Treatment of protein aggregation diseases

Abstract

To provide compositions, methods and systems for the treatment of a protein aggregation disease including, but not limited to Alzheimer's disease (AD), Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Huntington's disease (HD), Amylotrophic lateral sclerosis (ALS, which results from degeneration of the upper and lower motor neurones and affects the voluntary muscle system), Progressive Supranuclear Palsy (PSP), Type 2 Diabetes and Multiple systems atrophy (MSA).SOLUTION: A red blood cell preparation derived from one or more of the followings: i) a donor or donors, ii) the subject's red blood cells or the donor or donor's red blood cells that have been treated ex vivo to reduce the content of protein oligomers and / or aggregates, iii) derived from stem cells or other mononuclear cells, iv) derived from a xenotransfusion source, wherein the level of protein oligomers or aggregates in the red blood cell preparation has been measured and shown to be at a reduced level.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compositions, methods, and systems for treating protein aggregation disorders.

[0002] More particularly, the present invention relates to compositions, methods, and systems for the treatment of protein aggregation disorders, including, but not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS, which results from the degeneration of upper and lower motor neurons and affects the voluntary musculature), progressive supranuclear palsy (PSP), type 2 diabetes, and multiple system atrophy (MSA). [Background technology]

[0003] There is a particular need to provide treatments in the field of neurodegenerative diseases, such as dementia and Parkinson's disease. The term dementia encompasses a large class of neurodegenerative disorders with different causes and overlapping symptoms, of which Alzheimer's disease accounts for 62% of human cases. While each disorder benefits from tailored management and treatment by clinicians, families, and caregivers, accurate diagnosis and classification are difficult and usually based on subjective observation. Degenerative diseases can also include systemic neurological forms. One example is amyotrophic lateral sclerosis (ALS), which results from the degeneration of upper and lower motor neurons.

[0004] It is known that during the progression of neurodegenerative diseases such as Alzheimer's disease, aggregates of several different proteins form in the brain and may be involved in the pathogenesis. Detecting plaques and tangles composed of aggregated proteins in the brain using techniques such as in vivo imaging and postmortem histological examination is thought to confirm the presence of certain neurological diseases. Detecting the early stages of protein aggregation is presumed to enable intervention before irreversible neuronal damage occurs. The content of brain-derived proteins in cerebrospinal fluid (CSF), such as beta-amyloid (also known as Abeta) and tau, is useful for diagnosing and stratifying related dementia diseases. For example, CSF Abeta content is not only a promising biomarker for distinguishing early AD from normal aging, but also allows prediction of patients with mild cognitive impairment (MCI), now described as "early Alzheimer's disease," that will later transform into moderate to severe Alzheimer's disease (NPL 1, which is incorporated herein by reference). A recent paper reporting on a 7-year study showed that levels of Abeta, total tau, and phosphorylated tau in CSF, measured by standard immunoassays, can be used to predict both the onset and severity of Alzheimer's disease (NPL 2, which is incorporated herein by reference). is incorporated herein by reference).

[0005] It has been established that oligomeric forms of certain proteins have neurotoxic properties. These proteins include Abeta (especially the 1-42 form) and alpha-synuclein. In type 2 diabetes, the protein amylin (IAPP) also undergoes an oligomerization process to generate molecular species that are thought to be toxic to pancreatic islet cells. Patent document 1 discloses that oligomeric and / or aggregated forms of Abeta and alpha-synuclein exist in the blood and can be detected by specific analytical procedures. Patent document 1 also discloses that Abeta and alpha-synuclein are involved in the development of neurotoxicity in some patients with Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies. It has been disclosed that blood levels of oligomers of ASN can be elevated. Patent document 1 discloses that oligomeric and / or aggregated forms of the protein are associated with cellular fractions in the blood, with much lower levels in plasma.

[0006] There is a need for therapeutic treatments for such protein aggregation disorders.

[0007] According to one aspect of the present invention, i) single or multiple donors; ii) red blood cells of the subject, or red blood cells of said single or multiple donors, which have been treated ex vivo to reduce their content of protein oligomers and / or aggregates; iii) derived from stem cells or other mononuclear cells; iv) derived from a xenotransfused source; 2. A red blood cell preparation derived from one or more of: An erythrocyte preparation is provided in which the level of protein oligomers or aggregates in the erythrocyte preparation is measured by an analytical method and shown to be at a reduced level, preferably below the detection limit of the analytical method.

[0008] The present invention is based on the discovery that in AD and Lewy body disease MSA, a significant proportion of a patient's whole-body content of oligomeric forms of certain proteins thought to be involved in protein aggregation disorders is present in the red blood cell layer after Ficoll gradient separation. Since the majority of cells in this layer are red blood cells, with few neutrophils and granulocytes present, it can be assumed that the oligomeric forms are associated with red blood cells. Using analytical procedures using unfractionated whole blood, estimation of Abeta was achieved in elderly (over 50 years old), apparently healthy subjects, Alzheimer's disease patients, and patients with Lewy body disease, Parkinson's disease, and MSA. Elevated levels of toxic oligomeric forms were detected. Similarly, elevated levels of putative toxic oligomeric forms of alpha-synuclein were detected in the blood of Alzheimer's disease patients, Parkinson's disease patients, and MSA disease patients by the same analytical procedure. Because red blood cells have a very large surface area, it is proposed that red blood cells form a large reservoir of toxic oligomeric proteins in the bodies of elderly, apparently healthy subjects, as well as AD, PD, and MSA patients. The purpose of the therapeutic apheresis step of the present invention is to deplete the patient's body of these putative toxic reservoirs of oligomeric and / or aggregated proteins. Because these protein aggregation diseases develop slowly over many years in AD, PD, MSA, and DLB, as well as other related diseases, younger donors are preferred as they have been shown by the analytical procedures used in the present invention to have much lower blood levels of putative toxic oligomeric and aggregated forms.

[0009] Patent Document 2 reports the presence of various forms of Abeta peptide in the blood, which may be a reliable indicator of the early onset and progression of Alzheimer's disease. Patent Document 2 describes that a certain percentage of Abeta peptide in the blood is associated with blood cells, but does not describe the presence of oligomeric or aggregated forms on red blood cells. Patent Document 3 describes that the use of surface-enhanced laser desorption time-of-flight (SELDI-TOF) mass spectrometry has shown that higher concentrations of Abeta dimers are present in the blood of some Alzheimer's patients, and that these dimers are associated with the membranes of blood cells. In Patent Document 3 There is no mention of oligomers larger than dimers present in blood, no differentiation between red blood cells and other blood cells is reported, and furthermore, it is stated that oligomeric toxic forms of the protein bind to lipid membranes.

[0010] There is growing interest in the use of plasma therapy in the treatment of diseases of aging, including neurodegenerative diseases. The hypothesis is that plasma from young subjects contains factors that can stimulate neurogenesis in older subjects. Results of heterochronic blood exchange studies in mouse models have shown that blood from old mice has a rapid inhibitory effect on neurogenesis and stimulates inflammation in the associated tissues of young mice. This suggests that aged blood composition is probably somehow harmful to young animals (Non-Patent Document 3). Rebo et al. reported that plasma from young subjects in their heterochronic blood exchange model contains factors that can stimulate neurogenesis in older subjects and stimulate inflammation in the associated tissues of young mice. Although they speculate that it may be interesting to isolate the effects of the plasma fraction on the cellular composition of the patient, they do not provide any information regarding the characteristics of the cell fraction. Patent document 4 describes a dosing regimen for treating patients with cognitive impairment involving periodic treatment with a plasma fraction or plasma protein fraction, preferably derived from a young donor source, preferably over the following 5-7 days (pulse dosing basis). Patent document 5 also describes the use of various plasma fractions containing albumin from young donors to treat patients diagnosed with cognitive impairment. Both Patent document 4 and Patent document 5 describe the use of various plasma fractions containing albumin from young donors to treat patients diagnosed with cognitive impairment. The use of blood-derived cell fractions, particularly red blood cells, in this study has not been described. Patent Document 6 describes removing a patient's plasma and treating the plasma in an ex vivo process that specifically removes amyloid precursor protein (APP) and Abeta 1-40 and Abeta 1-42 using binding receptors such as antibodies. The depleted plasma is then infused back into the patient.

[0011] One aspect of the invention involves the partial or total removal and replacement of a subject's red blood cells with a red blood cell preparation using a therapeutic apheresis procedure, where the replaced red blood cells in the preparation are derived from a number of different sources, including donors preferably under the age of 50, more preferably under the age of 40, or more preferably under the age of 30, or derived from stem cells or other mononuclear cells, or derived from a xenogeneic transfusion source such as a pig or other mammal having red blood cells with similar characteristics to humans, or derived from the subject in an autologous process.

[0012] In autophagy apheresis procedures, red blood cells are removed from a subject and subjected to an ex vivo process to remove oligomeric or aggregated forms of certain proteins, and the treated red blood cell preparation is then administered to the subject. This ex vivo process may include the use of a compound that reverses the aggregation state of oligomeric and aggregated proteins. In this case, the compound and the resulting monomeric forms can be removed by dialysis or other washing procedures such as centrifugation before administering the treated red blood cell preparation to the subject. Optionally, the monomeric forms of proteins resulting from this treatment can be removed by an affinity adsorption step using specific binding agents, such as antibodies or synthetic antibodies, such as aptamers or specific binding polymers, before administering the treated red blood cell preparation to the subject. Alternatively, nonspecific binding techniques, such as ion exchange or size exclusion chromatography, can be used to separate monomers from red blood cells.

[0013] Compounds suitable for reversing the aggregation state of oligomeric and aggregated proteins include polymers such as pentosan polysulfate, which have been shown to be effective against prion protein aggregation and are used in the treatment of prion diseases. Similar polyionic compounds, such as heparan sulfate, are known to bind to aggregated proteins such as Abeta and alpha-synuclein, and may therefore be able to affect the interaction of oligomers with erythrocyte membranes. Other polyionic polymers, such as heparin, are known to inhibit protein aggregation. Phenothiazines and bicyclic and cyclic ... Small molecules such as tricyclic pyridones are known to affect the aggregation state of proteins, including Abeta. Other compounds, such as chlorpromazine and quinacrine, have been shown to affect the aggregation state of prion proteins and have been proposed for the treatment of prion diseases, where they are thought to affect the aggregation state of proteins. The compounds described in Patent Document 8 have been shown to convert the oligomeric form of Abeta to the monomeric form. Patent Document 8 also shows that certain compounds can reduce aggregates in vitro and can reduce plaque content in mouse brains. Patent Document 8 also describes a method for reversing aggregation. The compound of choice is described as dibenzodiazipentrimipramine, which has a tricyclic structure.

[0014] This ex vivo process can also be used with blood from donors that initially have relatively high levels of oligomers or aggregates and are otherwise unsuitable for therapeutic apheresis procedures.

[0015] Optionally, this ex vivo process may involve removing leukocytes prior to the addition of the disaggregating compound. Leukocyte removal can be achieved by size filtration, continuous or intermittent flow centrifugation, or the use of specific leukocyte reduction filters. This step also serves to remove any toxic oligomeric forms of proteins that may be associated with leukocyte membranes.

[0016] Analytical methods are used to measure the presence and levels of oligomeric forms of specific proteins in a patient's blood before treatment begins and to monitor the reduction in levels as red blood cell replacement therapy progresses. Analytical methods can also be used to determine when red blood cell replacement therapy should be repeated if oligomeric levels exceed a predetermined threshold. Analytical methods can also be used to confirm that the source of red blood cells is free of oligomeric forms and to confirm that the ex vivo treatment process of the donor's or subject's blood has successfully reduced the levels of oligomeric or aggregated protein forms present. It is also possible to do so.

[0017] In neurodegenerative diseases, oligomeric forms of certain proteins have been shown to have neurotoxic properties. These proteins include Abeta (particularly the 1-42 form) and alpha-synuclein. In type 2 diabetes, the protein amylin (IAPP) also undergoes an oligomerization process to generate molecular species that are thought to be toxic to pancreatic islet cells. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] International Publication No. 2017 / 067672 Brochure [Patent Document 2] International Publication No. 2011 / 070174 Brochure [Patent Document 3] US Patent Application Publication No. 2011 / 0263450 [Patent Document 4] International Publication No. 2018 / 200560 Brochure [Patent Document 5] US Patent Application Publication No. 2018 / 110839 [Patent Document 6] U.S. Patent No. 7,935,252 [Patent Document 7] U.S. Patent No. 6,030,984 [Patent Document 8] U.S. Patent No. 8,383,617 [Non-patent literature]

[0019] [Non-Patent Document 1] The Amyloid-Oligomer Count in Cerebrospinal Fluid is a Biomarker for Alzheimer's Disease.Wang-Dietricha,L,Journal of Alzheimer's Disease 34(2013)985-994,DOI 10.3233 / JAD-122047 [Non-patent document 2] Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later.Roe et al,Neurology 2013;80;1784-1791 [Non-patent document 3] Rebo et al.A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood DOI:10.1038 / ncomms13363 Summary of the Invention [Problem to be solved by the invention]

[0020] Patent Document 1 discloses that oligomeric and / or aggregated forms of these proteins exist in the blood and can be detected by specific analytical procedures. Patent Document 1 discloses that blood levels of oligomers of Abeta and ASN may be elevated in some patients with Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies. Patent Document 1 discloses that oligomeric and / or aggregated forms of the proteins are associated with cellular fractions in the blood, with plasma levels being much lower, but does not provide direct evidence of association with the erythrocyte fraction. [Means for solving the problem]

[0021] The present applicant has discovered that the majority of oligomeric forms of certain proteins thought to be involved in certain protein aggregation diseases are associated with erythrocytes. Putative toxic oligomeric forms of Abeta have been detected in the erythrocyte fractions of relatively elderly (over 50 years old), apparently healthy subjects, Alzheimer's disease patients, and MSA patients. Similarly, putative toxic oligomeric forms of alpha-synuclein have been detected in the erythrocyte fractions of Alzheimer's disease patients and MSA patients. Putative toxic oligomeric forms of Abeta and alpha-synuclein have also been detected in the unfractionated blood of Parkinson's disease patients, and these forms are also associated with erythrocytes. It is speculated that because red blood cells have a very large surface area, they form a large reservoir of toxic oligomeric proteins in the bodies of patients with these diseases. The therapeutic apheresis step of the present invention depletes and / or reduces these putative toxic reservoirs of oligomeric and / or aggregated proteins from the bodies of elderly patients. Because these protein aggregation disorders develop slowly over many years in AD, PD, DLB, and other related diseases, younger donors are preferred, as the analytical procedures used in the present invention have shown that they have much lower blood levels of putative toxic oligomeric and aggregated forms.

[0022] To ensure a lower content of oligomers or aggregates, the donor or donors are preferably under 50 years of age, more preferably under 40 years of age, or more preferably under 30 years of age.

[0023] According to another aspect of the present invention, i) single or multiple donors; ii) red blood cells of the subject, or red blood cells of said single or multiple donors, which have been treated ex vivo to reduce their content of protein oligomers and / or aggregates; iii) derived from stem cells or other mononuclear cells; iv) derived from a xenotransfused source; 2. A red blood cell preparation administered to a subject in a therapeutic apheresis procedure, the red blood cell preparation being derived from one or more of: A red blood cell preparation is provided in which the level of protein oligomers or aggregates in the administered red blood cells is measured by an analytical method and shown to be at a reduced level, preferably below the detection limit of the analytical method.

[0024] According to a further aspect of the present invention, i) single or multiple donors; ii) red blood cells of the subject, or red blood cells of said single or multiple donors, which have been treated ex vivo to reduce their content of protein oligomers and / or aggregates; iii) derived from stem cells or other mononuclear cells; iv) derived from a xenotransfused source; a method of treating a protein aggregation disorder in a subject comprising administering red blood cells derived from one or more of: Methods are provided in which the level of protein oligomers or aggregates in the administered red blood cells is measured by an analytical method and shown to be at a reduced level, preferably below the detection limit of the analytical method.

[0025] According to a further aspect of the present invention, i. Single or multiple donors under 50 years of age; ii. Red blood cells of a subject that have been treated ex vivo to remove toxic oligomers and / or aggregates; iii. derived from stem cells or other mononuclear cells; iv. Originating from xenogeneic transfusion; a method of treating a protein aggregation disorder comprising administering to said subject red blood cells derived from one or more of: Methods are provided in which an assay is used to confirm that the levels of toxic oligomers or aggregates in the administered red blood cells are below the detection limit of an analytical method, and then the analytical method is used to detect an increase in levels in the subject's blood above a predetermined threshold, thereby triggering a repeat therapeutic apheresis procedure.

[0026] Oligomeric or aggregated proteins that may be measured include, but are not limited to, Abeta, alpha-synuclein, DJ-1 (also known as Park7, a protein thought to be associated with Parkinson's disease), tau, superoxide dismutase (SOD, a protein associated with ALS), or IAPP.

[0027] Oligomeric forms of proteins can range in size from dimers to structures containing 10-20 units, and multimeric associations of protein subunits can contain 20-100 units, whereas aggregates can be defined as larger structures that can contain hundreds or even thousands of protein molecules. Proteins that form oligomers and aggregates can be in their native, normally folded form, or they can be misfolded or structurally abnormal and therefore prone to aggregation.

[0028] According to another aspect of the present invention, there is provided a method for preventing, ameliorating, or treating a protein aggregation disorder, comprising removing aggregating proteins from the surface of red blood cells.

[0029] The removal of aggregating proteins from the surface of red blood cells is advantageously carried out ex vivo.

[0030] According to another aspect, there is provided a method of removing aggregated proteins from the surface of red blood cells, comprising contacting the red blood cells of a subject with a means for removing protein aggregates from the surface of the cells.

[0031] The means for removing protein aggregates from the surface of red blood cells may include an antibody or antibody fragment or synthetic antibody capable of binding to the aggregated protein of interest.

[0032] The antibody, antibody fragment, or synthetic antibody may be immobilized on a support, which may include one or more of a membrane filter, magnetic or non-magnetic beads preferably having a diameter in the range of 0.1 μm to 150 μm, or a monolithic high surface area support.

[0033] The method may further comprise separating the red blood cells from the agglutinated proteins.

[0034] The red blood cells may then be reintroduced into the subject.

[0035] According to a further aspect of the present invention there is provided a system for use in the treatment of an aggregating protein disease comprising a means for binding to an aggregating protein of interest, said aggregating protein of interest itself being associated with red blood cells, said means being immobilised on a support.

[0036] The system may further include separating the agglutinated proteins from the red blood cells.

[0037] According to a further aspect of the present invention there is provided a method for removing aggregating proteins from the surface of red blood cells, the method being used in the treatment of aggregating protein-associated diseases.

[0038] According to another aspect of the present invention, there is provided an in vitro method for removing aggregating proteins from the surface of red blood cells, comprising the steps of: i) contacting a blood sample with an immobilized antibody or antibody fragment; ii) washing to remove unbound material, leaving the immobilized red blood cells; and iii) releasing the red blood cells from the immobilized antibody or antibody fragment.

[0039] According to one aspect of the present invention, there is provided an erythrocyte preparation obtained from the erythrocytes of a subject treated with a protein oligomer disaggregating compound, wherein the erythrocyte preparation is depleted of said compound.

[0040] The present invention will now be described, by way of example only, with reference to the following examples and figures. [Brief explanation of the drawings]

[0041] [Figure 1] FIG. 1 shows oligomer depletion with A11 antibody prior to use of the full assay protocol. [Figure 2] Figure 1 shows levels of oligomeric Abeta in whole blood samples obtained from healthy normal controls, Alzheimer's disease (AD) patients, multiple system atrophy (MSA) patients, and Parkinson's disease (PD) patients. The x-axis indicates the age and sex of the controls and patients, with "S" indicating samples obtained from age-matched spouses. The y-axis indicates the signal obtained from the oligomeric Abeta assay protocol using europium labeling in relative fluorescence units (RFU) as measured by an LFB-Wallac time-resolved fluorometer. For the oligomeric ASN study, the y-axis indicates the signal obtained using a FIRP enzyme conjugate. In this case, the signal is reported as optical density measured on a Biotek colorimetric microplate reader. [Figure 3a] FIG. 10 shows the analysis of control samples as a box plot, confirming that there is an increase in median levels of oligomeric Abeta with age. [Figure 3b] FIG. 10 shows additional data from AD patients by age group, as well as box plots including MSA and PD patients. [Figure 3c] FIG. 1 shows box plots of control samples and AD, MSA, and PD patients. [Figure 4a] Figure 1 shows the results of Ficoll gradient separation of whole blood obtained from two AD patients, showing the levels of oligomeric Abeta in three fractions: plasma, buffy coat (white blood cells), and red blood cells. [Figure 4b] Figure 1 shows the results of Ficoll gradient separation of whole blood obtained from two MSA patients, showing the levels of oligomeric Abeta in three layers: plasma, buffy coat (lymphocytes), and primarily erythrocytes. [Figure 5] 1 shows levels of oligomeric ASN in whole blood samples from healthy normal controls, AD patients, MSA patients, and PD patients. The X-axis indicates the age and sex of the controls and patients. [Figure 6] Figure 1 shows box plots of control samples and AD and MSA analyses, confirming that no age-related increase in median levels of oligomeric ASN was observed, whereas AD, MSA, and PD patients showed an increase in oligomeric ASN. [Figure 7a] Figure 1 shows the results of Ficoll gradient separation of whole blood obtained from two AD patients, showing the levels of oligomeric ASN in three layers: plasma, buffy coat (lymphocytes), and primarily erythrocytes. [Figure 7b] Figure 1 shows the results of Ficoll gradient separation of whole blood obtained from two MSA patients, showing the levels of oligomeric ASN in three layers: plasma, buffy coat (lymphocytes), and primarily erythrocytes. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0042] Oligomer depletion with A11 antibody Abeta 1-42 and ASN were aggregated according to the method described in Patent Document 1. Protein A-coated magnetic beads (GE Flealthcare) with a diameter of 37-100 μM were derivatized with the A11 antibody provided by Thermo Fisher Scientific (2 μl of A11 antibody was added to 50 μl of bead suspension) and then added to 1 ml of a 100 μg / ml solution of aggregated protein in PBS buffer, pH 7.5. The mixture was then placed in a rotating incubator at room temperature for 1 hour. The tube was transferred to a magnetic separator, and the depleted supernatant was collected for further processing according to the full assay protocol described in Patent Document 1. The A11 antibody has specificity for the oligomeric forms of both Abeta and ASN, but it does not distinguish between these proteins; it likely recognizes the conformation of the peptide backbone in the oligomers. Figure 1 shows that the signal in the assay decreased to background after treatment with the A11-coated beads, thus indicating that the full assay protocol measured only the oligomeric forms of these proteins. [Example]

[0043] The complete assay protocol described in Patent Document 1 was applied to frozen whole blood samples collected from healthy normal controls, as well as patients with Alzheimer's disease (AD), multiple system atrophy (MSA), and Parkinson's disease (PD). Controls were obtained from healthy volunteers and collected with full ethical permission from the Liverpool Bioinnovation Biobank, UK. Control blood samples were also provided by Tissue Solutions, Glasgow, UK. Additionally, control samples from age-matched spouses were provided by Salford Royal Infirmary, UK. Figure 2 shows the results of the Abeta assay protocol, and Figure 5 shows the results of the ASN assay protocol. [Example]

[0044] Fresh whole blood (unfrozen) from AD and MSA patients was subjected to Ficoll (GE Healthcare) gradient separation using the manufacturer's instructions. 1 ml aliquots were taken from each layer within the gradient and analyzed using the complete oligomeric protein assay protocol. Figures 4a and 4b show the results of the complete assay protocol for each layer from the gradient.

Claims

1. i) single or multiple donors; ii) red blood cells of the subject, or red blood cells of said single or multiple donors, which have been treated ex vivo to reduce their content of protein oligomers and / or aggregates; iii) derived from stem cells or other mononuclear cells; iv) derived from a xenotransfusion source; 2. A red blood cell preparation derived from one or more of: A red blood cell preparation wherein the level of protein oligomers or aggregates in said red blood cell preparation is measured and shown to be at a reduced level.

2. v) single or multiple donors; vi) red blood cells of the subject, or red blood cells of said single or multiple donors, which have been treated ex vivo to reduce their content of protein oligomers and / or aggregates; vii) derived from stem cells or other mononuclear cells; viii) derived from a xenotransfusion source; 2. A red blood cell preparation administered to a subject in a therapeutic apheresis procedure, the red blood cell preparation being derived from one or more of: A red blood cell preparation in which the level of protein oligomers or aggregates in the administered red blood cells has been measured and shown to be at a reduced level.

3. 3. The red blood cell preparation of claim 1, wherein the level of protein oligomers or aggregates in the administered red blood cells is measured by an analytical method and shown to be at a reduced level below the detection limit of the analytical method.

4. v) single or multiple donors; vi) red blood cells of the subject, or red blood cells of said single or multiple donors, which have been treated ex vivo to reduce their content of protein oligomers and / or aggregates; vii) derived from stem cells or other mononuclear cells; viii) derived from a xenotransfusion source; 1. A method of treating a protein aggregation disorder in a subject, comprising administering red blood cells derived from one or more of: The level of protein oligomers or aggregates in the administered red blood cells is measured and shown to be at a reduced level.

5. v. Single or multiple donors under the age of 50; vi. Red blood cells of a subject that have been treated ex vivo to remove toxic oligomers and / or aggregates; vii. derived from stem cells or other mononuclear cells; viii. resulting from xenogeneic blood transfusion; 1. A method of treating a protein aggregation disorder comprising administering to said subject red blood cells derived from one or more sources of: A method of using an assay to confirm that the level of toxic oligomers or aggregates in the administered red blood cells is below the detection limit of an analytical method, and then using the analytical method to detect an increase in the level in the subject's blood above a predetermined threshold, thereby triggering a repeat of the therapeutic apheresis process.

6. 6. The method of claim 4 or 5, wherein the level of protein oligomers or aggregates in the administered red blood cells is measured by an analytical method and shown to be at a reduced level below the detection limit of the analytical method.

7. 7. The red blood cell preparation or method of any one of claims 1 to 6, wherein the oligomeric or aggregated proteins comprise any one or more of Abeta, alpha synuclein, DJ-1 (also known as Park7), tau, superoxide dismutase (SOD), or IAPP.

8. A method for treating a protein aggregation disorder, comprising removing aggregated proteins from the surface of red blood cells.

9. The method of claim 8, wherein the removal of the aggregation proteins from the surface of the red blood cells is performed ex vivo.

10. A method for removing aggregated proteins from the surface of red blood cells comprising contacting the red blood cells of a subject with a means for removing protein aggregates from the surface of the cells.

11. 11. The method of claim 10, wherein the means for removing protein aggregates from the surface of the red blood cells comprises an antibody, antibody fragment, and / or synthetic antibody capable of binding to the aggregated protein of interest.

12. The method of claim 11 , wherein the antibody, antibody fragment, and / or synthetic antibody is immobilized on a support.

13. 13. The method of claim 12, wherein the support comprises one or more of a membrane filter, a magnetic bead, a non-magnetic bead, or a monolithic high surface area support.

14. The method of claim 13, wherein the support comprises magnetic and / or non-magnetic beads having a diameter in the range of 0.1 μm to 150 μm.

15. 15. The method of claim 14, further comprising separating the red blood cells from the aggregated proteins.

16. 16. The method of claim 15, comprising the subsequent step of reintroducing the red blood cells into the subject.

17. 1. A system for use in treating an aggregating protein disease, comprising a means for binding to an aggregating protein of interest, said protein being associated with red blood cells, said means being immobilized on a support.

18. The system of claim 17 , wherein the aggregated proteins are separated from the red blood cells.

19. An erythrocyte preparation obtained from the erythrocytes of a subject treated with a protein oligomer disaggregating compound.

20. 20. The red blood cell preparation of claim 19, wherein the protein oligomer disaggregating compound has been removed.

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