism verification of synaptic functions, autophagy/apoptosis channels, oxidative stress and the like. Therefore, the prior art still has obvious defects in the aspects of targeting, comprehensive functional recovery and long-term safety of STXBP gene therapy, and can not meet the requirements of preclinical transformation research, and particularly lacks a gene therapy product for improving abnormal nerve electrical activity and nerve development function for a long time. 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, such as the problems that the existing STXBP gene-related encephalopathy lacks effective and specific treatment means, and the defects of poor targeting, unstable expression, insufficient safety verification, incomplete improvement of nerve functions and the like in the existing gene therapy, the invention provides a nucleic acid construct and a pharmaceutical composition for long-acting treatment of STXBP-related nervous system diseases, which have the following purposes of (1) effectively recovering STXBP1 protein expression, (2) targeting delivery to a central nervous system, preferentially expressing in neurons, (3) improving synaptic transmission dysfunction and related behavioral abnormality phenotypes for a long time, and (4) keeping good tissue biocompatibility and systemic safety. In certain embodiments, the invention provides targeted intervention in neurological abnormalities caused by the STXBP gene loss of function or mutation by precisely controlling the sequence composition, packaging system, and dosing regimen of the nucleic acid construct. 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 long-term treatment or amelioration of STXBP a related neurological 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 long-term treatment or amelioration of STXBP-related neurological diseases, wherein the pharmaceutical composition comprises a nucleic acid construct according to the first aspect. In certain embodiments, the pharmaceutical composition for the long-acting treatment or amelioration of STXBP a-related neurological diseases according to the present invention, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant. In certain embodiments, the pharmaceutical composition for the long-acting treatment or amelioration of STXBP a-related neurological diseases according to the present invention, wherein the pharmaceutic