Porous molded body for removing α-synuclein oligomer, and system for removing α-synuclein oligomer

Abstract

This porous molded body for removing α-synuclein oligomer contains a hydrophobic polymer. The ratio of the surface area of pores that are 1000 nm2 or larger to the area of an entire SEM image of the surface of the porous molded body is at least 1.5%.

Description

Porous molded body for removing α-synuclein oligomers and α-synuclein oligomer removal system

[0001] The present disclosure relates to a porous molded body for removing α-synuclein oligomers, an α-synuclein oligomer removal system, and the like.

[0002] Parkinson's disease is a progressive disorder of the central nervous system characterized by decreased spontaneous movement, difficulty walking, postural instability, muscle rigidity, and tremor. Parkinson's disease is known to be caused by the degeneration of dopamine-containing pigmented neurons in the substantia nigra of the midbrain, which reduces dopamine concentrations in the striatum and impairs the motor control function of the cerebral cortex. Pathologically, Parkinson's disease is primarily characterized by the presence of Lewy bodies in the substantia nigra, and it has been found that the main component of Lewy bodies is protein aggregates containing α-synuclein. Because patients with early-onset familial Parkinson's disease have a major mutation of two amino acids in α-synuclein, it is believed that these Lewy bodies contribute to neurodegeneration in Parkinson's disease and related disorders.

[0003] Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by degeneration of neurons in the cerebellar cortex, pontine nuclei, olivary nuclei, striatum, substantia nigra, autonomic nuclei in the brainstem and spinal cord, as well as the motor cortex, and the accumulation of insoluble α-synuclein inclusions in the cytoplasm of oligodendroglia. Compared to Parkinson's disease, resting tremors are less frequent, progression is more rapid, and anti-Parkinson's drugs are less effective.

[0004] Lewy body dementia is a disease characterized by the appearance of Lewy bodies in the brain, and its main symptoms include cognitive impairment, hallucinations, delusions, and sleep disorders. While motor dysfunction specific to Parkinson's disease may also occur, unlike Parkinson's disease, cognitive decline is often observed from the early stages. In Lewy body dementia, Lewy bodies are often distributed over a wide area of ​​the brain, including the cerebral cortex, thalamus, and brainstem.

[0005] Currently, the standard treatment for motor dysfunction in synucleinopathies, including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies, is the administration of L-dopa, a precursor molecule to dopamine. L-dopa crosses the blood-brain barrier and is converted to dopamine in the brain. While this drug alleviates symptoms of dopamine deficiency, it does not halt the progressive neurodegeneration that characterizes synucleinopathies. To prevent the progression of synucleinopathies, it is necessary to understand the mechanisms that cause neuronal loss. Currently, no fundamental treatments or drugs exist. In Japan, synucleinopathies are designated as intractable diseases (specified diseases) due to the small number of cases and the long-term disruption they cause to daily life.

[0006] Although the physiological functions of α-synuclein, which constitutes Lewy bodies, remain largely unknown, it has been reported that it plays a defensive role against viral infection, in addition to membrane fusion and synaptic vesicle maintenance and release. When these α-synuclein monomers aggregate under certain influences to form α-synuclein oligomers, they acquire pathogenic properties that cause calcium regulation disorders, mitochondrial dysfunction, and intracellular transport disorders.

[0007] Although the process by which α-synuclein monomers aggregate to form α-synuclein oligomers in vivo is unclear at the time of filing of this application, the α-synuclein oligomer transmission hypothesis has recently been proposed, which suggests that α-synuclein oligomers may propagate between cells due to their prion protein-like properties, resulting in the pathology of synucleinopathies. In vitro, a self-templating phenomenon has been observed, in which α-synuclein oligomers with a β-sheet structure serve as templates to promote the aggregation of α-synuclein monomers with a normal structure. Furthermore, animal experiments using mice have reported that intracerebral, intraperitoneal, oral, or intravenous administration of α-synuclein oligomers resulted in neurological symptoms and the formation of α-synuclein aggregates in the central nervous system (Non-Patent Document 1).

[0008] Although the pathway by which α-synuclein oligomers propagate in the α-synuclein oligomer propagation hypothesis is not fully understood, it has been reported that larger amounts of α-synuclein oligomers are present in the plasma of Parkinson's disease patients compared to healthy individuals (Non-Patent Document 2).

[0009] Patent Document 1 aims to provide blood processing beads with improved blood compatibility while maintaining the adsorptive properties of the porous beads, and describes blood processing beads having porous beads and a polymer supported on the surface of the porous beads. The porous beads are made of at least one resin selected from the group consisting of acrylic resins, styrene resins, and cellulose resins, and the polymer contains a specific monomer as a monomer unit. Patent Document 1 describes that the porous beads remove inflammatory mediators, such as cytokines and alarmins, from the blood of a patient, but does not describe the removal of α-synuclein oligomers from biologically derived fluids.

[0010] Patent Document 2 aims to provide an instrument for efficiently removing amyloid beta (Aβ), a cause of Alzheimer's disease, from biologically derived fluids, and describes a column containing a porous carbon material within the Aβ removal instrument. The column has a blood inlet for introducing blood and a blood outlet for discharging purified blood, and the porous carbon material has a peak pore diameter of 3 to 500 nm. Patent Document 2 describes that the Aβ removal instrument efficiently removes not only Aβ monomers but also Aβ oligomers from biologically derived fluids, but does not describe a porous molded body containing a hydrophobic polymer that removes α-synuclein oligomers from biologically derived fluids.

[0011] Patent Document 3 describes a synuclein adsorbent and an adsorptive removal system for selectively adsorbing and removing synuclein, which is thought to be the etiological agent of neurodegeneration in various synucleinopathies including Parkinson's disease, from a liquid containing synuclein, such as a body fluid. The synuclein adsorptive removal system is capable of removing synuclein from a liquid, such as a body fluid, by treating the liquid containing synuclein with an adsorbent comprising a hydrophilic porous water-insoluble carrier to which a ligand with high affinity for synuclein is immobilized. Patent Document 3 also describes that the synuclein adsorbent adsorbs synuclein monomers, but does not describe a porous molded body containing a hydrophobic polymer that removes α-synuclein oligomers.

[0012] International Publication No. 2020 / 009008 Japanese Patent Application Laid-Open No. 2020-081165 Japanese Patent Application Laid-Open No. 2012-193112

[0013] LOHMANN, Stephanie, et al., “Oral and intravenous transmission of α-synuclein fibrils to mice”, Acta Neuropathologica, (2019), 138: 515-533.EL-AGNAF, Omar MA, et al., “Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson's disease”, The FASEB journal, (2006), 20(3): 419-425.

[0014] An object of the present disclosure is to provide a porous molded body, a system, and the like that can remove α-synuclein oligomers from biologically derived fluids.

[0015]

[0023] The following are examples of embodiments of the present disclosure. [1] A porous shaped body for removing α-synuclein oligomers, the porous shaped body containing a hydrophobic polymer, and a surface area of ​​the porous shaped body measured at 1000 nm２ [2] A porous molded article for removing α-synuclein oligomers, wherein the ratio of the pore area of ​​1000 nm or more to the total area of ​​the SEM image is 1.5% or more. ２ The porous shaped body according to item 1, wherein the pore area ratio of the porous shaped body to the hydrophobic polymer is 8.0% or more. [3] The porous shaped body according to item 1 or 2, wherein the porous shaped body has no electric charge. [4] The porous shaped body according to any one of items 1 to 3, wherein the hydrophobic polymer is a polystyrene-based polymer. [5] The porous shaped body according to any one of items 1 to 4, wherein the harmonic mean particle diameter of the porous shaped body is 800 μm or less. [6] The porous shaped body according to any one of items 1 to 5, wherein the removal rate of α-synuclein oligomers is 30% or more. [7] The porous shaped body according to any one of items 1 to 6, wherein the removal rate of amyloid β oligomers is 10% or less. [8] An α-synuclein oligomer removal system, comprising: a column having a container having an inlet and an outlet for a biologically derived fluid, and a porous body filled in the container; a biologically derived fluid inlet flow path for introducing the biologically derived fluid into the inlet; and a biologically derived fluid outlet flow path for discharging the biologically derived fluid that has passed through the column from the outlet, wherein the porous body contains a hydrophobic polymer, and a surface area of ​​the porous body is 1000 nm ２ [9] A system for removing α-synuclein oligomers, wherein the ratio of the pore area of ​​1000 nm or more to the total area of ​​the SEM image is 1.5% or more. ２The system according to item 8, wherein the pore area ratio of the porous shaped body is 8.0% or more.

[10] The system according to item 8 or 9, wherein the porous shaped body has no electric charge.

[11] The system according to any one of items 8 to 10, wherein the hydrophobic polymer is a polystyrene-based polymer.

[12] The system according to any one of items 8 to 11, wherein the harmonic mean particle size of the porous shaped body is 800 μm or less.

[13] The system according to any one of items 8 to 12, wherein the porous shaped body has an α-synuclein oligomer removal rate of 30% or more.

[14] The system according to any one of items 8 to 13, wherein the porous shaped body has an amyloid β oligomer removal rate of 10% or less.

[15] The system according to any one of items 8 to 14, wherein the biologically derived fluid is blood.

[16] A method for removing α-synuclein oligomers, the method comprising contacting a porous body with a biologically derived fluid containing α-synuclein oligomers and removing the α-synuclein oligomers from the biologically derived fluid, the porous body comprising a hydrophobic polymer, and a surface area of ​​the porous body measured at 1000 nm of the entire surface area of ​​an SEM image of the porous body. ２

[17] A method for removing α-synuclein oligomers, wherein the ratio of the area of ​​the pores to the total area of ​​the SEM image is 1.5% or more. ２

[18] The method for removing α-synuclein oligomers according to item 16, wherein the pore area ratio of the porous body or the hydrophobic polymer is 8.0% or more.

[19] The method for removing α-synuclein oligomers according to any one of items 16 to 18, wherein the porous body is uncharged.

[20] The method for removing α-synuclein oligomers according to any one of items 16 to 19, wherein the harmonic mean particle size of the porous body is 800 μm or less.

[21] The method for removing α-synuclein oligomers according to any one of items 16 to 20, wherein the removal rate of α-synuclein oligomers by the method is 30% or more.

[22] The method for removing α-synuclein oligomers according to any one of items 16 to 21, wherein the biologically derived fluid further contains amyloid β oligomers, and the removal rate of the amyloid β oligomers by the method is 10% or less.

[23] Use of a porous shaped body for producing purified blood by removing α-synuclein oligomers, wherein the porous shaped body contains a hydrophobic polymer, and the removal rate of the amyloid β oligomers by the method is 10% or less. ２

[24] Use of a porous shaped body for removing α-synuclein oligomers, wherein the porous shaped body contains a hydrophobic polymer, and the ratio of the pore area of ​​1000 nm to the total area of ​​an SEM image of the surface of the porous shaped body is 1.5% or more. ２ The percentage of the pore area is 1.5% or more.

[0016] According to the present disclosure, it is possible to provide a porous molded body, a system, and the like that can remove α-synuclein oligomers from biologically derived fluids.

[0017] Fig. 1(a) is an SEM image of the surface of the porous molded article of Example 1, and Fig. 1(b) is its binary image. Fig. 2 is an image of the cross section of the porous molded article of Example 1, to which fluorescently stained α-synuclein oligomers were adsorbed, observed with a fluorescence microscope. Fig. 3 shows the results of a flow test of the α-synuclein oligomer removal rate from blood using the α-synuclein oligomer removal system of Example 10.

[0018] The porous shaped article of the present disclosure is a porous shaped article for adsorbing and removing α-synuclein oligomers (hereinafter, in the present disclosure, it may also be referred to as a "porous shaped article for removing α-synuclein oligomers"). The porous shaped article contains a hydrophobic polymer, and the surface area of ​​the porous shaped article is measured by a SEM image of the surface of the porous shaped article. ２ The above pore area ratio is 1.5% or more, thereby enabling removal of α-synuclein oligomers from biologically derived fluids. Based on the α-synuclein oligomer propagation hypothesis (Non-Patent Documents 1 and 2, etc.), the present inventors believed that removing α-synuclein oligomers from biologically derived fluids and blocking the propagation pathway of α-synuclein oligomers would be effective in inhibiting the progression of synucleinopathy, and they conducted extensive research into means for removing α-synuclein oligomers. As a result, the present inventors discovered a previously unknown attribute: a porous carrier containing a hydrophobic polymer and having a specific proportion of pores of a specific size or larger on its surface, capable of adsorbing and removing α-synuclein oligomers, leading to the configuration of the present invention.

[0019] <Ratio of pore area> The porous molded body of the present disclosure has a surface area of ​​1000 nm with respect to the entire area of ​​the SEM image. ２ The pore area ratio (hereinafter also referred to simply as "pore area ratio") is 1.5% or more. The pore area ratio is calculated by taking an 80,000x SEM image of the surface of the porous formed body according to the method described in the examples below, and analyzing the binarized image (1576.4 nm x 1104.7 nm) using the image processing software ImageJ. The binarization threshold is set to a range of 0 to 70 gradations out of 0 to 255 gradations in the order of black to white, and the pore area ratio is the average value of the values ​​analyzed and calculated for at least four images.

[0020] The porous shaped bodies used in conventional blood purification therapy are generally required not to adsorb albumin (molecular weight: approximately 56 kDa) in order to process blood, and the pore size is designed to adsorb proteins smaller than albumin. Therefore, it is thought that the porous shaped bodies used in blood purification therapy cannot adsorb such large proteins. In this regard, the inventors have found that a porous shaped body containing a hydrophobic polymer and having a pore structure of a specific size on the surface can adsorb and remove α-synuclein oligomers, which are large molecules. The reason for this is, without being limited by theory, that the porous shaped bodies are capable of adsorbing and removing α-synuclein oligomers, which are large molecules, even though they are smaller than 1000 nm. ２ This is thought to be because "pores with a radius of 17.8 nm or more" correspond to circles with a radius of 17.8 nm or more, and because α-synuclein oligomers are stick-shaped proteins, they enter the pores on the surface of the porous body and are adsorbed to the surface of the porous body. In fact, as shown in the Examples described below, the inventors adsorbed fluorescently modified α-synuclein oligomers into a porous body, then prepared frozen sections of the porous body and observed the cross-sections. This revealed that a specific porous body of the present disclosure adsorbed α-synuclein oligomers on its outer surface. While various methods, such as gas adsorption, are known as common methods for determining pore size, the gas adsorption method is an analytical method that calculates the specific surface area and pore size of not only the outermost surface but also the interior of a sample, and therefore is thought not to adequately reflect the adsorption mechanism of α-synuclein oligomers described in the present disclosure. Therefore, the inventors focused on the proportion of pore area of ​​a specific size in SEM images as a parameter focusing on the outermost surface of the porous body.

[0021] The shape of α-synuclein oligomers can be confirmed using a transmission electron microscope (TEM) as follows: 1. Dilute α-synuclein oligomers to 200 μg / ml with phosphate-buffered saline (PBS). 2. Drop the resulting PBS solution onto a support membrane that has been hydrophilized. 3. Drop 2 wt % phosphotungstic acid-phosphate buffer onto the support membrane. 4. Absorb excess solution with filter paper. 5. Air-dry the support membrane to use it as an observation sample. A measurement device such as the HT7700 manufactured by Hitachi High-Tech Corporation can be used, and the accelerating voltage can be set to, for example, 120 kV.

[0022] In the pore area ratio, the area of ​​the pores to be measured (pores included in the pore area ratio) is 1000 nm ２ That's all. The area is 1000 nm ２ Pores smaller than this are not included in the pore area ratio. There is no upper limit to the area of ​​the pores to be measured, but it is preferably 500,000 nm ２ This is because pores of this size are thought to contribute to the adsorption of α-synuclein oligomers.

[0023] The lower limit of the pore area ratio is 1.5% or more, preferably 3.0% or more, more preferably 5.0% or more, and even more preferably 8.0% or more. The higher the pore area ratio, the higher the removal rate of α-synuclein oligomers tends to be. The upper limit of the pore area ratio is not limited, but is preferably 50% or less, more preferably 40% or less, and even more preferably 30% or less. A lower pore area ratio tends to increase the mechanical strength of the porous molded body.

[0024] <Hydrophobic Polymer> The material constituting the porous shaped body preferably contains a hydrophobic polymer, and may optionally contain other materials. The material constituting the porous shaped body may be a porous shaped body made of a hydrophobic polymer. The hydrophobic polymer contained in the porous shaped body may be any hydrophobic polymer capable of forming the porous shaped body. Examples of hydrophobic polymers include polystyrene-based polymers such as polystyrene and styrene-divinylbenzene copolymers; divinylbenzene-based polymers such as divinylbenzene-styrene copolymers; polysulfone-based polymers, polyethersulfone-based polymers, polyetherimide-based polymers, polyvinylidene fluoride-based polymers, polyvinylidene chloride-based polymers, polymethyl methacrylate-based polymers, polyimide-based polymers, polyarylethersulfone-based polymers, polypropylene-based polymers, polyethylene-based polymers, polyacrylamide-based polymers, and polycarbonate-based polymers. Among these, polystyrene-based polymers, such as styrene-divinylbenzene copolymers, are preferred because of their excellent ability to remove α-synuclein oligomers, thermal stability, acid resistance, alkali resistance, and mechanical strength. The degree of polymerization and molecular weight of the hydrophobic polymer are not particularly limited.

[0025] <Coating Polymer> The porous shaped body may contain a coating polymer. For example, the porous shaped body may contain a hydrophobic polymer core (carrier) and a coating polymer coated and / or impregnated on the core. By containing a coating polymer in the porous shaped body, biocompatibility can be imparted to the porous shaped body. The coating polymer may be a hydrophilic polymer. Examples of the coating polymer include polymers having one or more of a sulfonic acid group, a carboxyl group, a carbonyl group, an ester group, an amino group, an amide group, a cyano group, a hydroxyl group, a methoxy group, a phosphate group, an oxyethylene group, an imino group, an iminoether group, a pyridine group, a pyrrolidone group, an imidazole group, a quaternary ammonium group, and the like. Specific examples of the coating polymer include polyvinylpyrrolidone (PVP)-based polymers, such as polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymers, vinylpyrrolidone-vinylcaprolactam copolymers, and vinylpyrrolidone-vinyl alcohol copolymers; polyacrylonitrile (PAN)-based polymers; and poly(meth)acrylate-based polymers, such as poly(2-methoxyethyl acrylate) (PMEA), poly(2-methoxyethyl methacrylate) (PMEMA), poly(2-hydroxyethyl methacrylate) (PHEMA), ethylene glycol dimethacrylate copolymers, and hexadecyl group-modified polymethacrylates, as well as copolymers thereof.

[0026] <Charge> The porous shaped body may have a charge. In this specification, "having a charge" means having a functional group that is partially or completely positively or negatively charged under a pH of 7.0. Specifically, the polymer that constitutes the porous shaped body, for example, the coating polymer, may contain a charged monomer as a monomer unit. Examples of the charged monomer include an amino group (-NH ２ , -NHR, and NR ２ , where R is a hydrocarbon group, a carboxyl group (—COOH), a phosphate group (—OPO ３ H ２ ), sulfonic acid group (—SO ３H), and a zwitterionic group.

[0027] The porous shaped body preferably has no electric charge, and more preferably has no positive charge. In the present disclosure, "having no electric charge" means that the polymer constituting the porous shaped body does not have a functional group that is positively or negatively charged under a pH of 7.0 condition. In other words, the polymer constituting the porous shaped body preferably does not contain, as a monomer unit, a monomer having the above-mentioned charged functional group. When the porous shaped body has no electric charge, particularly no positive charge, it tends to have the characteristic of efficiently removing α-synuclein oligomers while not removing amyloid β oligomers (Aβ oligomers).

[0028] <Shape of porous shaped body> The porous shaped body is a carrier having a porous structure with a large number of pores of appropriate sizes. The shape of the porous shaped body is not particularly limited, and may be any shape such as a particle, a thread, a sheet, a hollow fiber, a cylinder, or a hollow cylinder, and is preferably a spherical particle shape. Spherical particles mean that the particle shape is substantially spherical, and may be a true sphere or an oval sphere. The harmonic mean particle diameter of the spherical particles is 40 μm or more, preferably 300 μm or more, more preferably 400 μm or more, and preferably 1,000 μm or less, more preferably 800 μm or less, and even more preferably 700 μm or less. By having a harmonic mean particle diameter of 150 μm or more, it is possible to effectively suppress pressure increase when blood / plasma is passed through a column. By having a harmonic mean particle diameter of 1,000 μm or less, it is possible to exhibit rapid adsorption performance.

[0029] <α-Synuclein Oligomer Removal Rate> Examples of α-synuclein oligomers include oligomers and aggregates formed from two or more α-synuclein monomer molecules, as well as phosphorylations thereof. In the technical field, α-synuclein oligomers are also referred to as "AS seeds." The porous shaped article of the present disclosure can remove α-synuclein oligomers from a biologically derived fluid by contacting the porous shaped article with the biologically derived fluid. The α-synuclein monomer removal rate of the porous shaped article is preferably 30% or more, more preferably 35% or more, even more preferably 40% or more, and even more preferably 45% or more.

[0030] The ability to remove α-synuclein oligomers can slow the progression of synucleinopathies such as Parkinson's disease, multiple system atrophy, and / or dementia with Lewy bodies. Therefore, the porous shaped article of the present disclosure can preferably be used to slow the progression of synucleinopathies. That is, the porous shaped article of the present disclosure may be used for blood purification, for example, to remove α-synuclein oligomers, or may be used to produce purified blood by removing α-synuclein oligomers. The use of the porous shaped article of the present disclosure may be ex vivo, and may include, for example, providing blood from which α-synuclein oligomers and the like have been removed to a medical professional. The porous shaped article of the present disclosure may also be used for pharmaceutical applications, for example, to produce blood products using blood from which α-synuclein oligomers have been removed. In this embodiment, the use may include providing blood from which α-synuclein oligomers and the like have been removed to a medical professional for the production of a blood product. Alternatively, the porous shaped article of the present disclosure may be used for diagnostic purposes, for example, to concentrate, recover, and detect α-synuclein oligomers in a biologically derived fluid, thereby diagnosing a synucleinopathy. In this embodiment, the use may include providing the concentrated and recovered α-synuclein oligomers to a medical professional for the diagnosis of a synucleinopathy.

[0031] <Aβ Oligomer Removal Rate> Amyloid β oligomers (Aβ oligomers) are oligomers consisting of two or more Aβ42 monomer molecules that are generated by cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase, and are involved in the pathogenesis of Alzheimer's disease. The porous molded body of the present disclosure may remove Aβ oligomers from a biologically derived liquid, but it is preferable that the removal rate of amyloid β oligomers by the porous molded body is 10% or less.

[0032] Since the porous molded body removes α-synuclein oligomers while the removal rate of Aβ oligomers is 10% or less, it is believed that Aβ oligomers do not fill the adsorption sites of the porous molded body, thereby enabling efficient removal of α-synuclein oligomers. Furthermore, although it was not clear at the time of filing the present application, it is presumed that side effects such as amyloid-related imaging abnormalities (ARIA), which can occur in conventional Alzheimer's treatments using anti-Aβ oligomer antibodies, are unlikely to occur. That is, many reports have suggested that the cause of ARIA caused by anti-Aβ oligomer antibodies is the forced removal of amyloid, and the so-called "pumping hypothesis" has classically been proposed, which states that a decrease in Aβ oligomer concentration outside the blood-brain barrier (BBB) ​​leads to active excretion of Aβ oligomers inside the BBB. Furthermore, data showing that Aβ oligomers are not present only in the brain has been known, and based on this, there have been reports of treating Alzheimer's by removing Aβ oligomers through extracorporeal circulation. Based on these facts, it is presumed that α-synuclein oligomers and Aβ oligomers may coexist in biologically derived fluids, and that removing α-synuclein oligomers without removing Aβ oligomers (removal rate of 10% or less) will reduce the occurrence of side effects such as ARIA, which may occur in the past.

[0033] <Bio-derived fluid> The bio-derived fluid to be treated with the porous shaped body is preferably blood, plasma, serum, spinal fluid, ascites, urine, saliva, tears, nasal discharge, sweat, digestive fluid, breast milk, etc., with blood (whole blood) or plasma being particularly preferred. Because treatment is simple, blood (whole blood) is more preferred as the bio-derived fluid to be treated with the porous shaped body. Because blood contains many impurities, including albumin (Alb), globin (IgG), fibrinogen (Fib), etc., it is generally difficult to selectively remove large molecules from blood. In this regard, the porous shaped body of the present disclosure can remove α-synuclein oligomers from blood, and therefore can be used in an environment closer to therapeutic conditions. The biological fluid is preferably blood, plasma, serum, spinal fluid, ascites, urine, saliva, tears, nasal discharge, sweat, digestive fluid, breast milk, etc. from a patient with Parkinson's disease, multiple system atrophy, and / or dementia with Lewy bodies, and is particularly preferably blood (whole blood) or plasma.

[0034] <<Method for manufacturing a porous shaped body>> The method for manufacturing a porous shaped body of the present disclosure is not limited as long as the pore area ratio can be adjusted to the specific range of the present disclosure. A hydrophobic polymer is used as the material for the porous shaped body, and the porous shaped body can be manufactured according to the method for manufacturing a porous shaped body used in conventional blood purification therapy. A commercially available porous shaped body may be used as the porous shaped body of the present disclosure. A porous shaped body having the pore area ratio described above may be used as the porous shaped body.

[0035] When the porous shaped body is coated with a coating polymer, the method for coating the coating polymer on the surface of the porous shaped body carrier can be a conventional coating method, such as a coating method, a spray method, or a dipping method. More specifically, it is preferable to swell the porous shaped body with ultrapure water, mix and stir a solution containing the coating polymer, and coat the porous shaped body with the coating polymer. After the coating treatment, the solution is removed, and the porous shaped body is classified and washed to obtain the porous shaped body of the present disclosure.

[0036] <<Method for Removing α-synuclein Oligomers>> A method for removing α-synuclein oligomers comprises contacting a porous shaped article of the present disclosure with a biologically-derived fluid containing α-synuclein oligomers. The manner of contact is not particularly limited as long as it can reduce the concentration of α-synuclein oligomers in the biologically-derived fluid. For example, the removal method preferably comprises introducing a biologically-derived fluid containing α-synuclein oligomers into a container having an inlet and an outlet for the biologically-derived fluid and filled with a porous shaped article of the present disclosure, allowing the biologically-derived fluid to contact the porous shaped article of the present disclosure and pass through the container, and discharging the biologically-derived fluid through the outlet. The removal method may further comprise collecting the biologically-derived fluid from a patient's body and returning the biologically-derived fluid that has contacted the porous shaped article of the present disclosure back into the patient's body. Alternatively, the method for removing α-synuclein oligomers may be an ex vivo method and may further comprise, for example, providing the blood from which α-synuclein oligomers, etc. have been removed to a medical professional. When used for pharmaceutical purposes, the method may further comprise providing the blood from which α-synuclein oligomers, etc. have been removed to a medical professional for the production of a blood product. When used for diagnostic purposes, the method may further comprise providing the blood from which α-synuclein oligomers, etc. have been removed to a medical professional for the diagnosis of a synucleinopathy.

[0037] In the present disclosure, "removal" does not mean complete removal of α-synuclein oligomers from a biologically derived fluid, but rather refers to the reduction of the concentration of α-synuclein oligomers contained in the biologically derived fluid. The removal method can remove preferably 30% or more, more preferably 35% or more, even more preferably 40% or more, and even more preferably 45% or more of the α-synuclein oligomers contained in the biologically derived fluid.

[0038] As described above, blood or plasma is particularly preferred as the biologically derived fluid. In this case, the removal method may include contacting blood containing α-synuclein oligomers with a porous shaped article of the present disclosure to obtain blood from which α-synuclein oligomers have been removed. Alternatively, the removal method may further include previously separating plasma containing α-synuclein oligomers from the blood, contacting the separated plasma with a porous shaped article of the present disclosure to remove α-synuclein oligomers from the plasma, and combining the plasma from which α-synuclein oligomers have been removed with the separated hemocyte concentrate to obtain blood from which α-synuclein oligomers have been removed. The removal method may or may not further include removing blood from the patient's body and / or returning the blood that has been contacted with a porous shaped article of the present disclosure back into the patient's body.

[0039] <α-Synuclein Oligomer Removal System> The porous shaped article of the present disclosure can be incorporated into an α-synuclein oligomer removal system. The α-synuclein oligomer removal system of the present disclosure includes a column having a container having an inlet and an outlet for a biologically-derived fluid and a porous shaped article packed in the container, a biologically-derived fluid inlet channel for introducing the biologically-derived fluid into the inlet, and a biologically-derived fluid outlet channel for discharging the biologically-derived fluid that has passed through the column from the outlet. The biologically-derived fluid inlet channel and the biologically-derived fluid outlet channel are preferably made of flexible tubing. During use of the system, the biologically-derived fluid inlet channel may be fluidically connected to the inside of a patient's body to collect the biologically-derived fluid from the patient's body. Furthermore, the biologically-derived fluid outlet channel may be fluidically connected to the inside of a patient's body to return the biologically-derived fluid after contacting the porous shaped article to the patient's body.

[0040] The α-synuclein oligomer removal system can remove preferably 30% or more, more preferably 35% or more, even more preferably 40% or more, and even more preferably 45% or more of α-synuclein oligomers contained in a biologically derived fluid.

[0041] As described above, blood or plasma is particularly preferred as the biologically derived fluid, and in this case, the system is used as a blood purification system. One example of a blood purification system includes a blood inlet flow path consisting of a flexible tube for removing blood from a patient's body and introducing it into a column, a column packed with a porous molded article of the present disclosure, and a blood outlet flow path consisting of a flexible tube for returning the blood leaving the column to the body. When the blood purification system is in use, the blood inlet flow path and the blood outlet flow path are connected to the patient's blood vessels.

[0042] The blood purification system described above is merely an example, and is not limited to the above configuration. Various modifications are possible by appropriately applying conventional blood purification techniques. For example, the blood purification system may include two or more α-synuclein oligomer adsorption / removal columns connected in series or parallel. As another example, the blood purification system may include a plasma separator between the α-synuclein oligomer adsorption / removal column and the bio-derived fluid introduction channel, and configured to pass plasma separated from blood through the column. More specifically, examples of the plasma separator include a membrane-type plasma separator using a plasma separation membrane and a centrifugal plasma separator. In this case, the blood purification system may be further configured to remove α-synuclein oligomers from the plasma, combine the plasma from which α-synuclein oligomers have been removed with the blood cell concentrate separated by the plasma separator, and return the resulting α-synuclein oligomer-free blood to the patient. Further, other elements that can be included in the blood purification system include elements used in conventional blood purification systems, such as an anticoagulant addition device, a pressure gauge, a flow rate detection device, an abnormality detection device, a particulate removal filter, an air chamber, and a hemolysis sensor.

[0043] Examples and comparative examples of the present disclosure will be specifically described below, but the present disclosure is not limited to these examples and comparative examples.

[0044] Evaluation and Measurement Methods Pore Area Ratio (1) Scanning Electron Microscope (SEM) Imaging The freeze-dried porous molded body was fixed to a sample stage, and then coated with osmium (Os) to a thickness of 1 nm or less, followed by SEM observation. The images were taken at an accelerating voltage of 1.0 kV and a magnification of 80,000 times, and four SEM images were obtained that extracted the average structure of each sample.

[0045] (2) SEM Image Analysis The analysis of the acquired SEM images was carried out using the image processing software ImageJ. First, as pre-processing of the SEM images, noise was removed by averaging filtering (radius 2 pixels). The binarization process was carried out for all images using the same threshold value, with the range of 0 to 70 gradations out of 0 to 255 gradations in the order from black to white. Then, as shown in "Binary images" in Figure 1, the white parts in the binary images were regarded as holes, and 1000 nm ２ The area of ​​the above holes was calculated, and the ratio of 1000 nm to the area of ​​the entire SEM image (1576.4 nm × 1104.7 nm) was ２ The percentage of the above pore area was calculated by averaging the four images obtained.

[0046] <Charge amount> The charge amount (μmol / ml - wet carrier) of the porous molded body was obtained by neutralization titration of the obtained porous molded body. Specifically, 0.2 mL of the porous molded body was measured and placed in a 3.0 mL Libra tube (manufactured by HiPep Research Institute), washed with 10 mL of physiological saline, and then the porous molded body was transferred to a 25 mL centrifuge tube, and 6 mL of 1 M NaOH water was added and shaken and stirred for 30 minutes. The porous molded body was recovered using a Libra tube, washed with 12 mL of ultrapure water (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and then transferred to a 100 mL centrifuge tube, and 50 mL of ultrapure water was added and shaken and stirred for 30 minutes. The porous formed body was again recovered using a Libra tube, washed with 12 mL of ultrapure water, and then transferred to a centrifuge tube. 0.4 mL to 100 mL of 0.01 M HCl water was added and shaken and stirred for 30 minutes. After the reaction, 0.1 mL to 5 mL of the supernatant was collected, and 0.1 M NaOH water was added dropwise while stirring. The charge amount of the porous formed body (μmol / ml-wet carrier) was calculated from the amount of HCl added at the pH inflection point. At this time, the proportion of HCl ion-exchanged with the porous formed body out of the HCl added to the porous formed body was calculated as the HCl consumption rate. If the HCl consumption rate was 20% or more and 40% or less, the charge amount measurement was deemed to be appropriate. If the charge amount of the porous formed body was 10 μmol / ml-wet carrier or less, the porous formed body was deemed to have no charge.

[0047] <Harmonic Mean Particle Diameter> The harmonic mean particle diameter of the porous formed body was measured by swollen the porous formed body with ultrapure water using a particle analyzer (CAMSIZER X2, manufactured by Microtrackbell Co., Ltd.), and the harmonic mean of the measured values ​​was calculated as the harmonic mean particle diameter (μm).

[0048] <Method for measuring α-synuclein oligomer removal rate (AS seed removal rate) by batch test> 0.18 mL of a porous molded body was measured and placed in a 3.0 mL Libra tube (manufactured by HiPep Research Institute) and washed with phosphate-buffered saline (PBS-, manufactured by TAKARA Bio Inc.) and physiological saline (manufactured by Otsuka Pharmaceutical Factory, Inc.). Then, 0.9 mL of commercially available heparin-anticoagulated bovine plasma or heparin-anticoagulated bovine blood adjusted to a concentration of approximately 32 ng / mL of α-synuclein oligomer (Recombinant Human Alpha-synuclein protein aggregate (Active), manufactured by Abcam) was added. The mixture was stirred at 5 rpm at 37°C for 1 hour, and the α-synuclein concentration in the plasma supernatant was measured by sandwich ELISA using two antibodies (Anti-Alpha-Synuclein Filament MJFR14-6-4-2 Conformation Specific, Abcam, and Purified Mouse Anti-α-Synuclein Clone 42 / α-Synuclein (RUO), BD Transduction Laboratories). The measured value of α-synuclein oligomers in a sample without a porous body was set to 100%, and the value obtained by subtracting the residual rate (%) of α-synuclein oligomers from 100% was defined as the α-synuclein oligomer removal rate (%) of the porous body. When a porous body adsorbs little or no α-synuclein oligomers, the removal rate may take a negative value due to the effects of increased sensitivity of ELISA measurement caused by the adsorption and removal of plasma proteins other than α-synuclein oligomers by the porous body and / or variability in ELISA measurement.

[0049] <Method for measuring α-synuclein oligomer removal rate (AS seed removal rate) by flow test> A porous molded body was packed into a 350 mL container and washed with physiological saline (Otsuka Pharmaceutical Factory), creating a column packed with the porous molded body. An inlet flow path for biologically derived fluid and an outlet flow path for biologically derived fluid were then connected to the column, creating an α-synuclein oligomer removal system. The biologically derived fluid was prepared by adding 4 L of heparin-anticoagulated bovine blood to a concentration of approximately 16 ng / mL of α-synuclein oligomer (Recombinant Human Alpha-synuclein protein aggregate (Active), Abcam). This blood volume was designed to simulate the blood volume in the human body. The prepared biological fluid was then brought into contact with the column for 4 hours while circulating at 100 mL / min at 37°C using the blood adsorption (HA) mode of a blood purification system ACH-Σ (manufactured by Asahi Kasei Medical Corporation), and samples were taken from the biological fluid pool over time. The sampled biological fluid was centrifuged, and the plasma α-synuclein concentration in the supernatant was measured by sandwich ELISA using two types of antibodies (Anti-Alpha-synuclein filament MJFR14-6-4-2 Conformation specific, Abcam, and Purified Mouse Anti-α-Synuclein Clone 42 / α-Synuclein (RUO), BD Transduction Laboratories). The measured value of α-synuclein oligomers in the biologically derived fluid (initial pool) before circulation was set to 100%, and the value obtained by subtracting the residual rate (%) of α-synuclein oligomers from 100% was used to determine the α-synuclein oligomer removal rate (%) of the porous shaped body. When the porous shaped body adsorbs little or no α-synuclein oligomers, the removal rate may take a negative value due to the effects of increased sensitivity of ELISA measurement caused by the adsorption and removal of plasma proteins other than α-synuclein oligomers by the porous shaped body and / or variability in ELISA measurement.

[0050] <Method for measuring Aβ oligomer removal rate> 0.18 mL of the porous molded body was measured into a 3.0 mL Libra tube (manufactured by HiPep Research Institute) and washed with phosphate-buffered saline (PBS-, manufactured by TAKARA Bio Inc.) and physiological saline (manufactured by Otsuka Pharmaceutical Factory). Then, 0.9 mL of commercially available heparin-anticoagulated bovine plasma adjusted to an Aβ42 oligomer concentration of approximately 100 ng / mL was added. The mixture was stirred at 37°C for 1 hour and then at 5 rpm for 1 hour, and the Aβ42 oligomer concentration in the supernatant plasma was measured by sandwich ELISA using the Polymer Amyloid β Oligomer ELISA Kit Wako Ver. 2 (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). Aβ42 oligomers were prepared by incubating amyloid β-protein (human, 1-42) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) at 37°C for 6 hours. The Aβ42 oligomer measurement value for the sample without the porous molded body was set to 100%, and the value obtained by subtracting the residual rate (%) of Aβ42 oligomers from 100% was used to determine the Aβ oligomer removal rate (%) of the porous molded body. When the porous molded body adsorbs little or no Aβ42 oligomers, the removal rate may take a negative value due to the effects of increased sensitivity of ELISA measurement caused by the adsorption and removal of plasma proteins other than Aβ42 oligomers by the porous molded body and / or variability in ELISA measurement.

[0051] Example 1 Synthesis of Coating Polymer (Biocompatible Polymer) A copolymer of 2-methoxyethyl methacrylate (MEMA) and N-methacryloyloxyethyl-N,N-dimethylammonium-α-N-methylcarboxybetaine (CMB) was synthesized by conventional solution polymerization. The polymerization conditions were as follows: in an ethanol solution, in the presence of 0.0025 mol / L of azoisobutyronitrile (AIBN) as an initiator, each monomer concentration was 1 mol / L, and the polymerization reaction was carried out at a reaction temperature of 60°C for 8 hours to obtain a polymer polymerization solution. The obtained polymer polymerization solution was added dropwise to diethyl ether, and the precipitated polymer was recovered. The recovered polymer was purified by reprecipitation using diethyl ether. The obtained polymer was then dried under reduced pressure for 24 hours to obtain a coating polymer (biocompatible polymer).

[0052] The molar ratio of MEMA monomer units to CMB monomer units in the coating polymer (biocompatible polymer) was measured as follows: After dissolving the obtained coating polymer (biocompatible polymer) in dimethyl sulfoxide, １ The molar ratio was calculated from the area ratio of the peak at 4.32 ppm (attributed to H atoms specific to CMB) to the peak from 0.65 to 2.15 ppm (total amount of H atoms) in a chart calculated by H-NMR measurement, using the following formula: Molar ratio of CMB monomer = (area ratio of 4.32 ppm region / 2) / (area ratio of 0.65-2.15 ppm region / 5) x 100 Molar ratio of MEMA monomer = 100 - molar ratio of CMB monomer The molar ratio of MEMA monomer units to CMB monomer units in the coating polymer (biocompatible polymer) was calculated to be 90:10.

[0053] <Preparation of Coating Solution> The above coating polymer (biocompatible polymer) was added to 70 wt % ethyl alcohol, and then stirred for 12 hours to prepare a coating solution with a coating polymer concentration of 0.1 wt %.

[0054] <Production of porous molded body> (Method of coating a hydrophobic polymer with a coating polymer) Amberlite was used as a porous molded body. ＴＭ XAD ＴＭ 1180N (styrene polymer beads manufactured by Organo Corporation) was used. 3 L of Amberlite swelled with ultrapure water. ＴＭ XAD ＴＭ 5 L of 1180N and 1 L of the coating solution were placed in a 5 L beaker and gently stirred for 12 hours to coat the beads with the polymer. Subsequently, the solution was removed after the coating process, and the resulting beads were classified and washed using a Beads Sepawash (mesh opening 328 μm, manufactured by Nippon Coke Co.) to obtain coated beads with a harmonic mean particle size of 573 μm.

[0055] The performance of the obtained porous molded body is shown in the following Table 1. According to the above-mentioned method for measuring the "pore area ratio", the ratio of 1000 nm to the total area of ​​the SEM image was ２The pore area ratio was calculated. Figure 1(a) is an SEM image of the surface of the porous molded body of Example 1, and Figure 1(b) is its binary image. As a result, the pore area ratio was 10.3%. As a result of neutralization titration, the porous molded body had no charge. The α-synuclein oligomer removal rate from plasma of the porous molded body (batch test) was 30% or more. It was revealed that the obtained porous molded body efficiently removed α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous molded body was 10% or less. It was revealed that the obtained porous molded body did not remove Aβ42 oligomers.

[0056] Figure 2 shows an image of a cross section of the porous molded article of Example 1, in which fluorescently stained α-synuclein oligomers were adsorbed, observed under a fluorescence microscope. More specifically, α-synuclein oligomers (Recombinant human α-synuclein aggregate, Abcam) were fluorescently labeled with the fluorescent dye ATTO590 manufactured by ATTO-TEC and purified by gel filtration. The porous molded article was then contacted with 0.5% BSA / PBS (bovine serum albumin / phosphate-buffered saline) spiked with the fluorescently modified α-synuclein oligomers, and then washed with saline to wash away any unadsorbed fluorescently modified α-synuclein oligomers. Finally, a frozen section of the porous molded article was prepared and observed under a fluorescence microscope. As shown in FIG. 2, it was found that α-synuclein oligomers (shown in a lighter color than the surrounding area) were adsorbed only on the outer surface of the porous molded body.

[0057] Example 2 Amberlite as a porous body ＴＭ FPX66 (styrene polymer beads, manufactured by Organo Corporation, harmonic mean particle diameter 751 μm) was used. The performance of the porous molded body is shown in Table 1 below.

[0058] 1000 nm relative to the entire area of ​​the SEM image ２The pore area ratio above was 5.1%. Neutralization titration results showed that the porous shaped body had no charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was 30% or more. It was revealed that the obtained porous shaped body efficiently removes α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was 10% or less. It was revealed that the obtained porous shaped body does not remove Aβ42 oligomers.

[0059] Example 3 Amberlite as a porous body ＴＭ XAD ＴＭ No. 18 (styrene polymer beads, harmonic mean particle diameter 434 μm, manufactured by Organo Corporation) was used.

[0060] The performance of the obtained porous molded body is shown in the following Table 1. ２ The pore area ratio above was 2.1%. Neutralization titration results showed that the porous shaped body had no charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was 30% or more. It was revealed that the obtained porous shaped body efficiently removes α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was 10% or less. It was revealed that the obtained porous shaped body does not remove Aβ42 oligomers.

[0061] Example 4: PuroSorb as a porous body ＴＭ PAD1200 (vinylbenzene polymer beads, harmonic mean particle size 728 μm, manufactured by Purolite) was used.

[0062] The performance of the obtained porous shaped body is shown in Table 1 below. The ratio of the pore area of ​​1000 nm2 or more to the total area of ​​the SEM image was 5.9%. Neutralization titration showed that the porous shaped body had no charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was 30% or more. It was revealed that the obtained porous shaped body efficiently removes α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was 10% or less. It was revealed that the obtained porous shaped body does not remove Aβ42 oligomers.

[0063] Example 5: CytoSorb 300 as a porous molded body ＴＭ (styrene polymer beads manufactured by CytoSorbents, harmonic mean particle diameter 439 μm) were used.

[0064] The performance of the obtained porous molded body is shown in the following Table 1. ２ The pore area ratio above was 8.8%. Neutralization titration results showed that the porous shaped body had no charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was 30% or more. It was revealed that the obtained porous shaped body efficiently removes α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was 10% or less. It was revealed that the obtained porous shaped body does not remove Aβ42 oligomers.

[0065] Example 6 DIAION as a porous body ＴＭ HP50 (styrene vinyl benzene polymer beads, harmonic mean particle size 429 μm, manufactured by Mitsubishi Chemical Corporation) was used.

[0066] The performance of the porous molded body is shown in Table 1 below. ２The pore area ratio above was 6.2%. Neutralization titration results showed that the porous shaped body had no charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was 30% or more. It was revealed that the obtained porous shaped body efficiently removes α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was 10% or less. It was revealed that the obtained porous shaped body does not remove Aβ42 oligomers.

[0067] Example 7: As a porous molded body, the polymer-coated Amberlite obtained in Example 1 was used. ＴＭ XAD ＴＭ 1180N (styrene polymer beads, harmonic mean particle diameter 573 μm, manufactured by Organo Corporation) was used.

[0068] The performance of the porous molded body is shown in Table 1 below. ２ The pore area ratio was 10.3%. Neutralization titration showed that the porous body had no charge. The α-synuclein oligomer removal rate from blood of the porous body (batch test) was 30% or more. It was revealed that the obtained porous body efficiently removed α-synuclein oligomers from blood.

[0069] Example 8: CytoSorb 300 as a porous body ＴＭ (styrene polymer beads manufactured by CytoSorbents, harmonic mean particle diameter 439 μm) were used.

[0070] The performance of the porous molded body is shown in Table 1 below. ２ The pore area ratio was 8.8%. Neutralization titration showed that the porous body had no charge. The α-synuclein oligomer removal rate from blood of the porous body (batch test) was 30% or more. It was revealed that the obtained porous body efficiently removed α-synuclein oligomers from blood.

[0071] Comparative Example 1

[0072] Amberlite as a porous compact ＴＭ XADＴＭ No. 4 (styrene polymer beads, harmonic mean particle diameter 774 μm, manufactured by Organo Corporation) was used.

[0073] The performance of the porous molded body is shown in Table 1 below. ２ The pore area ratio above was 0.4%. Neutralization titration results showed that the porous shaped body had no charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was less than 30%. It was revealed that the obtained porous shaped body does not remove α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was 10% or less. It was revealed that the obtained porous shaped body does not remove Aβ42 oligomers.

[0074] Example 9 Plasova BR (styrene-based polymer beads, manufactured by Asahi Kasei Medical Corporation, harmonic mean particle size: 376 μm) was used as the porous molded body. This porous molded body had a methylene group as the linker structure and a trimethylamine group as the aliphatic amine structure. The amount of amine structure introduced was 346.8 μmol / ml-wet carrier, and the porous molded body had a positive charge.

[0075] The performance of the porous molded body is shown in Table 1 below. ２ The pore area ratio above was 12.2%. Neutralization titration results showed that the porous shaped body had a positive charge. The α-synuclein oligomer removal rate from plasma of the porous shaped body (batch test) was 30% or more. It was revealed that the obtained porous shaped body efficiently removes α-synuclein oligomers from plasma. The Aβ42 oligomer removal rate from plasma of the porous shaped body was higher than 10%. It was revealed that the obtained porous shaped body removes Aβ42 oligomers.

[0076] Example 10 Polymer-coated Amberlite TMXADTM1180N (styrene polymer beads, manufactured by Organo Corporation, harmonic mean particle size 573 μm) obtained in Example 1 was used as the porous molded body.

[0077] The performance and test conditions of the porous molded body are shown in Table 2 below, and the results are shown in Table 3 and Figure 3. ２ The pore area ratio was 10.3%. Neutralization titration revealed that the porous body had no charge. The α-synuclein oligomer removal system using the porous body achieved an α-synuclein oligomer removal rate from blood (flow test) of 30% or more. It was revealed that the obtained α-synuclein oligomer removal system efficiently removed α-synuclein oligomers from blood.

[0078]

[0079]

[0080]

[0081] The porous molded article of the present disclosure can be suitably used for efficiently removing α-synuclein oligomers from biologically derived fluids.

Claims

1. A porous shaped body for removing α-synuclein oligomers, the porous shaped body comprising a hydrophobic polymer, and a surface area of ​​the porous shaped body measured by SEM imaging of 1000 nm ２ The porous molded article for removing α-synuclein oligomers has a pore area ratio of 1.5% or more.

2. 1000 nm relative to the entire area of ​​the SEM image ２ 2. The porous formed body according to claim 1, wherein the pore area ratio is 8.0% or more.

3. The porous formed body according to claim 1 or 2, wherein the porous formed body has no electric charge.

4. The porous molded body according to claim 1 or 2, wherein the hydrophobic polymer is a polystyrene-based polymer.

5. The porous formed body according to claim 1 or 2, wherein the harmonic mean particle size of said porous formed body is 800 μm or less.

6. The porous molded body according to claim 1 or 2, which has an α-synuclein oligomer removal rate of 30% or more.

7. A porous molded body according to claim 1 or 2, having an amyloid β oligomer removal rate of 10% or less.

8. An α-synuclein oligomer removal system, comprising: a column having a container having an inlet and an outlet for a biologically derived fluid, and a porous body filled in the container; a biologically derived fluid inlet flow path for introducing the biologically derived fluid into the inlet; and a biologically derived fluid outlet flow path for discharging the biologically derived fluid that has passed through the column from the outlet, wherein the porous body contains a hydrophobic polymer, and a surface area of ​​the porous body is measured at 1000 nm of the entire area of ​​an SEM image. ２ The α-synuclein oligomer removal system has a pore area ratio of 1.5% or more.

9. 1000 nm of the entire area of ​​the SEM image ２ 9. The system of claim 8, wherein the percentage of open area is 8.0% or greater.

10. The system according to claim 8 or 9, wherein the porous formed body has no electric charge.

11. The system of claim 8 or 9, wherein the hydrophobic polymer is a polystyrene-based polymer.

12. The system according to claim 8 or 9, wherein the harmonic mean particle size of the porous compact is 800 μm or less.

13. The system according to claim 8 or 9, wherein the porous molded body has an α-synuclein oligomer removal rate of 30% or more.

14. The system described in claim 8 or 9, wherein the porous molded body has a removal rate of amyloid β oligomers of 10% or less.

15. The system according to claim 8 or 9, wherein the biological fluid is blood.

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