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HMGB1 INHIBITORS FOR TREATMENT OF APOE4-RELATED TAUOPATHIES INCLUDING ALZHEIMER'S DISEASE

NºPublicación:  EP4543459A1 30/04/2025
Solicitante: 
THE J DAVID GLADSTONE INST A TESTAMENTARY TRUST ESTABLISHED UNDER THE WILL OF J DAVID GLADSTONE [US]
THE REGENTS OF UNIV OF CALIFORNIA [US]
The J. David Gladstone Institutes, A Testamentary Trust Established under The Will of J. David Gladstone,
The Regents of University of California
CN_119630405_A

Resumen de: WO2023250249A1

As described herein, inhibitors of High mobility group box protein 1 (HMGB1) can significantly reduce HMGB1 nucleo-cytoplasmic translocation, gliosis, neurodegeneration, Tau pathologies, and myelin deficits, especially in subjects having an AP0E4 allele. Methods are therefore described herein that include administering one or more inhibitors of High mobility group box protein 1 (HMGB1) to a subject having at least one genomic AP0E4 allele.

METHOD OF TREATING PRECLINICIAL ALZHEIMER'S DISEASE

NºPublicación:  US2025127867A1 24/04/2025
Solicitante: 
JANSSEN PHARMACEUTICALS INC [US]
AC IMMUNE SA [CH]
JANSSEN PHARMACEUTICALS, INC,
AC IMMUNE SA

Resumen de: US2025127867A1

The application describes a phosphorylated tau targeted active immunotherapy to treat preclinical Alzheimer's Disease.

BLOCKING ITGB8 IN NEURODEGENERATIVE DISEASE

NºPublicación:  AU2023351193A1 24/04/2025
Solicitante: 
THE BRIGHAM AND WOMENS HOSPITAL INC
THE REGENTS OF THE UNIV OF CALIFORNIA
THE BRIGHAM AND WOMEN'S HOSPITAL, INC,
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
AU_2023351193_A1

Resumen de: AU2023351193A1

Provided herein are methods and compositions that block Integrin Subunit beta 8 (ITGB8, also known as integrin αvβ8) to treat neurodegenerative diseases associated with microglial impairment including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).

APOE GENE THERAPY

NºPublicación:  AU2023360721A1 24/04/2025
Solicitante: 
SPARK THERAPEUTICS INC
SPARK THERAPEUTICS, INC
AU_2023360721_PA

Resumen de: AU2023360721A1

The present relates to polynucleotide constructs encoding an ApoE3 related protein optionally containing one or more intron. Potential uses of the different constructs include gene therapy targeting one or more disease or disorder, for example, diseases or disorders related to cholesterol levels, atherosclerosis, coronary heart disease, dementia, cerebral amyloid angiopathy, or Alzheimer's disease.

COMPOUND BINDING TO CRBN PROTEIN AND DEGRADATION AGENT OF PROTEIN

NºPublicación:  WO2025082069A1 24/04/2025
Solicitante: 
OCEAN UNIV OF CHINA [CN]
\u4E2D\u56FD\u6D77\u6D0B\u5927\u5B66
WO_2025082069_A1

Resumen de: WO2025082069A1

The present invention belongs to the technical field of medicinal chemistry, specifically relates to a compound capable of binding to a CRBN protein and a composition thereof, and also relates to a protein degradation agent based on a CRBN protein and the use thereof. Specifically disclosed is a compound capable of binding to a CRBN protein, wherein the compound is composed of two sub-structure units A and B, the two sub-structures A and B are connected by means of a chemical single bond between Y of the sub-structure A and one of C2 (carbon at position 2), C4 (carbon at position 4), C5 (carbon at position 5), C6 (carbon at position 6) and C7 (carbon at position 7) of the sub-structure B, and the compound is as shown in formula I. The compound can be used as a structural unit of an E3 ubiquitin ligase ligand in PROTAC technology, thereby providing more therapeutic means for cancers or diseases such as prostate cancer, breast cancer, non-small cell lung cancer, Alzheimer's disease, neuroblastoma, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, malignant rhabdomyosarcoma, and oral squamous cell carcinoma.

INHIBITORS OF RAB-RILPL INTERACTIONS AND USES THEREOF

NºPublicación:  WO2025085624A1 24/04/2025
Solicitante: 
UNIV OF GEORGIA RESEARCH FOUNDATION INC [US]
UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC
WO_2025085624_PA

Resumen de: WO2025085624A1

The present disclosure provides synthetic polypeptides that mimic the Switch 2 domain of a Rab protein. The synthetic polypeptides described are capable of inhibiting, modulating, or decreasing the interaction between a Rab protein and an RILPL protein. Methods of treating neurological diseases, disorders, or conditions, such as Parkinson's disease, are also provided.

BRAIN-CELL SPECIFIC PARTIAL CELLULAR REPROGRAMMING TREATMENT AND PREVENTION METHODS FOR ALZHEIMER'S DISEASE AND PROGERIA, COMPOSITIONS THEREFORE, AND USES THEREOF

NºPublicación:  WO2025085704A1 24/04/2025
Solicitante: 
YOUTHBIO THERAPEUTICS INC [US]
YOUTHBIO THERAPEUTICS INC
WO_2025085704_PA

Resumen de: WO2025085704A1

This disclosure relates to vectors, compositions, pharmaceutical compositions, and kits that provide for brain cell-specific expression of reprogramming genes such as the Yamanaka factors Oct4, Sox2, Klf4 and c-Myc (OSKM). Also provided are methods and uses comprising the same for treating Alzheimer' s disease and progeria through brain cell-specific expression of reprogramming genes such as OSKM.

COMPOSITION FOR DELAYING OR TREATING HUNTINGTON'S DISEASE COMPRISING LIN28A INHIBITOR AS ACTIVE INGREDIENT

NºPublicación:  WO2025084727A1 24/04/2025
Solicitante: 
KOREA UNIV RESEARCH AND BUSINESS FOUNDATION [KR]
\uACE0\uB824\uB300\uD559\uAD50 \uC0B0\uD559\uD611\uB825\uB2E8
WO_2025084727_PA

Resumen de: WO2025084727A1

The present invention relates to a composition for delaying or treating Huntington's disease, comprising a Lin28A inhibitor as an active ingredient. The present invention relates to various inhibitors capable of having the effect of preventing or treating Huntington's disease by inhibiting the expression of Lin28A, which is highly secreted specifically in Huntington's disease, and a screening method therefor.

COMPOSITIONS AND METHODS USING REELIN IN ALZHEIMER'S DISEASE

NºPublicación:  AU2023358527A1 24/04/2025
Solicitante: 
THE GENERAL HOSPITAL CORP
MASSACHUSETTS EYE AND EAR INFIRMARY
BANNER HEALTH
THE GENERAL HOSPITAL CORPORATION,
MASSACHUSETTS EYE AND EAR INFIRMARY,
BANNER HEALTH
AU_2023358527_A1

Resumen de: AU2023358527A1

Described herein are methods and compositions for treating Alzheimer's Disease (AD), as well as compositions comprising a reelin-derived peptide and methods of use thereof.

CAR-TREG-BASED THERAPIES FOR TREATING NEURODEGENERATIVE DISEASES

NºPublicación:  US2025129158A1 24/04/2025
Solicitante: 
AZTHERAPIES INC [US]
AZTherapies, Inc
JP_2024086870_A

Resumen de: US2025129158A1

The invention provides compositions and methods for suppressing autoimmune components of neurodegenerative diseases and thereby providing therapeutic effects to patients suffering from such diseases. Compositions and methods include immunosuppressive moieties such as regulatory T cells (Tregs) and proteins expressed by Tregs coupled to a chimeric antigen receptor or protein that specifically binds one or more glial cell markers. Therapeutically effective doses of said compounds for treating neurodegenerative diseases including progressive supranuclear palsy (PSP), Parkinson's disease (PD), Alzheimer's, Huntington's disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), and prion diseases are disclosed.

USE OF FACTOR H FOR THE TREATMENT OF DEMENTIA

NºPublicación:  WO2025083211A1 24/04/2025
Solicitante: 
INSTITUT NATIONAL DE LA SANTE ET DE LA RECH MEDICALE [FR]
UNIV DE BORDEAUX [FR]
INSTITUT NATIONAL DE LA SANT\u00C9 ET DE LA RECHERCHE M\u00C9DICALE,
UNIVERSIT\u00C9 DE BORDEAUX
WO_2025083211_A1

Resumen de: WO2025083211A1

The inventors hypothesized that inhibition of complement activation could reduce the inflammatory period observed even before clinical signs of Alzheimer's disease and thus slow down the onset and progression of AD. In order to validate the hypothesis, the inventors injected Factor H (FH: the main inhibitor of complement activation) into the brain of APP/PS1 AD- mice model at early or late stage of this pathology. The results showed effects of FH brain injection on the AD-onset as well as progression by reducing pro-inflammatory IL6, TNF-α, Il1β, MAC and Aβ levels associated with an increase of VGLUT1 and Psd95 neurotransmitters levels in hippocampal region leading to improvement of cognitive functions even at late stage of the pathology. The results thus prompt the inventors to consider that FH would be suitable for the treatment of dementia, and more particularly for the curative treatment of dementia.

METHOD OF INDUCING DENDRITIC AND SYNAPTIC GENESIS IN NEURODEGENERATIVE CHRONIC DISEASES

NºPublicación:  US2025127775A1 24/04/2025
Solicitante: 
PETCAVICH ROBERT JOHN [US]
Petcavich Robert John
CA_3148256_PA

Resumen de: US2025127775A1

The present invention discloses a method to recover and restore dendritic and synaptic neuron connections that have been degraded or destroyed by neurodegenerative diseases. In the present invention tryptamines are used to induce neuro plasticity and restore both dendritic density and synaptic connections of neurons in the brain. In the preferred embodiment LSD given in micro doses can induce dendritic and synaptic genesis in neuronal networks and improve the quality of life of people with neurodegenerative diseases such as Alzheimer's, Huntington's, Multiple Sclerosis, Parkinson's and Frontotemporal dementia.

APPLICATION OF BMSC-EXOS IN TREATING PD

NºPublicación:  US2025127817A1 24/04/2025
Solicitante: 
NANTONG UNIV [CN]
NANTONG UNIVERSITY
JP_2024514740_PA

Resumen de: US2025127817A1

An application of Bone Marrow Mesenchyml Stem Cell Exosomes (BMSC-Exos) in treating Parkinson's disease (PD) is provided, wherein the BMSC-Exos are generated by stimulating BMSCs with a culture solution and extracted from the culture solution after passage; and the culture solution of the BMSCs is an α-MEM culture solution containing FBS and PS. The BMSC-Exos can greatly improve a motor function of a model mouse with PD, protect dopaminergic neurons of the model mouse with PD, improve an olfactory function of the model mouse with PD, and also inhibit the activation of olfactory astrocytes of the model mouse with PD.

PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING PARKINSON'S DISEASE, CONTAINING PDK INHIBITOR AS ACTIVE INGREDIENT

NºPublicación:  WO2025080080A1 17/04/2025
Solicitante: 
IUCF HYU INDUSTRY UNIV COOPERATION FOUNDATION HANYANG UNIV [KR]
RESEARCH \uFF06 BUSINESS FOUNDATION SUNGKYUNKWAN UNIV [KR]
INDUSTRY ACADEMIC COOPERATION FOUNDATION GYEONGSANG NATIONAL UNIV [KR]
\uD55C\uC591\uB300\uD559\uAD50 \uC0B0\uD559\uD611\uB825\uB2E8,
\uC131\uADE0\uAD00\uB300\uD559\uAD50 \uC0B0\uD559\uD611\uB825\uB2E8,
\uACBD\uC0C1\uAD6D\uB9BD\uB300\uD559\uAD50 \uC0B0\uD559\uD611\uB825\uB2E8
WO_2025080080_PA

Resumen de: WO2025080080A1

According to pharmaceutical composition for preventing or treating Parkinson's disease, containing a pyruvate dehydrogenase kinase (PDK) inhibitor as an active ingredient, a pharmaceutical preparation for preventing or treating Parkinson's disease, containing same, and a method for predicting a Parkinson's disease therapeutic effect of a candidate drug, of the present invention, it can be expected that a candidate drug treating Parkinson's disease and having an optimal therapeutic effect can be selected.

TREATMENT OF NEUROPSYCHIATRIC DISORDERS WITH TILIVAPRAM

NºPublicación:  WO2025080415A1 17/04/2025
Solicitante: 
ALTO NEUROSCIENCE INC [US]
ALTO NEUROSCIENCE, INC
WO_2025080415_PA

Resumen de: WO2025080415A1

This invention relates to the treatment of a neuropsychiatric disorder, such as schizophrenia or Parkinson's disease, by administration (for example, transdermally) of tilivapram, zatolmilast, roflumilast, or a pharmaceutically acceptable salt thereof.

METHODS OF USE OF (4R,5R)-5-(2-CHLOROPHENYL)-4-(5-(PHENYLETHYNYL)PYRIDIN-3-YL)OXAZOLIDIN-2-ONE

NºPublicación:  WO2025080252A1 17/04/2025
Solicitante: 
ALLYX THERAPEUTICS INC [US]
YALE UNIV [US]
ALLYX THERAPEUTICS, INC,
YALE UNIVERSITY
WO_2025080252_A1

Resumen de: WO2025080252A1

The present disclosure provides methods of treating Alzheimer's disease and other disorders using (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one (Compound 1).

RECOMBINANT VIRUS EXPRESSING TPK AND USE THEREOF IN TREATMENT OF ALZHEIMER'S DISEASE

NºPublicación:  US2025121095A1 17/04/2025
Solicitante: 
SHANGHAI RAISING PHARMACEUTICAL CO LTD [CN]
SHANGHAI RAISING PHARMACEUTICAL CO., LTD
US_2025121095_PA

Resumen de: US2025121095A1

Provided is a recombinant adeno-associated virus (rAAV) or recombinant lentivirus, comprising an expression cassette in the genome, the expression cassette comprises a polynucleotide encoding thiamine pyrophosphokinase (TPK), which is operatively linked to a promoter. Also provided are also a pharmaceutical composition comprising the rAAV or recombinant lentivirus, and use of the rAAV, recombinant lentivirus and the pharmaceutical composition in the preparation of a medicament for treating or preventing Alzheimer's disease.

COMPOUNDS FOR REDUCING NEUROINFLAMMATION

NºPublicación:  US2025122146A1 17/04/2025
Solicitante: 
THE SCRIPPS RES INSTITUTE [US]
THE SCRIPPS RESEARCH INSTITUTE
US_2025122146_A1

Resumen de: US2025122146A1

Disclosed herein are compounds, their pharmaceutical compositions, and their methods of use for treating a neurodegenerative disease, such as Alzheimer's disease. Lewy body dementia, or Parkinson' disease. In some embodiments, the compound is one that activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and/or heat-shock factor-1 (HSF-1) transcription-mediated signaling pathway: the compound is administered with at least one antibody that is directed against an aberrant misfolded protein. The compound, illustrated by camosic acid in one example, is unexpectedly effective in reducing the type of neuroinflammation resulting from antibody-protein complexes encountered in antibody therapies of the disease. The compounds also are useful in a method of treating neuroinflammation in a subject who suffers from a neurodegenerative disease and/or has been administered at least one antibody that is directed against an aberrant misfolded protein.

TREATMENT OF NEUROPSYCHIATRIC DISORDERS WITH TILIVAPRAM

NºPublicación:  US2025120957A1 17/04/2025
Solicitante: 
ALTO NEUROSCIENCE INC [US]
Alto Neuroscience, Inc
US_2025120957_PA

Resumen de: US2025120957A1

This invention relates to the treatment of a neuropsychiatric disorder, such as schizophrenia or Parkinson's disease, by administration (for example, transdermally) of tilivapram, zatolmilast, roflumilast, or a pharmaceutically acceptable salt thereof.

COMPOSITION FOR IMPROVING MEMORY AND PREVENTING, ALLEVIATING, OR TREATING COGNITIVE DISORDER COMPRISING YUKGUNJATANG AS EFFECTIVE COMPONENT

NºPublicación:  US2025121020A1 17/04/2025
Solicitante: 
KOREA INST OF ORIENTAL MEDICINE [KR]
KOREA INSTITUTE OF ORIENTAL MEDICINE
US_2025121020_PA

Resumen de: US2025121020A1

A composition including Yukgunjatang as effective component is effective for improving memory and preventing, alleviating, or treating cognitive disorder. Yukgunjatang, which is prepared by boiling a mixture of Gingseng Radix, Atractylodes rhizoma alba, Hoelen, Glycyrrhizae Radix, Aurantii Nobilis Pericarpium, Pinelliae Rhizoma, Zingiberis Rhizoma, and Zizyphi Fructus in water, exhibits superior neuroprotective effect compared to individual extracts of Gingseng Radix, Atractylodes rhizoma alba, Hoelen, Glycyrrhizae Radix, Aurantii Nobilis Pericarpium, Pinelliae Rhizoma, Zingiberis Rhizoma, and Zizyphi Fructus, and, in an animal model of cognitive decline induced by scopolamine, administration of Yukgunjatang shows the effect of improving memory and cognitive function. Thus, the composition can be advantageously used as a food product, a medicinal product, or the like for preventing or treating brain diseases including Alzheimer's disease, Parkinson's disease, and mild cognitive impairment.

THE BRI2 BRICHOS DOMAIN FOR TREATMENT OF PARKINSON ́S DISEASE

NºPublicación:  WO2025078660A1 17/04/2025
Solicitante: 
ALPHABETA AB [SE]
ALPHABETA AB
WO_2025078660_PA

Resumen de: WO2025078660A1

An isolated protein comprising (i) a first protein moiety selected from the group of proteins comprising an amino acid sequence having at least 70% identity to residues 113-231 of Bri2 from human (SEQ ID NO: 2); and proteins comprising an amino acid sequence having at least 70% identity to any one of the BRICHOS domains of Bri2 from human (SEQ ID NO: 5), chimpanzee (SEQ ID NO: 6), bovine (SEQ ID NO: 7), pig (SEQ ID NO: 8), mouse (SEQ ID NO: 9) and rat (SEQ ID NO: 10); and and optionally (ii) a second protein or polypeptide moiety, preferably containing at least 50 amino acid residues, wherein the second protein or polypeptide moiety is selected from the group consisting of protein drugs, polypeptide drugs, antibodies and/or neurotrophic factors; wherein the second protein or polypeptide moiety is effective for treatment of Parkinson's Disease; for use as a medicament, in particular for treatment of Parkinson's Disease.

USE OF BACILLUS AMYLOLIQUEFACIENS FOR PREVENTING AND TREATING PARKINSON'S DISEASE

NºPublicación:  US2025121013A1 17/04/2025
Solicitante: 
ARTUGEN THERAPEUTICS LTD [IE]
Artugen Therapeutics Ltd
US_2025121013_PA

Resumen de: US2025121013A1

Disclosed herein are compositions and methods for preventing, ameliorating, or treating Parkinson's disease and/or reducing the severity of one or more risk factors, signs, or symptoms associated with Parkinson's disease. In particular, the technology of the present disclosure relates to methods for administering an effective amount of a composition comprising one or more strains of an operational group Bacillus amyloliquefaciens bacteria, identified as ART24 and ART12, to a subject suffering from or at risk for Parkinson's disease.

USE OF α-KETOGLUTARIC ACID IN PREPARATION OF DRUG FOR PREVENTING AND TREATING DEMYELINATION-RELATED DISEASES

NºPublicación:  WO2025077839A1 17/04/2025
Solicitante: 
WEST CHINA SECOND UNIV HOSPITAL SICHUAN UNIV [CN]
\u56DB\u5DDD\u5927\u5B66\u534E\u897F\u7B2C\u4E8C\u533B\u9662
WO_2025077839_PA

Resumen de: WO2025077839A1

The use of α-ketoglutaric acid in the preparation of a drug for preventing and treating demyelination-related diseases. The α-ketoglutaric acid or a derivative thereof is used for preventing and/or treating myelin sheath defects in demyelination-related diseases, such as demyelinating diseases, amyotrophic lateral sclerosis, Huntington's disease, hypomyelinating leukodystrophy, Alzheimer's disease, Parkinson's syndrome and diabetes-related visual impairment, and can promote myelin sheath generation, regeneration or repair, and improve the immune microenvironment in the lesion area.

DYRK/CLK PROTACS AND USES THEREOF

NºPublicación:  WO2025080753A1 17/04/2025
Solicitante: 
ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIV OF ARIZONA [US]
RHEINISCH WESTFAELISCHE TECHNISCHE HOCHSCHULE AACHEN RWTH AACHEN KOERPERSCHAFT DES OEFFENTLICHEN REC [DE]
ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA,
RHEINISCH-WESTF\u00C4LISCHE TECHNISCHE HOCHSCHULE AACHEN (RWTH AACHEN), K\u00D6RPERSCHAFT DES \u00D6FFENTLICHEN RECHTS
WO_2025080753_A1

Resumen de: WO2025080753A1

The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) one or more of the following kinases: DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8/19, PI3K, PDGFrA/B, mTOR, HIPKs, and/or CMGC kinases leading to inhibition of WNT signaling. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds one or more of the following kinases: DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8/19, PI3K, PDGFrA/B, mTOR, HIPKs, and/or CMGC kinases leading to inhibition of WNT signaling, such that the one or more kinases is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the one or more kinases. The bifunctional compounds serve as therapeutics for the treatment of Alzheimer's disease, down syndrome, diabetes, an autoimmune disease, an inflammatory disorder (e.g., airway inflammation, osteoarthritis (e.g., knee related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer, acute myeloid leukemia, myelodysplastic syndrome), a viral infection (e.g., SARS-CoV-2 infection (e.g., COVID-19)), and other diseases.

METHOD FOR CONTROLLING MEMBRANE POTENTIAL-DEPENDENT ION CHANNEL THROUGH TYPE I TASTE RECEPTORS (T1RS)

Nº publicación: EP4537845A1 16/04/2025

Solicitante:

ION CHAT RES CORPORATE [JP]
SAITO MITSUYOSHI [JP]
Ion Chat Research Corporate,
Saito, Mitsuyoshi

EP_4537845_A1

Resumen de: EP4537845A1

The present invention pertains to a method for controlling a membrane potential-dependent ion channel (VGSC or the like) through a type I taste receptor present in a nerve cell or the like. In the present invention, it has been found that an A β peptide, or a sweet amino acid or an umami substance specifically binds to a type I taste receptor on the surface of a nerve cell to exert an agonist-like or antagonist-like action, thereby amplifying or suppressing a VGSC active current.Moreover, with the binding of an Aβ peptide or the like to a type I taste receptor, the amplification of a VGSC active current occurs, the overactivity of nerve cells causing epileptiform attack occurs, and a large number of substances, which can effectively suppress the amplification of the VGSC active current, among ligand substances that specifically bind to the type I taste receptor, can be found.The present invention provides: a type I taste receptor-specific ligand substance that can control the amplification or suppression of a VGSC active current; and a pharmaceutical composition for preventing or treating various neurodegenerative diseases, such as Alzheimer's disease (AD), due to the amplification of a VGSC active current caused by the binding of an Aβ peptide or the like to a type I taste receptor. Moreover, a method for using, as a target receptor, a type I taste receptor present in a nerve cell or the like to screen a ligand substance for controlling a VGSC or the like in the cell is a

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