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WO2023171828A1 - Nouveau modèle de la maladie d'alzheimer et son procédé de construction - Google Patents

Nouveau modèle de la maladie d'alzheimer et son procédé de construction Download PDF

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WO2023171828A1
WO2023171828A1 PCT/KR2022/003176 KR2022003176W WO2023171828A1 WO 2023171828 A1 WO2023171828 A1 WO 2023171828A1 KR 2022003176 W KR2022003176 W KR 2022003176W WO 2023171828 A1 WO2023171828 A1 WO 2023171828A1
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protein
disease
alzheimer
tau
fusion protein
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Korean (ko)
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이치건
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Alzmed Inc
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Alzmed Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention relates to a novel Alzheimer's model and method of producing the same.
  • Alzheimer's disease is the most common degenerative brain disease that causes dementia, and was first reported in 1907 by Dr. Alois Alzheimer, a German psychiatrist. Alzheimer's disease is characterized by a very slow onset and gradual progression. In the beginning, problems mainly occur with memory for recent events, but as the disease progresses, abnormalities in other cognitive functions such as language function and judgment occur, and eventually, all daily life functions are lost. Recently, with the rapid development of medicine, the average human lifespan has increased, and geriatric neurological diseases such as stroke, Alzheimer's disease (AD), and Parkinson's disease are increasing, but the most common among them is Alzheimer's disease.
  • AD Alzheimer's disease
  • the core mechanism of Alzheimer's disease appears to be the excessive production of a small protein called beta-amyloid, which is deposited in the brain and has a harmful effect on brain cells.
  • beta-amyloid a small protein called beta-amyloid
  • studies have shown that hyperphosphorylation of tau protein, which plays an important role in maintaining the skeleton of brain cells, inflammatory response, and oxidative damage, also contribute to brain cell damage and affect the development of the disease.
  • Neurogenic plaques or senile plaques
  • neurofibrillary tangles are associated with tau protein hyperphosphorylation.
  • a fundamental treatment method for Alzheimer's disease has not yet been developed, and only drugs that can relieve symptoms and delay progression, such as acetylcholine enzyme inhibitors, are used in clinical settings. Accordingly, research is actively being attempted to find a fundamental treatment for Alzheimer's disease, but there are limitations in screening and research on candidate therapeutic drugs due to the absence of cell models and animal models that can fully represent Alzheimer's disease.
  • the present invention relates to a novel Alzheimer's model, and more specifically, to a nerve cell model treated with a fusion protein in which a guide protein is bound to a tau protein. Since these cells can embody the characteristics of Alzheimer's disease, they are expected to be actively used as a new drug screening platform for developing treatments for Alzheimer's disease.
  • the present invention was conceived to solve the problems in the prior art as described above, and relates to a novel Alzheimer's model and a method of manufacturing the same.
  • neurodegenerative disease broadly includes all conditions in which nerve cells degenerate, but in general, it can be caused by factors other than distinct nervous system cells, such as cerebrovascular disorders, trauma, and metabolic abnormalities. It does not include what is there. Includes Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, polyglutamine disease including Huntington's disease, human prion disease, etc. In modern medicine, there is a lack of understanding of the clear cause of development or treatment methods.
  • Alzheimer's disease is a type of neurodegenerative disease and the most common degenerative brain disease that causes dementia, and was first reported in 1907 by Dr. Alois Alzheimer, a German psychiatrist.
  • Alzheimer's disease is characterized by a very slow onset and gradual progression. In the beginning, problems mainly occur with memory for recent events, but as the disease progresses, abnormalities in other cognitive functions such as language function and judgment occur, and eventually, all daily life functions are lost.
  • geriatric neurological diseases such as stroke, Alzheimer's disease (AD), and Parkinson's disease are increasing, but the most common among them is Alzheimer's disease.
  • the core mechanism of Alzheimer's disease appears to be the excessive production of a small protein called beta-amyloid, which is deposited in the brain and has a harmful effect on brain cells.
  • beta-amyloid a small protein called beta-amyloid
  • studies have shown that hyperphosphorylation of tau protein, which plays an important role in maintaining the skeleton of brain cells, inflammatory response, and oxidative damage, also contribute to brain cell damage and affect the development of the disease.
  • Neurogenic plaques or senile plaques
  • neurofibrillary tangles are associated with tau protein hyperphosphorylation.
  • a fundamental treatment method for Alzheimer's disease has not yet been developed, and only drugs that can relieve symptoms and delay progression, such as acetylcholine enzyme inhibitors, are used in clinical settings. Accordingly, research is actively being attempted to find a fundamental treatment for Alzheimer's disease, but there are limitations in screening and research on candidate therapeutic drugs due to the absence of cell models and animal models that can fully represent Alzheimer's disease.
  • Tau protein is a type of microtubule associated protein with a molecular weight of 50,000 to 70,000, and has the function of maintaining the stability of nerve cells by binding microtubules and preventing their collapse. It is a protein that performs. Abnormal aggregation of tau protein (tau) in brain nerve cells is a major feature of Alzheimer's disease (AD) and several other neurodegenerative diseases (collectively called tauopathies) (Biochimica et Biophysica Acta , 01 Jan 2005, 1739(2-3):331-354). In healthy nerves, tau stabilizes microtubules by promoting growth from axons and neuron polarization.
  • AD Alzheimer's disease
  • tauopathies Biochimica et Biophysica Acta , 01 Jan 2005, 1739(2-3):331-354.
  • tau When pathologically hyperphosphorylated, tau dissociates from microtubules and forms insoluble aggregates (Mol Neurodegeneration 4, 13 (2009). https://doi.org/10.1186/1750-1326-4- 13).
  • NFTs neurofibrillary tangles
  • a guide peptide refers to a protein that binds to the N-terminal of a target protein and induces overexpression or inhibition of the function of the target protein. Therefore, in terms of a fusion protein in which a guide protein and a target protein are combined, the target protein is located at the C-terminal of the guide protein, and a linker, etc. may be located between the guide protein and the target protein. The orientation serves as an important factor in the function of the guide protein expected in the present invention.
  • HRS hepatocyte growth factor-regulated tyrosine kinase substrate
  • GST glutthione Stransferase
  • FD T4 fibritin foldon bound to the N-terminal of the target protein (Tau-4R) domain
  • DDT D-dopachrome tautomerase
  • SCL Streptococcus pyogenes collagen-like protein
  • CDA human cytidine deaminase
  • NPM nucleophosmin 1
  • HFQ a host factor for bacteriophage Q ⁇ RNA replication
  • HSP90 ⁇ heat- Shock protein 90 alpha isoform
  • the above target protein can be any protein involved in the progression of neurodegenerative disease, and is not limited thereto, but is preferably Tau, A ⁇ , or apoE, and more specifically, Tau, A ⁇ 40 , A ⁇ 42 , apoE2, and apoE3. , apoE4, or apoJ.
  • guided oligomerization is a method of preparing a set of oligomeric conformers of any pathogenic protein or peptide with a soluble and biologically active structure, which is bound to the guide protein. Includes dimers, trimers, tetramers, pentamers and hexamers of the target protein. This is called an oligomeric conformer set.
  • the set of oligomeric conformers can be prepared using any expression system utilizing bacterial, yeast, insect, and mammalian cells.
  • the drug screening platform refers to a system that performs screening of candidate drugs expected to have therapeutic effects on target diseases using the guide oligomerization conformer set of the present invention.
  • a fusion protein in which a guide protein is bound to a tau protein, the tau protein is Tau-4R, and the guide protein is HRS (hepatocyte growth factor-regulated tyrosine).
  • HRS hepatocyte growth factor-regulated tyrosine
  • kinase substrate GST (glutathione Stransferase), FD (T4 fibritin foldon domain), DDT (D-dopachrome tautomerase), SCL (Streptococcus pyogenes collagen-like protein), CDA (human cytidine deaminase), NPM (nucleophosmin 1), HFQ (a host factor for bacteriophage Q ⁇ RNA replication), and HSP90 ⁇ (heat-shock protein 90 alpha isoform).
  • the fusion protein is a dimer, trimer, or tetramer.
  • a fusion protein having a hexameric, pentameric, or hexameric three-dimensional structure is provided
  • a gene encoding the above fusion protein is provided.
  • a vector containing the above gene is provided.
  • a transformant transformed with the above vector wherein the transformant is a cell isolated from an individual, and the transformant is a human Provides a transformant that is an excluded individual.
  • the guide proteins include HRS (hepatocyte growth factor-regulated tyrosine kinase substrate), GST (glutathione Stransferase), FD (T4 fibritin foldon domain), DDT (D-dopachrome tautomerase), SCL (Streptococcus pyogenes collagen-like protein), and CDA.
  • Alzheimer's disease cells which are at least one selected from the group consisting of (human cytidine deaminase), NPM (nucleophosmin 1), HFQ (a host factor for bacteriophage Q ⁇ RNA replication), and HSP90 ⁇ (heat-shock protein 90 alpha isoform).
  • a method for manufacturing a model is provided, wherein the fusion protein has a dimer, trimer, tetramer, pentamer, or hexamer three-dimensional structure.
  • the guide proteins include HRS (hepatocyte growth factor-regulated tyrosine kinase substrate), GST (glutathione Stransferase), FD (T4 fibritin foldon domain), DDT (D-dopachrome tautomerase), and SCL (Streptococcus pyogenes collagen).
  • fusion protein has a dimer, trimer, tetramer, pentamer, or hexameric three-dimensional structure.
  • the present invention relates to a nerve cell model treated with a fusion protein in which a guide protein is bound to tau protein. Since these cells can embody the characteristics of Alzheimer's disease, they are expected to be actively used as a new drug screening platform for developing treatments for Alzheimer's disease.
  • FIG 1 is a schematic diagram of an oligomer set prepared by applying guided oligomerization to Tau-4R, according to an embodiment of the present invention.
  • Tau-4R (gray) is represented as a recombinant protein linked to a guide peptide at the N terminus (white) and a spacer peptide containing a thrombin cleavage site (black).
  • DA / DB is a dimer
  • TA / TB / TC are a trimer
  • QA is a tetramer
  • PA is a pentamer
  • HA / HB is a hexamer
  • Mw ( kDa) is the size of the oligomer as a fusion structure.
  • Figure 2 shows the results confirmed by SDS-PAGE without incubation (A) or with incubation (B) of the oligomer set prepared in the present invention, according to an embodiment of the present invention.
  • M is the molecular weight standard
  • lane 1 is M-4R (monomeric Tau-4R)
  • lane 2 is DA-4R
  • lane 3 is DB-4R
  • lane 4 is TA-4R
  • lane 5 is is TB-4R
  • lane 6 is DA-4R
  • lane 7 is PA-4R
  • lane 8 is HA-4R.
  • Figure 3 shows the results of a toxicity test on SH-SY5Y cells of the oligomer set prepared in the present invention, according to an embodiment of the present invention.
  • Figure 4 shows the results of observing the cell morphology after treating hippocampal neurons derived from mouse embryos with the oligomer set prepared in the present invention, according to an embodiment of the present invention.
  • Figure 5 shows the results of a cytotoxicity test after treating hippocampal neurons derived from mouse embryos with the oligomer set prepared in the present invention, according to an embodiment of the present invention.
  • Figure 6 shows the morphology of cells after co-treating hippocampal neurons derived from mouse embryos with thrombin at various concentrations of oligomeric trimer TA-4R and TB-4R prepared in the present invention, according to an embodiment of the present invention. This is the result of observation.
  • Figure 7 shows cytotoxicity after co-treating oligomeric trimers TA-4R and TB-4R prepared in the present invention with thrombin at various concentrations to hippocampal neurons derived from mouse embryos, according to an embodiment of the present invention. This is the result of the test.
  • Figure 8 shows the results of confirming the LC50 values of the oligomer trimer (TB-4R), tetramer (QA-4R), or pentamer (PA-4R) prepared in the present invention according to an embodiment of the present invention.
  • One embodiment of the present invention relates to a fusion protein in which a guide protein is bound to a tau protein.
  • Another embodiment of the present invention relates to a gene encoding a fusion protein in which a guide protein is bound to a tau protein.
  • Another embodiment of the present invention relates to a vector containing a gene encoding the fusion gene.
  • Another embodiment of the present invention relates to a transformant transformed with the above vector.
  • Another embodiment of the present invention includes preparing a fusion protein in which a guide protein is bound to a tau protein; and processing the fusion protein into nerve cells. It relates to a method of producing an Alzheimer's disease cell model including.
  • Another embodiment of the present invention includes preparing a fusion protein in which a guide protein is bound to a tau protein; Processing the fusion protein into nerve cells; and treating the nerve cells with a candidate substance for treating Alzheimer's disease.
  • Full-length tau represented by SEQ ID NO: 1, has an N-terminal projection domain (aa1-165), a proline-rich region (aa166-242), and an MT binding region (MTBR). , aa243-367) and C-terminal domain (aa368-441), and the MT binding region (MTBR), also named Tau-4R, consists of R1 (aa243-273), R2 (aa274-304) , contains four partially repeated sequences named R3 (aa305-335) and R4 (aa336-367). The above-mentioned Tau-4R tends to form ⁇ -strands, and is pointed out as the cause of tau aggregation (J Neurosci, 2008. 28(3): p. 737-48.).
  • the oligomer set shown in Figure 1 was prepared by applying guided oligomerization (GO) to the Tau-4R. More specifically, the target is expressed as a fusion structure whose N-terminal portion consists of a guide peptide and a short stretch of amino acids that are recognized and cleaved by the protease thrombin. Detailed sequence information and amino acid positions of the guide peptide are shown in Table 1.
  • DA-4R (lane 2), DB-4R (lane 3) as a dimer, and TB-4R (glutathione S-transferase) (lane 5) as a trimer maintain their identity as oligomers while running on an SDS-PAGE gel. It was found that it was not sufficiently stabilized to maintain. On the other hand, TA-4R (lane 4), QA-4R (lane 6), PA-4R (lane 7), and HA-4R (lane 8) maintained their oligomeric state well in SDS-PAGE.
  • the cytotoxicity of the tau oligomer set prepared in Example 1 was confirmed in neural cell lines or primary cells.
  • the human neuroblastoma cell line SH-SY5Y was seeded in a 96 -well culture dish at a density of 6 It was replaced with serum medium (3.5% FBS). Cell viability was measured daily for 3 days using PrestoBlue, and each measured value was converted to % based on the negative control and shown in Figure 3.
  • the experimental results showed that among all oligomers, QA-4R was the most cytotoxic. TA-4R and PA-4R were also cytotoxic at low levels, but monomers, dimers, and hexamers had little cytotoxicity. These results imply that Tau-4R oligomeric conformations such as trimers, tetramers, and pentamers cause cytotoxicity. The cytotoxicity caused by Tau-4R oligomers increased significantly after one day of exposure to Tau-4R.
  • hippocampal neuronal cells were induced and cultured from mouse embryos.
  • the primary cultured cells were seeded in a 24 -well culture dish at a density of 1.2 It was replaced with .
  • the procedure was divided into two groups: those with or without the addition of thrombin.
  • Co-processing with thrombin can affect the function of target proteins by removing the guide peptide from the N-terminus, or can induce neuroprotective effects and neuroticism. Therefore, treatment with Tau-4R and any target protein in combination with thrombin was expected to better reflect the neuropathological state in vivo.
  • Cells were treated with the Tau-4R oligomer set, and the morphology of the cells 6 days later is shown in Figure 4.
  • sandwich ELISA was performed. Briefly, cells were treated with 0.5 ml of lysis buffer per well, and 100 ⁇ l was dispensed and transferred to an ELISA plate pre-coated with anti-SNAP25 mouse monoclonal primary antibody. Since SNAP25 is expressed only in neuronal cells, it is used as a characteristic of neuronal cells. Plates were then washed, treated with affinity-purified rabbit polyclonal secondary antibodies, and the extent of captured SNAP25 was quantified using rabbit IgG and HRP-conjugated antibodies that recognize the TMB substrate. This was converted to % based on the negative control group and is shown in Figure 5.
  • the LC50 values of TB-4R, QA-4R, and PA-4R were 36 nM, 16 nM, and 73 nM, respectively, showing that the toxicity was strong in the order of QA-4R > TB-4R > PA-4R. I was able to.
  • the fusion protein of the present invention was found to form LC50 values at the nM level.
  • the guide protein of the present invention has an excellent effect in regulating the function of the target protein, and includes dimers, trimers, tetramers, pentamers, and hexamers of the target protein in a state bound to the guide protein. It was found that the oligomer conformer set can be used as an excellent cell model or animal model for screening drugs for the treatment of the desired disease.
  • guide proteins include HRS (hepatocyte growth factor-regulated tyrosine kinase substrate), GST (glutathione Stransferase), FD (T4 fibritin foldon domain), DDT (D-dopachrome tautomerase), SCL (Streptococcus pyogenes collagen-like protein), and CDA.
  • HRS hepatocyte growth factor-regulated tyrosine kinase substrate
  • GST glutase
  • FD T4 fibritin foldon domain
  • DDT D-dopachrome tautomerase
  • SCL Streptococcus pyogenes collagen-like protein
  • CDA CDA.
  • human cytidine deaminase human cytidine deaminase
  • NPM nucleophosmin 1
  • HFQ a host factor for bacteriophage Q ⁇ RNA replication
  • HSP90 ⁇ heat-shock protein 90 alpha isoform
  • the nerve cells
  • the present invention relates to a novel Alzheimer's model, and more specifically, to a nerve cell model treated with a fusion protein in which a guide protein is bound to a tau protein. Since these cells can embody the characteristics of Alzheimer's disease, they can be used as a new drug screening platform to develop a treatment for Alzheimer's disease.

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Abstract

La maladie d'Alzheimer est la maladie cérébrale dégénérative la plus courante qui provoque la démence, l'hyperphosphorylation de la protéine tau étant connue comme étant la cause principale. Cependant, il existe des limitations dans le criblage et la recherche de médicaments candidats thérapeutiques en raison de l'absence de modèles cellulaires et de modèles d'animaux pouvant mettre en œuvre complètement la maladie d'Alzheimer. La présente invention concerne un nouveau modèle de la maladie d'Alzheimer, et plus particulièrement, un modèle de cellule neuronale traitée avec une protéine de fusion dans laquelle une protéine guide est couplée à la protéine tau. Les cellules peuvent reproduire les caractéristiques de la maladie d'Alzheimer telles qu'elles, elles représentent ainsi une nouvelle plateforme pour le criblage de médicaments visant le développement d'un agent thérapeutique contre la maladie d'Alzheimer.
PCT/KR2022/003176 2022-03-07 2022-03-07 Nouveau modèle de la maladie d'alzheimer et son procédé de construction Ceased WO2023171828A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040038397A1 (en) * 1998-12-30 2004-02-26 Smith Mark A. Alzheimer model for drug screening
US20090280110A1 (en) * 2006-06-27 2009-11-12 University Of Virginia Patent Foundation Cell Model for Alzheimer's Disease Pathology
US9464122B2 (en) * 2008-08-20 2016-10-11 Oligomerix, Inc. Methods and compositions comprising tau oligomers
KR20180112558A (ko) * 2017-04-04 2018-10-12 (주) 메디프론디비티 알츠하이머병 형질전환 돼지 모델 및 이의 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040038397A1 (en) * 1998-12-30 2004-02-26 Smith Mark A. Alzheimer model for drug screening
US20090280110A1 (en) * 2006-06-27 2009-11-12 University Of Virginia Patent Foundation Cell Model for Alzheimer's Disease Pathology
US9464122B2 (en) * 2008-08-20 2016-10-11 Oligomerix, Inc. Methods and compositions comprising tau oligomers
KR20180112558A (ko) * 2017-04-04 2018-10-12 (주) 메디프론디비티 알츠하이머병 형질전환 돼지 모델 및 이의 제조방법

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MCINNES JOSEPH, ZHOU LUJIA, VERSTREKEN PATRIK: "Purification of Soluble Recombinant Human Tau Protein from Bacteria Using Double-tag Affinity Purification", BIO-PROTOCOL, BIO-PROTOCOL.ORG, SUNNYVALE, CA, USA, vol. 8, no. 22, 20 November 2018 (2018-11-20), Sunnyvale, CA, USA , pages 1 - 9, XP093090922, ISSN: 2331-8325, DOI: 10.21769/BioProtoc.3043 *

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