A method of suppressing a neurological disorder

Abstract

The invention provides a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: administering to the subject a therapeutically effective amount of a CD63+ complementary binding partner, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the subject remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder.

Description

[0001] A method of suppressing a neurological disorder Field of the invention The present invention relates to a method for suppressing a neurological disorder associated with motor neuron degeneration in a subject. The method extends to pre- symptomatic subjects, and includes subjects with a confirmed diagnosis as well as subjects without a confirmed diagnosis. In the latter scenario, the subject may be suspected to have a neurological disorder, for example a familial form or may otherwise be considered at risk of developing a neurological disorder. The invention also relates to a method for monitoring responsiveness to therapeutic intervention in a subject having or suspected to have a neurological disorder. Background to the invention The term neurological disorder defines a genus of disorders that affect the nervous system and includes disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington disease (HD), and Frontotemporal Dementia (FTD). This term includes certain neuromuscular disorders such as Myasthenia Gravis (MG), Amyotrophic Lateral Sclerosis (ALS), familial ALS (fALS), sporadic ALS (sALS), fast- progression ALS, slow-progression ALS, severe disease ALS, mild disease ALS, Charcot-Marie-Tooth (CMT), Multiple Sclerosis (MS), Muscular Dystrophy (MD), Myasthenia gravis (MG), Spinal-Bulbar Muscular Atrophy (SBMA) and Spinal Muscular Atrophy (SMA), Spinal Muscular Atrophy type II (SMAII), Spinal Muscular Atrophy type III / IV (SMAIII / IV), Facioscapulohumeral muscular dystrophy (FSHD), Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS), Duchenne muscular dystrophy, and the disease spectrum known as ALS-FTD (in which FTD clinically overlaps with ALS). Amongst this broad genus of neurological disorders exists a subgroup of disorders that are associated with motor neuron degeneration, in particular Amyotrophic Lateral Sclerosis (ALS), familial ALS (fALS), sporadic ALS (sALS), fast-progression ALS, slow- progression ALS, severe disease ALS, mild disease ALS, Spinal-Bulbar Muscular Atrophy (SBMA), Spinal Muscular Atrophy (SMA), Spinal Muscular Atrophy type II (SMAII), Spinal Muscular Atrophy type III / IV (SMAIII / IV), Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS), Parkinson’s Disease (PD), such as sporadic PD, and the disease spectrum known as ALS-FTD (in which FTD clinically overlaps with ALS). The association of the ALS disorders with motor neuron degeneration is well established, and indeed ALS is also known as motor neuron disease. Similarly, the association SBMA, SMA, SMAII, SMAIII / IV, PMA and PLS with motor neuron degeneration is well established. The association of PD with motor neuron degeneration has also been established, for example as described in Mes et al (J Electromyogr Kinesiol.2021 Dec:61:102606). Thus, motor neuron degeneration is also a recognised part of Parkinson’s Disease (PD) pathology. Many neurological disorders (including those associated with motor neuron degeneration as mentioned above) include one or more form known to have a genetic cause, making them potentially amenable to genetic intervention. Regrettably, however, the progress of gene therapy related opportunities into the clinic has been slow. To- date, clinical approval for therapeutic opportunities of this type has been limited to a small number of neurological disorders, for example, lipoprotein lipase deficiency and RPE65 mutation-associated inherited retinal dystrophy, and survival motor neuron 1 (SMN-1) deficiency in children with SMA. One unavoidable limitation with therapeutics of this type is that they are highly specific to the genetic disorder they have been designed to address and therefore lack any broader spectrum clinical utility. On the other hand, many neurological disorders (including those associated with motor neuron degeneration as mentioned above) arise from epi-genetic dispositions or non- genetic events, such as trauma, disease (e.g. cancer), lifestyle and environmental stimuli, and combinations thereof. In such cases, the underlying cause may be unknown, of an irreversible nature, or otherwise fail to present in a form that offers a single defined target suitable for therapeutic intervention. As a consequence, there remains an unmet need for a method of suppressing a broad spectrum of different neurological disorders associated with motor neuron degeneration; alternatively expressed as, an unmet need for a method of treating a neurological disorder associated with motor neuron degeneration, wherein said method is not specific to said neurological disorder. There is also an unmet need for a method of suppressing neurological disorders arising from a genetic or non-genetic cause alike. To the extent recognised methods exist for monitoring responsiveness to therapeutic intervention in a subject having (or to have) a neurological disorder, such methods are typically complex and highly specific to the disorder in question. A need therefore exists for such a method having utility across a broad spectrum of different neurological disorders associated with motor neuron degeneration. Summary of the invention The present invention solves one or more of said problems or shortfalls as discussed in more detail below. A neurological disorder that is “associated with motor neuron degeneration” is neurological disorder in which motor neuron degeneration is an underlying pathology. For example, a neurological disorder that is associated with motor neuron degeneration can be referred to as such disorder that characterised by a progressive loss of motor neurons (e.g. in the CNS such as in the spinal cord), e.g. leading to muscle weakness and / or atrophy. The motor neurons (that suffer degeneration) may be upper and / or lower motor neurons. An aspect of the invention provides a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: administering to the subject a therapeutically effective amount of a CD63+ complementary binding partner, wherein the CD63+ complementary binding partner does not bind to CD63 negative (“CD63-”) EVs such that a subpopulation of CD63- CD81+ (e.g. CD63 positive and CD81 positive) EVs present in the subject remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder; and optionally administering to the subject a therapeutically effective amount of a CD82+ complementary binding partner (e.g. wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the subject remains unchanged), wherein the CD82+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD82+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder. An aspect of the invention provides a CD63+ complementary binding partner (and optionally CD63+ complementary binding partner) for use in a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: administering to the subject a therapeutically effective amount of the CD63+ complementary binding partner, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the subject remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder; and optionally administering to the subject a therapeutically effective amount of a CD82+ complementary binding partner (e.g. wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the subject remains unchanged), wherein the CD82+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD82+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder. An aspect of the invention provides a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having said disorder (e.g. wherein said subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory extracellular vesicles (EVs)), the method comprising: administering to the subject a therapeutically effective amount of a CD63 complementary binding partner, wherein said binding partner forms a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject, and optionally administering to the subject a therapeutically effective amount of a CD82 complementary binding partner, wherein said binding partner forms a bound complex with extracellular vesicles having a CD82+ cell surface marker present in the subject. In other words, an aspect of the provides a CD63 complementary binding partner, and optionally a CD82 complementary binding partner, for use in a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having said disorder (e.g. wherein said subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory extracellular vesicles (EVs)), the method comprising: administering to the subject a therapeutically effective amount of a CD63 complementary binding partner, wherein said binding partner forms a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject, and optionally administering to the subject a therapeutically effective amount of a CD82 complementary binding partner, wherein said binding partner forms a bound complex with extracellular vesicles having a CD82+ cell surface marker present in the subject. Preferably, the bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the subject’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. Where the CD82 complementary binding partner is used, preferably the bound complex sequesters extracellular vesicles having a CD82+ cell surface marker from the subject’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. Said CD63+ complementary binding partner may be infused ex vivo into the patient’s blood, and optionally said CD82+ complementary binding partner may be infused ex vivo into the patient’s blood. That being said, it is preferred that said CD63+ complementary binding partner (and optionally said CD82+ complementary binding partner) is administered directly to the patient. For example, said CD63+ complementary binding partner (and optionally said CD82+ complementary binding partner) may be administered to the patient by intravenous administration, optionally wherein the binding partner is comprised within a pharmaceutical composition that additionally comprises a pharmaceutically acceptable carrier. Said binding partner forms a bound with extracellular vesicles having a CD63+ cell surface marker present in the in a targeted manner, while a subpopulation of CD63-CD81+EVs remains substantially unbound. By targeting the cytotoxic CD63+ EVs, the binding / neutralisation / depletion etc of otherwise ‘desired’ EVs can be avoided. Notably, EVs has been reported to have a role in delivering functional protein cargo (e.g. to muscle) – se Le Bihan et al (J Proteomics .2012 Dec 21:77:344-56). Thus, untargeted removal could also lead to removal of non- cytotoxic (beneficial) EVs, which can be avoided by the present invention’s approach. CD81 has been shown to be a common marker amongst various EVs reported to have such role in delivering functional protein cargo (see page 349, left hand column of said Le Bihan et al). Advantageously, the present inventors have shown that it is possible to remove / suppress cytotoxic EVs that are CD63+, but CD81-. Thus, a CD63+ complementary binding partner described herein can bind extracellular vesicles having a CD63+ cell surface marker present in the subject in a targeted manner, while a subpopulation of CD63-CD81+EVs remains substantially unbound. In methods / treatments of the invention, a population of CD63 negative extracellular vesicles (and optionally also a population of CD81 negative extracellular vesicles) is retained or is unbound by complementary binding partner described herein. Prior to administering said CD63+ complementary binding partner the total population of (e.g. unbound / non-complexed) extracellular vesicles present in the subject’s blood may comprise at most 30% muscle-derived extracellular vesicles; and / or prior to administering said CD63+ complementary binding partner the total population of extracellular vesicles present in the subject’s blood may comprise at least 70% extracellular vesicles derived from a non-muscle source. Another aspect of the invention provides a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, the method comprising: a) an ex vivo step of extracellular vesicles having a CD63+ cell surface marker from a sample (e.g. whole blood, plasma or serum), by i. contacting ex vivo blood (preferably obtained from the subject) with a CD63+ complementary binding partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged; and iii. removing bound complex from said blood; thereby providing a blood preparation that is substantially free of subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons; and b) administering the blood preparation to a subject having said neurological disorder; preferably wherein the blood sample is obtained from a subject having a neurological disorder (e.g. associated with motor neuron degeneration); more preferably wherein the blood sample is obtained from the subject undergoing treatment, e.g. wherein step b) comprises reinfusing the blood preparation (subsequent to step a)) to the subject. Another aspect of the invention provides a CD63+ complementary binding partner for use in a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, the method comprising: a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from a blood sample (e.g. whole blood, plasma or serum), by i. contacting ex vivo blood (preferably obtained from the subject) with a CD63+ complementary binding partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged; and iii. removing bound from said blood; thereby providing a blood preparation is substantially free of subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons; and b) administering the blood preparation to a subject having said neurological disorder; preferably wherein the blood sample is obtained from a subject having a neurological disorder (e.g. associated with motor neuron degeneration); more preferably wherein the blood sample is obtained from the subject undergoing treatment, e.g. wherein step b) comprises reinfusing the blood preparation (subsequent to step a)) to the subject. Step i) may comprises contacting ex vivo blood (preferably obtained from the subject) with a solid phase support comprising said CD63+ complementary binding partner immobilised thereon, and optionally contacting ex vivo blood (preferably obtained from the subject) with a solid phase support comprising an immobilised CD82+ complementary binding partner. Step (a) may be performed on a serum or plasma component of the subject’s blood; and / or wherein step (a) may comprise aphaeresis of the subject’s blood. Another aspect of the present invention provides a method of suppressing a neurological disorder associated with motor neuron degeneration in a subject having said disorder, wherein said subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory extracellular vesicles (EVs), said method comprising: a) depleting a sub-population of cytotoxic extracellular vesicles (EVs) having a CD63+ cell surface marker from said reservoir of circulatory EVs; and b) optionally depleting a sub-population of cytotoxic EVs having a CD82+ cell surface marker from said reservoir of circulatory EVs. Prior to step (a) the total population of extracellular vesicles present in the subject’s blood may comprises at most 30% muscle-derived extracellular vesicles; and / or prior to step (a) the total population of extracellular vesicles present in the subject’s blood may comprise at least 70% extracellular vesicles derived from a non-muscle source. Said non-muscle source is selected from: brain, gut, or liver; optionally said non-muscle source may comprise EVs derived from or liver. Step a) here comprises depleting a sub-population of cytotoxic extracellular vesicles (EVs) having a CD63+ cell surface marker from said reservoir of circulatory EVs in a targeted manner, while retaining a subpopulation of CD63-CD81+ EVs. Reference to “blood” includes plasma and serum, and so the depleting step may also be performed on plasma or serum extracted from blood obtained from the subject. In one embodiment, the depleting step is performed ex vivo on blood (e.g. whole blood, plasma or serum) obtained from the subject. Said blood may be provided in the form of a continuous blood supply obtained from the subject having the neurological disorder. The depleting step thereby “cleans” the blood obtained from a subject having a neurological disorder by progressively removing cytotoxic EVs (characterised by the presence of a CD63+ cell surface marker) from the subject’s broader reservoir of circulatory EVs. Optionally, said “depleting” step also progressively removes cytotoxic EVs (characterised by the presence of a CD82+ cell surface marker) from the subject’s broader reservoir of circulatory EVs. Details on suitable methodology to “clean” the blood is discussed in more depth in the detailed description, and includes methods such as centrifugation (e.g. with the blood or blood fraction sample subjected to a spin speed / program chosen to pull the cytotoxic EVs into a precipitate) as well as methods using a complementary binding partner to capture the cytotoxic EVs. A depleting step is performed by way of a complementary binding partner that preferentially (i.e. specifically) binds to the CD63+ cell surface marker present on an EV. The depleting step may also include a corresponding binding partner that preferentially (i.e. specifically) binds to the CD82+ cell surface marker present on an EV. Said complementary binding partner is typically immobilised on a surface (e.g. a surface of an exchange column or on beads suspended within such a column), thereby providing a capture means for removing cytotoxic EVs having a CD63+ cell surface marker, and optionally cytotoxic EVs having a CD82+ cell surface marker, from blood (incl. plasma or serum) obtained from the subject having a neurological disorder. Complementary binding partner is immobilised across most of the (e.g. the entire) surface area that blood (incl. plasma and serum) obtained from the subject will come into contact with during the depleting step. Expressed slightly differently, in use, all circulatory EVs present in blood (incl. plasma and serum) obtained from the subject will come into binding contact with a complementary binding partner that is capable of binding to a cytotoxic EV having a CD63+ cell surface marker, and optionally with a complementary binding partner that is capable of binding to a cytotoxic EV having a CD82+ cell surface marker. Thus, in a preferred embodiment, the complementary binding partner is immobilised on a surface that spans the flow path along which the blood obtained from the subject will travel and the flow rate of the blood is controlled to ensure optimal binding conditions are provided for immobilised complementary binding partner to bind (and sequester) all cytotoxic EVs present in the blood. In this way, blood (incl. plasma or serum) obtained from a subject and subsequently “cleaned” in accordance with the present invention is substantially free from cytotoxic EVs having a CD63+ cell surface marker, and optionally from cytotoxic EVs having a CD82+ cell surface marker. The above-described cleaning effect of the present invention may be controlled, for example, according to the volume of blood (incl. plasma and serum) obtained from the subject, or according to the volume of blood that one subjects to the depleting step. Moreover, since the depleting step removes any EV having a CD63+ cell surface marker, this step will inherently remove cytotoxic and healthy CD63+ EVs alike, subjects having a neurological disorder simply harbour a higher proportion of cytotoxic EVs. Thus, in the context of the present invention, the term “depleted” means that the number of circulatory EVs having a CD63+ cell surface marker is reduced by at least 50%, or by at least 70%, or by at least 90%, or by at least 95%. Alternatively, the term “depleted” means that the sub-population of circulatory EVs present having a CD63+ cell surface marker and present in the subject’s reservoir of circulatory EVs is reduced by at least 40%, or by at least 60%, or by at least 80%, or by at least 90%. The same approach applies when, optionally, also depleting EVs having a CD82+ cell surface marker, and in which case the term “depleted” preferably means that the number of EVs having a CD82+ cell surface marker present as circulatory EVs is depleted in numbers by at least 50%, or by at least 70%, or by at least 90%, or by at least 95%. Alternatively, the term “depleted” means that number of EVs having a CD82+ cell surface marker is depleted by at least 40%, or by at least 60%, or by at least 80%, or by at least 90%. When considering what form of blood should be administered to a subject having the neurological disorder in order to replace the blood that has been removed, it is preferred that the subject’s very own “cleaned” blood be returned. In one embodiment, the “cleaned” blood from a subject suffering from the same neurologic disorder is employed, optionally together with the subject’s very own cleaned blood (subject to blood group compatibility). In this regard, when the depleting step is performed on plasma or serum, one would typically reconstitute the “cleaned” plasma or serum into blood before then administering to the subject. Optionally, this may be supplemented with an infusion of CD63+ EVs (and optionally with an infusion of CD82+ EVs) obtained from a healthy subject. Alternatively and / or in addition to returning “cleaned” blood (either from the same subject or from a subject having the neurological disorder), one may administer replacement blood in the form of blood obtained from a healthy donor (subject to appropriate blood-group matching). Another aspect provides a blood preparation (e.g. selected from whole blood, serum and plasma) substantially free from a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, and wherein said blood preparation comprises a subpopulation of CD63-CD81+EVs; and optionally wherein said blood preparation is substantially free from a subpopulation of CD82+ EVs that are cytotoxic to motor neurons. The invention also provides a blood preparation described herein (e.g. according to claim 5), for use in a method of suppressing a neurological disorder associated with motor neuron degeneration in a subject having said disorder, wherein the subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory EVs, said method comprising: a. administering the blood preparation to said subject in which a sub-population of cytotoxic circulatory EVs having a CD63+ cell surface marker has been depleted from said reservoir of circulatory EVs with a complementary binding partner that forms a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged. Also provided is method of suppressing a disorder associated with motor neuron degeneration in a subject having disorder, wherein the subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory EVs, the method comprising a. administering the blood preparation described herein (e.g. of claim 5) to said subject in which a sub-population of cytotoxic circulatory EVs having a CD63+ cell surface marker has been depleted from said reservoir of circulatory EVs with a complementary binding partner that forms a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged. The present invention also provides an ex vivo blood supply substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker, and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker, for use in a method of suppressing a neurological disorder in a subject having said disorder, wherein the subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory EVs, said method comprising: a) administering the ex vivo blood supply to said subject, b) in which a sub-population of cytotoxic circulatory EVs having a CD63+ cell surface marker has been depleted from said reservoir of circulatory EVs (e.g. in a targeted manner, while retaining a sub-population of CD63-CD81+EVs); and optionally a sub-population of cytotoxic circulatory EVs having a CD82+ cell surface marker has been depleted from said reservoir of circulatory EVs. Reference to “blood” includes plasma and serum, and all embodiments and descriptions hereinbefore discussed carry the same meaning. To the extent that any “depleting” step is alluded to, this concerns an historic event completed prior to any contemplated performance of the recited therapeutic use (presented in EPC2000 “purpose-limited product” claim format). The language does not therefore include any active method step (of ”depleting") that is performed directly on a human or animal body and is compliant with Article 53(c) EPC 2000. In one embodiment, the ex vivo blood is provided in the form of a discrete blood sample. As will be discussed in more detail below, the ‘depletion’ is put into effect by a complementary binding partner (e.g. antibody) for CD63+, and optionally CD82+. Another aspect of the present invention provides a method of suppressing a neurological disorder in a subject having said disorder, wherein said subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory extracellular vesicles (EVs), said method comprising: a) depleting a sub-population of cytotoxic extracellular vesicles (EVs) having a CD63+ cell surface marker from said reservoir of circulatory EVs; and b) optionally depleting a sub-population of cytotoxic EVs having a CD82+ cell surface marker from said reservoir of circulatory EVs. Step a) here comprises depleting a sub-population of cytotoxic extracellular vesicles (EVs) having a CD63+ cell surface marker from said reservoir of circulatory EVs in a targeted manner, while retaining a subpopulation of CD63-CD81+ EVs. Reference to “suppression or suppressing a neurological disorder” in the context of the present invention means that, when a subject is treated in accordance with the present invention, the rate of disease progression (in terms of overall disease status) has been suppressed when compared with what one would expect to observe with an otherwise identical subject receiving no treatment. Neurological disorders are typically progressive disorders, such that it is appropriate to refer to the presently claimed medical intervention as that which “suppresses” the neurological disorder, for example by suppressing neurological disorder progression. Noting the progression of many neurological disorders may be defined by stages (e.g. early, mid, late simply as examples), suppressing a neurological disorder may involve improving a patient’s prognosis by increasing the time before progression to a higher (e.g. later) stage of the disorder, or preventing progression to such higher stage of the disorder. Through suppression of the disorder, symptoms of the neurological disorder may be prevented from worsening in the patient. Additionally or alternatively, symptoms of the neurological disorder may be reduced (vs pre-treatment as claimed). When administering blood to a subject in accordance with the present invention, this may be supplemented with an infusion of EVs from a healthy donor. The number of supplementary CD63+ EVs (from a healthy donor) may be equivalent to the number of cytotoxic EVs depleted from the blood (e.g. + / - 20%, + / - 10%, or + / - 5%). Reference to the ex vivo blood supply being substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker means that either: 1) in the case of an ex vivo blood supply obtained from a subject having a (or the same) neurological disorder and subsequently “cleaned” in accordance with the present invention, the number of circulatory EVs having a CD63+ cell surface marker is reduced by at least 50%, or by at least 70%, or by at least 90%, or by at least 95% vis-à-vis the corresponding number of circulatory EVs having a CD63+ cell surface marker prior to any depleting step, or vis-à-vis the number of circulatory EVs having a CD63+ cell surface marker present in a blood sample obtained from the subject having the neurological disorder prior to any depleting step (applying any necessary correction factor to ensure a like-for-like comparative assessment); or 2) in the case of an ex vivo blood supply obtained from a healthy blood supply and / or from a blood supply of otherwise unknown cytotoxicity status, the ex vivo blood supply demonstrates a neuron cytotoxicity score that is at most 50%, or at most 30%, at most 10%, and is preferably at most 5% of the neuron cytotoxicity score vis-a-vis the corresponding neuron cytotoxicity score for a blood sample obtained from the subject having the neurological disorder prior to any depleting step (applying any necessary correction factor to ensure a like-for-like comparative assessment). An assessment of “neuron cytotoxicity score” can be made using a “neuron toxicity assay” taught herein. A “neuron toxicity assay” may comprise: a. applying an amount of a CD63+ EVs described herein to a culture of neuron cells (preferably motor neuron cells); b. following application, assessing the percentage of neuron cell death in the culture; and c. calculating the neuron cytotoxicity score that corresponds to the percentage of neuron cell death. More particular details are provided in the Examples section (particularly examples 2 and 26). The same approach and interpretation applies when optionally, the ex vivo blood supply is also substantially free from EVs a CD82+ cell surface marker, though with reference to “CD63+” replaced by “CD82+”. In one embodiment, the ex vivo blood supply administered to the subject having a neurological disorder is distinct from blood obtained from the subject and simultaneously “cleaned” in accordance with the present invention. For example, the ex vivo blood supply is obtained from a healthy donor or from a different subject having a (or the) neurological disorder, and / or the ex vivo blood supply is infused with non- cytotoxic CD63+ EVs (and optionally CD82+ EVs). Also provided is an ex vivo method for depleting cytotoxic circulatory EVs from a blood sample (e.g. whole blood, plasma or serum) obtained from a subject having a neurological disorder associated with motor neuron degeneration, the subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from the blood sample by i. contacting said ex vivo blood sample with a CD63+ complementary binding partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged; and iii. removing bound complex from said blood; thereby providing a blood preparation that is substantially free from a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons; and b) optionally an ex vivo step of removing extracellular vesicles having a CD82+ cell surface marker from the blood sample thereby providing a blood preparation that is substantially free from a subpopulation of CD63+ EVs and from a subpopulation of CD82+ EVs that are cytotoxic to motor neurons. Step b) in the paragraph just above preferably comprises: i. contacting said ex vivo blood sample with a CD82+ complementary binding partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD82+ cell surface marker (e.g. wherein the CD82+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged); and iii. removing bound complex from said blood. The present invention also provides an ex vivo method for depleting cytotoxic circulatory EVs from a blood supply obtained from a subject having a neurological disorder, said method comprising: a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from the blood supply; and b) optionally an ex vivo step of removing extracellular vesicles having a CD82+ cell surface marker from said blood supply. Step a) here comprises an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from the blood sample in a targeted manner, while retaining a sub-population of CD63-CD81+ EVs. Said “ex vivo method for depleting cytotoxic circulatory EVs from a blood supply” may be said to provide an ex vivo blood supply substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker (and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker) that is suitable for use in a method of suppressing a neurological disorder in a subject having said disorder (e.g. wherein the subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory EVs). As mentioned above, reference to blood may refer to whole blood, plasma or serum obtained from the subject. Thus, the method described directly above can include depletion of said EVs from a blood sample, as described below. The invention provides an ex vivo method for depleting cytotoxic circulatory EVs from a blood sample (e.g. whole blood, plasma or serum) obtained from a subject having a neurological disorder, said method comprising: a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from the blood sample; and b) optionally an ex vivo step of removing extracellular vesicles having a CD82+ cell surface marker from said blood sample. Step a) here comprises an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from the blood sample in a targeted manner, while retaining a sub-population of CD63-CD81+ EVs. Said “ex vivo method for depleting cytotoxic circulatory EVs from a blood sample” may be said to provide an ex vivo blood sample substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker (and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker) that is suitable for use in a method of suppressing a neurological disorder in a subject having said disorder (e.g. wherein the subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory EVs). Aspects of the invention also extend to a blood preparation obtainable by “an ex vivo method for depleting cytotoxic circulatory EVs from a blood supply obtained from a subject having a neurological disorder” described herein. Similarly, aspects of the invention also extend to a blood preparation obtainable by “an ex vivo method for depleting cytotoxic circulatory EVs from a blood sample obtained from a subject having a neurological disorder” described herein. Where performed on a blood fraction (e.g. plasma), said plasma, depleted of depleting cytotoxic circulatory EVs, represents a blood preparation obtainable by said ex vivo method. Where a subsequent reconstitution step is undertaken (e.g. blood is then reconstituted by returning any previously removed blood cells, platelets, and clotting factors are returned to provide reconstituted blood that is ready to be returned to the subject undergoing treatment), then such reconstituted blood represents a blood preparation obtainable by said ex vivo method. Said blood preparation comprises (e.g. retains) a sub-population of CD63-CD81+EVs. In said blood preparation obtainable by said method(s), the number of circulatory EVs having a CD63+ cell surface marker may be reduced by at least 50%, or by at least 70%, or by at least 90%, or by at least 95% vis-à-vis the number of circulatory EVs having a CD63+ cell surface marker in a corresponding blood sample that has not been depleted of circulatory EVs methods described herein. By performing this ex vivo method, one is preparing an optimal ex vivo blood supply that has been depleted in terms of its cytotoxic EV burden, and one that is immediately available and ready to be administered to a subject having a neurological disorder, in particular to a subject who is undergoing treatment of said neurological disorder by a method of the present invention. In this regard, the volume of ex vivo blood supply prepared (i.e. “cleaned”) by this method can be matched with the volume of blood removed from the subject during treatment (by a method of the present invention) such that the net difference in terms of the “volume of blood” removed versus administered is substantially zero. On the other hand, however, the net difference in terms of the “cytotoxic EV burden” before treatment versus after treatment is a significant reduction in the cytotoxic EV burden and the number of circulatory cytotoxic EVs. For example, by comparing the neuron cytotoxicity score of a blood sample obtained from a subject having a neurological disorder before and after treatment by a method of the present invention, the subject’s effective cytotoxicity score is reduced by at least 50%, or by at most 70%, or by at most 90%, and is preferably by at least 95%. The ex vivo depletion step is performed by way of a complementary binding partner that preferentially (i.e. specifically) binds to the CD63+ cell surface marker. A corresponding CD82+ complementary binding partner that preferentially (i.e. specifically) binds to the CD82+ cell surface marker may also be included. Said binding partner is typically immobilised on a surface (e.g. Sepharose or a resin) and coats or covers as much of the surface as possible. The immobilised surface is then positioned relative to the proposed direction of flow of the subject’s blood sample such that the entirety of the blood sample (e.g. where plasma, the entirety of plasma contained in a blood sample after separation from the corpuscular elements) will flow across the surface and in a manner that provides for a maximum contact time between the complementary binding partner and the EVs present in the blood sample (e.g. plasma or serum). In this way, the blood supply (obtained from a subject having a neurological disorder) is depleted of CD63+ EVs and optionally of CD82+ EVs. As will be discussed in more depth in the detailed description, the present invention is predicated on a key finding in which the have identified that a sub-population of EVs expressing a CD63+ cell surface marker (and optionally a sub-population of EVs expressing a CD82+ cell surface marker) circulating in the blood creates a cytotoxicity profile. While aspects described above exploit this finding to deplete the cytotoxicity profile (toward the technical effect of suppressing disease / providing blood supply), the invention extends to aspects that exploit this finding to use the cytotoxicity profile as a readout / marker of disease state. A further aspect of the present invention provides a method for monitoring responsiveness to therapeutic intervention (e.g. gene or gene expression modifying therapy) in a subject having a neurological disorder associated with motor neuron degeneration, said method comprising: - determining the total number of extracellular vesicles having a CD63+ cell surface marker per unit volume of blood, and optionally the total number of extracellular vesicles having a CD82+ cell surface marker per unit volume of a blood obtained from said subject at a first time point during or after therapeutic intervention; - comparing said total number of extracellular vesicles per unit volume of blood sample with: o the total number of extracellular vesicles having a CD63+ cell surface marker per unit volume of blood in a reference sample, and optionally the total number of extracellular vesicles having a CD82+ cell surface marker per unit volume of blood in a reference sample, wherein the reference sample has been obtained from the same subject and by otherwise comparable means at a second time point, wherein the first time point occurs after the second time point; or o a reference value calculated for a cohort of subjects having the same neurological disorder as the subject being monitored for responsiveness, said reference value being calculated as a “mean” value (per subject) for the total number of extracellular vesicles having a CD63+ cell surface marker per unit volume of blood of a reference sample, and optionally for the total number of extracellular vesicles having a CD82+ cell surface marker per unit volume of blood of a reference sample, wherein the reference sample obtained from each subject of the cohort has been obtained by otherwise comparable means as the reference sample obtained from the monitored for responsiveness, and wherein each of the of the cohort having the neurological disorder has a neurological disease progression state that corresponds to the neurological disease progression state of the subject being monitored for responsiveness at the second time point; and - wherein a decrease in the total number of extracellular vesicles having a CD63+ cell surface marker, and optionally a decrease in the total number of extracellular vesicles having a CD82+ cell surface marker, is indicative the subject has responded positively to the therapeutic intervention, whereas an increase in the total number of extracellular vesicles having a CD63+ cell surface marker, and optionally an increase in the total number of extracellular vesicles having a CD82+ cell surface marker, is indicative the subject has not responded positively to the therapeutic intervention. There may be scenarios in which simply preventing an increase (e.g. as opposed to providing an actual decrease) in the total number of extracellular vesicles having a CD63+ cell surface marker (and optionally of extracellular vesicles having a CD82+ cell surface marker) is advantageous. For example, to prevent disease progression. Thus, reference to said “decrease” (indicative of response to therapy) may embrace scenarios in which the said total number (CD63+ EVs and optionally CD82+ EVs) is the same as per the reference sample / value. On the other hand, there may be scenarios in which providing an actual decrease in the total number of extracellular vesicles having a CD63+ cell surface marker (and optionally of extracellular vesicles having a CD82+ cell surface marker) is desired, e.g. as opposed to just preventing an increase. Thus, references to said “increase” (indicative of no response to therapy) may embrace scenarios in which said total number (CD63+ EVs and optionally CD82+ EVs) is the same as per the reference sample / value. In one embodiment, the neurological disease state of the reference cohort of subjects and the neurological disease progression state of subject being monitored has a neurological disease progression state nexus or equivalence. In other words when a reference sample or reference value is employed, a direct comparison is possible as the reference cohort is selected so as to ensure that it tracks the anticipated neurological disease progression state of a subject having the neurological disorder and who is non-responsive to the intervention. Accordingly, the output of this test for identifying potential responders intervention is considered robust and credible. Expressed slightly differently, in another embodiment, the cohort of subjects is selected to ensure that the period of time through which disease progression is monitored (and for which reference value data are therefore available) aligns with (i.e. maps on to), or at least subsumes, the same disease progression phase (over the same period of time) as is contemplated for the method for monitoring responsiveness to therapeutic intervention as the reference value (provided by the cohort) is relied on to track the neurological disease progression that one would expect to observe should the subject being monitored for responsiveness to therapeutic intervention fail to respond. Additionally or alternatively, the cohort of subjects may be selected to ensure none of the cohort has recently (e.g. within the last 6 or 12 months) received therapeutic intervention that would distort the responsiveness profile the subject would otherwise demonstrate in accordance with the present invention. The cohort of subjects is preferably selected to ensure none of the cohort has ever received therapeutic intervention that would distort the responsiveness profile the subject would otherwise demonstrate in accordance with the present invention. Indeed, before enrolling candidates into a clinical trial employing the responsiveness method of the present invention, one would typically accept only those candidates receiving (incl. historic) “gold standard” treatment regimens that have been screened for compatibility with the present invention and / or for which any minor distortion in read-out can be accommodated by way of an acknowledged and robust adjustment means. In one embodiment, the first time point (i.e. during or after completion of the therapeutic intervention) is selected at a time interval of at least 1 or 2 weeks, preferably at least 1 or 2 months, more preferably at least 6 or 12 months after the second time point (e.g. preferably prior to commencement of the therapeutic intervention). Alternatively, the second time point may be selected at a time point after commencement of the therapeutic intervention (e.g. up to 1-2 or 3-4 days into the treatment phase). In principle, the second time point may be selected at any time point prior to completion of the therapeutic intervention, whereas selection immediately before (or on the same day as) the start of therapeutic intervention is preferred as this will optimise the period of time during which a response the most significant response) will be observed. As mentioned in the background section, a broad list of neuromuscular disorders include one or more of Myasthenia Gravis (MG), Amyotrophic Lateral Sclerosis (ALS), familial ALS (fALS), sporadic ALS (sALS), fast-progression ALS, slow progression ALS, severe disease ALS, mild disease ALS, Charcot-Marie-Tooth (CMT), Multiple Sclerosis (MS), Muscular Dystrophy (MD), Myasthenia gravis (MG), Spinal-Bulbar Muscular Atrophy (SBMA) and Spinal Muscular Atrophy (SMA), Spinal Muscular Atrophy type II (SMAII), Spinal Muscular Atrophy type III / IV (SMAIII / IV), Parkinson’s disease (PD), Alzheimer’s disease (AD), Facioscapulohumeral muscular dystrophy (FSHD), Myasthenia Gravis (MG), Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS), Duchenne muscular dystrophy, Huntington disease, Frontotemporal Dementia (FTD), Parkinson’s Disease and the disease spectrum known as ALS-FTD (in which FTD clinically overlaps with ALS). Examples of neurological disorders associated with motor neuron degeneration include Amyotrophic Lateral Sclerosis (ALS), familial ALS (fALS), sporadic ALS (sALS), fast- progression ALS, slow-progression ALS, severe disease ALS, mild disease ALS, Spinal-Bulbar Muscular Atrophy (SBMA), Spinal Muscular Atrophy (SMA), Spinal Muscular Atrophy type II (SMAII), Spinal Muscular Atrophy type III / IV (SMAIII / IV), Progressive Muscular Atrophy (PMA), Primary Lateral Sclerosis (PLS), Parkinson’s Disease (PD) and the disease spectrum known as ALS-FTD (in which FTD clinically overlaps with ALS). Particularly preferred neurological disorders to be treated by the present invention include ALS and PD. Reference here to ALS can embrace any (e.g. all) of Amyotrophic Lateral Sclerosis (ALS), familial ALS (fALS), sporadic ALS (sALS), fast-progression ALS, slow-progression ALS, severe disease ALS, mild disease ALS, and ALS-FTD. The advantageous solution(s) discussed also allow for the provision of (e.g. corresponding) products. Another aspect of the invention provides a solid phase support comprising an immobilised capture means for removing cytotoxic EVs having a CD63+ cell surface marker, and optionally cytotoxic EVs a CD82+ cell surface marker, from a blood sample, the capture means comprising: a. a CD63+ complementary binding partner (e.g. an antibody or antigen binding fragment thereof described herein, such as of claim 19 or claim 20), wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons; b. and optionally a CD82+ complementary binding partner, wherein the CD82+ complementary binding partner selectively binds to the CD82+ EVs and, when so bound, the CD82+ EVs have diminished cytotoxic effect on motor neurons; optionally wherein the solid phase support is provided in the form of beads (e.g. magnetic beads) having a surface on which the capture means is immobilised; and / or optionally wherein the solid phase support is provided in the form of a column (e.g. exchange column) having a surface on which the capture means is immobilised. An aspect of the invention provides a solid phase support comprising an immobilised capture means for removing cytotoxic EVs having a CD63+ cell surface marker (e.g. in a targeted manner while retaining a sub-population of CD63-CD81+EVs), and optionally cytotoxic EVs having a CD82+ cell surface marker, from a blood sample, the capture means comprising: a. a complementary binding partner that preferentially (i.e. specifically) binds to the CD63+ cell surface marker present on an EV; b. and optionally binding partner that preferentially (i.e. specifically) binds to the CD82+ cell surface marker present on an EV. The solid phase support is provided in the form of beads (e.g. magnetic beads) having a surface on which the capture means is immobilised. Additionally or alternatively, the solid phase support may be provided in the form of a column (e.g. exchange column) having a surface on which the capture means is immobilised. Also provided is extracorporeal blood processing system adapted for depleting a sub- population of cytotoxic extracellular vesicles (EVs) having a CD63+ cell surface marker (e.g. in a targeted manner while a sub-population of CD63-CD81+EVs), and optionally cytotoxic EVs having a surface marker, from blood, the system comprising: a density-based separation device (e.g. a centrifuge or rotating belt) configured to separate the blood’s fractions into density-separated phases, including a distinct phase comprising plasma and / or a distinct phase comprising serum; and a fluid connection configured to fluidly connect said distinct phase comprising plasma and / or said distinct phase comprising serum to a solid phase support described herein (e.g. at claim 21), the solid phase support being provided within a flow path along which the plasma and / or serum will travel at a flow rate controlled to allow for the immobilised capture means to bind (and sequester) cytotoxic EVs present in the plasma, to provide cleaned plasma and / or cleaned serum substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker, and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker. The extracorporeal blood processing system may be an apheresis system (e.g. therefore preferably comprising all components of a conventional apheresis system). The extracorporeal blood processing system may further comprise means to combine the cleaned plasma and / or cleaned serum with the remaining density-separated phases, thereby providing a reconstituted blood supply substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker, and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker. Detailed description of the invention The present inventors have demonstrated that the composition of circulating EVs differs both qualitatively and quantitatively in terms of protein and lipid composition (see Figure 1) and miR composition (see Figure 2), on the one hand, between a healthy subject and a subject having a neurological disorder and, on the other hand, subjects having different neurological disorders. The former finding is notable in that it demonstrates the general difference between neurological disorder patients and healthy patients, demonstrating the invention provides for treating a broad spectrum of patients. The latter finding demonstrates yet further advantages (informing further embodiments) in that patients with particularly high levels of the circulating (cytotoxic) EVs represent particularly suitable patient populations. Whilst not wishing to be bound by any the present inventors believe that Extracellular Vesicles (EVs), which are secreted by almost all cells of the body, provide a role in communicating the biological status of the cell from which they have been secreted as they circulate throughout the cardiovascular system. A key finding by the inventors is that EVs isolated from serum from subjects having a neurological disorder (e.g. ALS such as sALS and fALS) are toxic to neuronal cells, notably to the CNS, in particular for motor neurons (e.g. iPSC motor neuron cultures) (see Figure 3). This has been demonstrated to be generally applicable to the various neurological disorders (e.g. extending also to Parkinson’s Disease) that are associated with motor neuron degeneration. Moreover, the inventors have successfully mapped this cytotoxicity profile to a sub- population of EVs expressing a CD63+cell surface marker, and optionally to a sub- population of EVs expressing a CD82+ cell surface marker. Consequently, when the CD63+ subpopulation of EVs are bound and neutralised (e.g. sequestered) by an appropriate complementary binding partners for CD63, the cytotoxic profile is significantly diminished, else removed. Similarly, when the CD63+ subpopulation of EVs is removed from a serum (incl. blood or plasma) sample taken from a subject having a neurological disorder, the cytotoxic profile is significantly diminished, else removed. That this breakthrough was observed with EVs isolated from serum is highly significant. This is because blood (including plasma and serum) provides an accurate capture of the “biological status” of the broader population of circulatory EVs present in a subject having a neurological disorder associated with motor neuron degeneration. In this regard it should be noted that EVs are able to cross the blood brain barrier and provide a means of intercellular signalling to and from the central nervous system (CNS). They contribute to many physiological processes in the CNS, including: neural growth and development; CNS inflammation; the neuroprotective response to oxidative stress; and maintaining brain vascular integrity and post synaptic retrograde signalling. EVs are also implicated in the pathological processes of neurodegeneration, and large numbers of studies have in recent years evaluated the role of EVs in neurodegenerative diseases, including ALS, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Huntington’s Disease and prion diseases. The present inventors have demonstrated that the CD63+ subpopulation of EVs is cytotoxic to motor neurons, and effect which can be suppressed by neutralising (e.g. said EVs with a binding partner such as an anti-CD63 antibody. Again, the importance of working with EVs isolated from blood (including plasma or serum) becomes immediately apparent when one considers the respective contribution that each type of specialist cell (e.g. muscle) makes to the total population of circulatory EVs (see Figures 4A, 4B & 4C). Referring to Figure 4A the proportion of EVs derived from muscle cells (identified by the muscle specific marker DAG1) is higher in ALS than in subjects having PD. This reflects the higher muscle contribution in ALS than in PD, but can’t be generalised. The total population of circulating EVs is greater in subjects having these disorders than in healthy subjects. However, when compared to the total population of circulating EVs (see Figure 4A), the maximum contribution of EVs derived from muscle cells amounts to no more than 10% (in NDD subjects having SBMA or SMA) and to no more than 20% (in NMD subjects having ALS). In healthy subjects, the total contribution of EVs derived from muscle cells amounts to ~5% of the total population of circulating EVs. Based on these findings, the present inventors have devised a method for suppressing a neurological disorder associated with motor neuron degeneration in a subject having said disorder. Said method involves administering to a subject having said disorder a therapeutically effective amount of a CD63+ complementary binding partner, wherein said binding partner forms a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject in a targeted manner, while a subpopulation of CD63-CD81+EVs remains substantially unbound. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the subject’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject A further method involves the depletion of a cytotoxic sub-population of EVs present in the subject’s blood (incl. the plasma or serum component thereof). The method is performed on an ex vivo blood supply (or on a plasma or serum component thereof) of the subject having the neurological disorder and comprises depleting a sub-population of EVs having a CD63+cell surface marker, and optionally a sub-population of EVs having a CD82+ cell surface marker from the blood supply (or the plasma or serum component thereof). By cleaning the subject’s blood supply in this way, the cytotoxic EV burden of the subject’s circulatory blood supply (incl. surrounding tissues) is reduced. Thereafter, the cleaned blood (incl. plasma or serum following reconstitution into blood) is ready to be returned to the or the subject may receive blood or CD63-positive EV-containing plasma from a healthy donor. Thus, by “depleting” the blood of one or more subpopulation(s) of cytotoxic EVs (characterised by the presence of a CD63+ cell surface marker and optionally characterised by the presence of a CD82+ cell surface marker), one is able to reduce the cytotoxic EV burden carried by a subject. This reduces the inherent neurological disorder stimulating effect caused by this sub-population of EVs, which in turn allows one to suppress the neurological disorder. The sub-population of EVs bearing a CD63+ cell surface marker, and optionally a CD82+ cell surface marker may be sequestered from blood (including the plasma or serum component thereof) by any conventional means. For example, one may employ any complementary binding partner that selectively binds to one or more of a CD63+, and optionally a CD82+ cell surface marker. In one embodiment, one may employ two or more different complementary binding partners, each of which selectively binds a CD63+ cell surface marker. Similarly, one may employ several different complementary binding partners, each of which selectively binds a CD63+, and optionally a CD82+ cell surface marker. A CD63+ complementary binding partner described herein preferably binds to an epitope with an extracellular domain of CD63 (where all reference to “CD63” herein most preferably means human CD63). For example, said extracellular domain may be extracellular domain 1 (ED1) that is also known as the short extracellular domain (ECL1); additionally or alternatively said extracellular domain may be extracellular domain 2 (ED1) that is also known as the long extracellular domain (ECL2), Details of ED1 (aka ECL1) and ED2 (aka ECL2) can be found in Oren, R. et al. (1990) Mol Cell Biol 10, 4007-15; and / or Levy, S. et al. (1991) J Biol Chem 266, 14597-602; and / or Hemler, M.E. (2005) Nat Rev Mol Cell Biol 6, 801-11. For example, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 27-53 of human CD63 (e.g. in other words, ED1). For example, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 27-53 of SEQ ID NO: 55. When referring to regions of CD63 with to amino acid numbers throughout this specification, the amino acid numbering reflects a CD63 that comprises the initial (e.g. the N-terminal or starting amino acid) methionine. Most preferably, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 27-51 of human CD63 (e.g. within ED1). For example, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 27-53 of SEQ ID NO: 55. A CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 32-53 of human CD63. For example, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 32-53 of SEQ ID NO: 55. For example, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 105-209 of human CD63 (e.g. in other words, ED2). For example, a CD63+ complementary binding partner described herein may bind to an epitope within an extracellular domain defined by amino acids 105-209 of SEQ ID NO: 55. It is particularly preferred that a CD63+ complementary binding partner described herein may bind to an epitope (of CD63) within the sequence defined by SEQ ID NO: 53. For example, a CD63+ complementary binding partner described herein may preferably bind to an epitope (of CD63) defined by SEQ ID NO: 53. In one embodiment, the complementary binding partner is an antibody (or the antigen binding portion thereof that comprises the CDR sequences thereof). For example, the antibody may be a single-chain antibody such as a nanobody, a single-chain variable fragment (scFvs), a single-chain Fab (scFab), minibody, a diabody; or indeed a single- chain antibody such as a camelid or shark antibody. An antigen binding portion described herein may (in addition to comprising the CDR sequences of the referenced ‘parent’ antibody) be said to retain a framework structure that provides for substantially the same binding activity as that which is achievable by the ‘parent’ molecule. In one embodiment, the complementary partner is an antibody mimetic, which are organic compounds that, like can specifically bind antigens, but that are not structurally related to antibodies. They are usually artificial peptides or proteins with a Mw of about 3 to 20 kDa. (cf. antibodies are ~150 kDa). Examples of antibody mimetics include affibody molecules, affilins, affimers (adhirons), affitins, alphabodies, anticalins, aptamers, avimers (aka avidity multimers), DARPins, fvnomers, gastrobodies, kunitz domain peptides, monobodies, nanoCLAMPs, opimers, repebodies, pronectins, centryrins, and obodies. In the case of a complementary binding partner that binds to a CD63+ cell surface marker on an EV, the term “selectively binds” means that the complementary binding partner binds a CD63+ cell surface marker on an EV with greater specificity and affinity than it binds to a non-CD63+ cell surface marker on an EV. In some embodiments said binding may be at least 10 times, 50 times, 100 times, 500 times, or 1000 times greater than the binding to the non-CD63+ cell surface marker on an EV. In the case of a complementary binding partner that binds to a CD63+ cell surface marker on an EV, the term “selectively binds” may mean that the complementary binding partner binds to extracellular vesicles having a CD63+ cell surface marker (e.g. “CD63+ EVs”) with greater specificity and affinity than it binds to extracellular vesicles lacking a CD63+ cell surface marker (e.g. “CD63- EVs”). In some embodiments said binding may be at least 10 times, 50 times, 100 times, 500 times, or 1000 times greater than the binding to the extracellular vesicles lacking a CD63+ cell surface marker. In the case of a complementary binding partner that binds to a CD63+ cell surface marker on an EV, the term “selectively binds” may mean that the complementary binding partner binds to extracellular vesicles having a CD63+ cell surface marker (e.g. “CD63+ EVs”) with greater specificity and affinity than it binds to extracellular vesicles (i) lacking a CD63+ cell surface marker and (ii) having a CD81+ cell surface marker (e.g. “CD63-CD81+ EVs”). In some embodiments said binding may be at least 10 times, 50 times, 100 times, 500 times, or 1000 times greater than the binding to the extracellular vesicles lacking a CD63+ cell surface marker and having a CD81+ cell surface marker. In the case of a complementary binding partner that binds to a CD82+ cell surface marker on an EV, the term selectively binds means that the complementary binding partner binds a CD82+ cell surface marker on an EV with greater specificity and affinity than it binds to a non-CD82+ cell surface marker on an EV. In some embodiments said binding may be at least 10 times, 50 times, 500 times, or 1000 times greater than the binding to the non-CD82+ cell surface marker on an EV. In the case of a complementary binding partner that binds to a CD82+ cell surface marker on an EV, the term “selectively binds” may mean that the complementary binding partner binds to extracellular vesicles having a CD82+ cell surface marker (e.g. “CD63+ EVs”) with greater specificity and affinity than it binds to extracellular vesicles lacking a CD63+ cell surface marker (e.g. “CD63- EVs”). In some embodiments said binding may be at least 10 times, 50 times, 100 times, 500 times, or 1000 times greater than the binding to the extracellular vesicles lacking a CD63+ cell surface marker. In the case of a complementary binding partner that binds to a CD82+ cell surface marker on an EV, the term “selectively binds” may mean that the complementary binding partner binds to extracellular vesicles having a CD82+ cell surface marker (e.g. “CD63+ EVs”) with greater specificity and affinity than it binds to extracellular vesicles (i) lacking a CD63+ cell surface marker and (ii) having a CD81+ cell surface marker (e.g. “CD63-CD81+ EVs”). In some embodiments said binding may be at least 10 times, 50 times, 100 times, 500 times, or 1000 times greater than the binding to the extracellular vesicles lacking a CD63+ cell surface marker and having a CD81+ cell surface marker. A complementary binding partner that preferentially (i.e. specifically) binds to the CD63+ cell surface marker present on an EV may preferably be an antibody (or the antigen binding portion thereof that comprises the CDR sequences thereof). For convenience, such antibody may be referred to as an anti-CD63 antibody (or antigen binding portion thereof that comprises the CDR sequences thereof). Another aspect (e.g. independent claim) provides an anti-CD63 antibody (or antigen binding portion thereof that comprises the CDR sequences thereof), e.g. that preferentially (i.e. specifically) binds to the CD63+ cell surface marker present on an EV. Embodiments of the anti-CD63 antibody (or antigen binding portion thereof that comprises the CDR sequences thereof) will now be described, as they apply to both methods described herein and the anti-CD63 antibody (or antigen binding portion thereof) per se. A most preferable anti-CD63 antibody (or antigen binding portion thereof) comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. CDR sequences described herein may embrace functional variants thereof. An antibody or antigen binding portion thereof comprising said sequences may be referred to as “1G8” herein. Additionally or alternatively, an antibody or antigen binding portion thereof described herein may be described by means of a variable heavy (VH) chain and a variable light (VL) chain thereof. For example, the antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 7, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 8, or a functional variant thereof. The antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, or 95% sequence identity to the amino acid sequence of SEQ ID NO: 7 (or a functional variant thereof); and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% sequence identity to the amino acid sequence of SEQ ID NO: 8 (or a functional variant thereof); with the proviso that the anti-CD63 antibody (or antigen binding portion thereof) comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. CDR sequences described herein may embrace functional variants thereof. Another preferable anti-CD63 antibody (or antigen binding portion thereof) comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, CDR sequences described herein may embrace functional variants thereof. An antibody or antigen binding portion thereof comprising said sequences may be referred to as “1G3” herein. Additionally or alternatively, an antibody or antigen binding portion thereof described herein may be described by means of a variable heavy (VH) chain and a variable light (VL) chain thereof. For example, the antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 17, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 18, or a functional variant thereof. The antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, or 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 (or a functional variant thereof); and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% sequence identity to the amino acid sequence of SEQ ID NO: 18 (or a functional variant thereof); with the proviso that the anti-CD63 antibody (or antigen binding portion thereof) comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively. CDR sequences described herein may embrace functional variants thereof. Another example of an anti-CD63 antibody (or antigen binding portion thereof) may comprise a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26, respectively. CDR sequences described herein may embrace functional variants thereof. An antibody or antigen binding portion thereof comprising said sequences may be referred to as “2G10” herein. Additionally or alternatively, an antibody or antigen binding portion thereof described herein may be described by means of a heavy (VH) chain and a variable light (VL) chain thereof. For example, the antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g.100%) sequence identity to the amino acid sequence of SEQ ID NO: 27, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g. 100%) sequence identity to the amino acid sequence of SEQ ID NO: 28, or a functional variant thereof. The antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, or 95% sequence identity to the amino acid sequence of SEQ ID NO: 27 (or a functional variant thereof); and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% sequence identity to the amino acid sequence of SEQ ID NO: 28 (or a functional variant thereof); with the proviso that the anti-CD63 antibody (or antigen binding portion thereof) comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26, respectively. CDR sequences described herein may embrace functional variants thereof. Another example of an anti-CD63 antibody (or antigen binding portion thereof) may comprise a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively. CDR sequences described herein may embrace functional variants thereof. An antibody or antigen binding portion thereof comprising said sequences may be referred to as “1E12” herein. Additionally or alternatively, an antibody or antigen binding portion thereof described herein may be described by means of a variable heavy (VH) chain and a variable light (VL) chain thereof. For example, the antibody or antigen portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g.100%) sequence identity to the amino acid sequence of SEQ ID NO: 37, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g. 100%) sequence identity to the amino acid sequence of SEQ ID NO: 38, or a functional variant thereof. The antibody or antigen binding portion thereof may comprise: (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, or 95% sequence identity to the amino acid sequence of SEQ ID NO: 37 (or a functional variant thereof); and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% sequence identity to the amino acid sequence of SEQ ID NO: 38 (or a functional variant thereof); with the proviso that the anti-CD63 antibody (or antigen binding portion thereof) comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively. CDR sequences described herein may embrace functional variants thereof. An antibody or antigen binding portion thereof may suitably be comprised within a pharmaceutical composition, for example within a formulation suitable for administration to a patient. The term “pharmaceutical composition” refers to a preparation that is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. Such composition can be sterile, and can comprise a pharmaceutically acceptable carrier, such as physiological saline. Suitable pharmaceutical compositions can comprise one or more of a buffer (e.g., acetate, phosphate or citrate buffer), a surfactant (e.g., polysorbate), a stabilizing agent (e.g., human albumin), a preservative (e.g., benzyl alcohol), and absorption promoter to enhance bioavailability, and / or other conventional solubilizing or dispersing agents. As mentioned above, functional variants of the described CDR sequences may be embraced. Where the term “functional variant” is used in the context of a CDR sequence, this preferably means that the CDR has at most 2, preferably at most 1 amino acid differences when compared to a corresponding (reference) CDR sequence, and when combined with the remaining 5 CDRs (or functional variants thereof) enables the antibody (or antigen binding portion that comprises said functional variant(s) to bind to the same target CD63 antigen as an antibody (or antigen binding portion thereof) comprising all six of the corresponding (reference) CDR sequences, and preferably to exhibit the same antigen cross-reactivity as the reference antibody (or lack thereof). A functional variant may be referred to as a “variant antibody”. In one embodiment a variant antibody (or antigen binding fragment thereof) comprises: a light chain CDR1 having at most 2 amino acid difference when compared to a corresponding reference CDR sequence; a light chain CDR2 having at most 2 amino acid difference when compared to a corresponding reference CDR sequence; a light chain CDR3 having at most 2 amino acid difference when compared to a corresponding reference CDR sequence; a heavy chain CDR1 having at most 2 amino acid difference when compared to a corresponding reference CDR sequence; a heavy chain CDR2 having at most 2 amino acid difference when compared to a corresponding reference CDR sequence; and a heavy chain CDR3 having at most 2 amino acid difference when compared to a corresponding reference CDR sequence; wherein the variant antibody binds to the same target antigen as the reference antibody, and preferably exhibits the same antigen cross-reactivity (or lack thereof) as the reference antibody. Preferably a variant antibody (or antigen binding fragment thereof) comprises: a light chain CDR1 having at most 1 amino acid difference when compared to a corresponding reference CDR sequence; a light chain CDR2 having at most 1 amino acid difference when compared to a corresponding reference CDR sequence; a light chain CDR3 having at most 1 amino acid difference when compared to a corresponding reference CDR sequence; a heavy chain CDR1 having at most 1 amino acid difference when compared to a corresponding reference CDR sequence; a heavy chain CDR2 having at most 1 amino acid difference when compared to a corresponding reference CDR sequence; and a heavy chain CDR3 having at most 1 amino acid difference when compared to a corresponding reference CDR sequence; wherein the variant antibody binds to the same target antigen as the reference antibody, and preferably exhibits the same antigen cross-reactivity (or lack thereof) as the reference antibody. The amino acid difference may be an amino acid substitution, insertion or deletion. In one embodiment the amino acid difference is a conservative amino acid substitution as described herein. In one embodiment a variant antibody has the same framework sequences as the exemplary antibodies described herein. In another embodiment the variant antibody may comprise a framework region having at most 2, preferably at most 1 amino acid difference (when compared to a corresponding reference framework sequence). Thus, each framework region may have at most 2, preferably at most 1 amino acid difference (when compared to a corresponding reference framework sequence). In one embodiment a variant antibody may have at most 5, 4 or 3 amino acid differences total in the framework regions thereof when compared to a corresponding reference antibody, with the proviso that there is at most 2 (preferably at most 1) amino acid differences per framework region. Preferably a variant antibody has at most 2 (more preferably at most 1) amino acid differences total in the framework regions thereof when compared to a corresponding reference antibody, with the proviso that there is at most 2 amino acid differences per framework region. More preferably a variant antibody has at most 2 (more preferably at most 1) amino acid differences total in the framework regions thereof when compared to a corresponding reference antibody, with the proviso that there is at most 1 amino acid difference per framework region. Thus, a variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) when compared to a heavy chain sequence herein; and the light chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) when compared to a light chain sequence herein; wherein the variant antibody binds to the same target antigen as the reference antibody, and preferably exhibits the same cross-reactivity (or lack thereof) as the reference antibody. Said variant heavy or light chains may be referred to as “functional equivalents” of the reference heavy or light chains. In one embodiment a variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region) when compared to a heavy chain sequence herein; and the light chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region) when compared to a light chain sequence herein; wherein the variant antibody binds to the same target antigen as the reference antibody, and preferably exhibits the same antigen cross-reactivity (or lack thereof) as the reference antibody. A preferred method of the invention employs aphaeresis in which the plasma fraction is first separated from the blood, followed by removal (from the plasma) of a cytotoxic subpopulation of EVs characterised by the presence of a CD63+ cell surface marker, and optionally a cytotoxic subpopulation of EVs characterised by the presence of a CD82+ cell surface marker. The blood is then reconstituted (i.e. the removed blood cells, platelets, and clotting factors are returned) at which point the reconstituted blood is ready to be returned to the subject undergoing treatment. One benefit offered by the present invention is that it is minimally invasive. One major advantage provided by the invention is that it has universal application across a wide spectrum of neurological disorders as hereinbefore noted. The following neurological disorders represent preferred disorders for treatment by the present invention, namely: SMA, SBMA, PMA, PLS, ALS, and PD. The following neurological disorders represent particularly preferred disorders for treatment by the present invention, namely: ALS, and Parkinson’s disease. Without wishing to be bound by any the present inventors believe that the observed cytotoxicity issue underlies many (potentially all) neurological disorders associated with motor neuron degeneration long before (potentially 10s of years) the disorder itself starts to manifest. Accordingly, removal (else management of) the systemic levels of this disease-causing / -promoting EV subpopulation in a pre-clinical setting will defer the onset of the disorder (potentially forever). This provides a huge opportunity to treat many children, juveniles and young adults, and at a stage before their reservoir (and abnormal cargo) of cytotoxic CD63+ EVs and optionally their reservoir (and abnormal cargo) of cytotoxic CD82+ EVs start to reach critical levels. The present invention also provides a method for monitoring responsiveness to therapeutic intervention in a subject having a neurological disorder associated with motor neuron degeneration. This method relies on monitoring the number of cytotoxic EVs (i.e. the subpopulation of CD63+ EVs and optionally the subpopulation of CD82+ EVs) within the context of the total population of circulatory EVs. One significant advantage provided by this method is that it has application across a broad spectrum of different neurological disorders. Reference to “EVs” throughout the present specification refers to a particular sub- population of EVs having a size distribution of 30-300 nm. These EVs may be isolated (e.g. to perform in vitro experiments) from total serum, total plasma or total saliva, whole blood, serum, plasma, urine, or cerebrospinal fluid, with total plasma being a preferred source. Importantly, EVs can also be isolated from an organ or an organoid or cell culture, e.g. from myoblasts, motor neurons, hepatocytes, cardiomyocytes and so forth, which can be obtained directly from an organ biopsy or indirectly created using induced pluripotent stem cell technology. The 30-300 nm sub-population of EVs can be isolated (e.g. from total serum, total plasma, total saliva, etc) by any conventional means. One convenient method relies on conventional centrifugation techniques, comprising a first spin at say 1,500-3,000 g (eg. ~2000 g) for say 20-40 mins (e.g.25-35 mins, or ~30 mins), followed by recovery of the supernatant, and then a second spin at 8,000-15,000 g (e.g.9,000-13,000 g, or ~10,000 g) for say >5-20 mins (e.g.8-15 mins, or ~10 mins). The first spin is intended to remove large molecules having a size greater than say 500 nm (e.g. greater than 300 nm, or greater than 250 nm), and the second spin is intended to remove small molecules having a size less than say 20 nm (e.g. less than 30 nm, or less than 40 nm). When preparing the EV preparation, an polymer reagent, such as polyethylene glycol (PEG), is typically added to the supernatant recovered from the first spin. This provides a density gradient for the second spin, through which the EV fraction travels prior to pelleting. Finally, the ERV fraction (pellet) is resuspended in a conventional buffer, such a phosphate buffer saline (PBS). Different methods can be used to extract EVs, including: differential ultracentrifugation, polymer-based precipitation, size exclusion chromatography, ultrafiltration, and / or immunoaffinity. Brief description of the drawings The present invention is described with reference to the appended non-limiting examples and the accompanying drawings, in which: Figure 1 illustrates protein composition of circulating EVs in neuromuscular and neurodegenerative conditions. Circulating EVs were extracted from serum sample of ALS (n=17), Parkinson’s (n=6), SBMA (n=4) and SMAIII / IV (n=5) patients. Samples were taken at early stage of the disease, when patients were suspected to have ALS (confirmed later in the study). Protein biomarker candidates were ranked according to their abundance in MuEVs isolated from ALS patients. Circulating EVs isolated from serum were then tested for the presence of these biomarker candidates following protein extraction, and the following biomarkers were quantified by dot-blot analysis: ERP57 (an endoplasmic reticulum protein with elevated levels in peripheral blood mononuclear cells of sporadic ALS patients), CCDC80 (a coiled coil domain containing protein 80) and NCL (nucleolin – a RNA-binding protein). One data point = one patient. ANOVA 1F and Tukey’s Multiple comparison test: *, P<0.05, **, P<0.01, ***, P<0.001 and ****, P<0.0001. Figure 2 illustrates miR composition of circulating EVs in neuromuscular and neurodegenerative conditions. Circulating EVs were extracted from serum sample of ALS (n=12), Parkinson’s (n=9), and Healthy (n=13) subjects. Samples were taken at early stage of the disease, when patients were suspected to have ALS (confirmed later in the study). miR were extracted from circulating EVs. MIR3663-5p was quantified by RT-qPCR with higher levels being detected in PD patients than in ALS One data point = one patient. ANOVA 1F and Tukey’s Multiple comparison test: *, **. Figure 3 illustrates MuEVs isolated from NDD patient serum show elevated levels of neuronal toxicity. Percentage cell death observed in iPSC MN cultures treated with MuEVs isolated from patient serum. Circulating MuEVs were extracted from serum sample of ALS (n=4), Parkinson’s (n=4), and Healthy (n=4) subjects. One data point = one patient. ANOVA 1F and Dunnett’s Multiple comparison test: **, P<0.01, ****, P<0.0001. Figure 4 illustrates the quantity of muscle-derived EVs (MuEVs) circulating in neuromuscular and neurodegenerative conditions. A - Circulating EVs derived from muscle cells (MuEVs) immunoprecipitated from serum sample of ALS (n=10), SBMA (n=5), and SMAIII / IV (n=5) subjects. The MuEVs were eluted from the beads. The total lipid of MuEVs was quantified and normalized by the total of lipid of circulating EVs to obtain the percentage of circulating MuEVs. One data point = one patient. ANOVA 1F and Dunnett’s Multiple comparison test: ***, P<0.001. B - Circulating EVs were extracted from serum sample of ALS (n=26), SBMA (n=26), and Healthy (n=9) subjects. DAG1 was quantified using DAG1 ELISA kit following the manufacturer’s instructions. One data point = one patient. Brown-Forsythe ANOVA test and unpaired t with Welch’s correction: *, P<0.05. C – Circulating MuEVs were extracted from serum samples of ALS (n=2), Parkinson’s (n=2), and Healthy (n=2) subjects. Proteins were extracted from circulating MuEVs and CD63 expression level was quantified by dot-blot. One data point = one patient. ANOVA 1F and Dunnett’s Multiple comparison test: *, P<0.05, Figure 5 illustrates the cytotoxic effect demonstrated by serum-derived EVs from ALS & PD patients on motor neurons. Percentage cell death observed in iPSC MN cultures treated with EVs isolated from patient serum. Circulating EVs were extracted from serum sample of ALS (n=11), Parkinson’s (n=7), and Healthy (n=13) subjects. One data point = one patient. ANOVA 1F and Dunnett’s Multiple comparison test: ***, P<0.001, ****, P<0.0001. Figure 6 illustrates a schematic of how to deplete the CD63+ subpopulation of cytotoxic EVs blood (incl. plasma or serum) of a subject having a neurological disorder. The subject’s ex vivo blood (incl. plasma or serum) is passed through a column containing beads coated with a complimentary binding partner to the CD63+ cell surface marker present on the target EVs. Thus, as the ex-vivo blood (incl. plasma or serum) passes over the beads, the cytotoxic EVs become attached to the beads by way of the complementary binding partner which binds to the CD63+ cell surface marker present on the cytotoxic EV. In contrast, CD63- (negative) EVs do not stick to the beads and therefore pass straight through the column as eluate. Washing buffer is then typically passed through the column to ensure that all unbound non-CD63+ material is flushed through the column as washing buffer eluate. Once the beads have been cleared of all unbound CD63- material, the bound cytotoxic EVs can be released, for example, by use of a conventional releasing buffer set to a pH value and at which pH value the existing chemical bond between the complimentary binding partner present on the bead and the CD63+ cell surface marker of the cytotoxic bond becomes neutralised, thereby allowing the cytotoxic EVs to be released from the beads and collected as part of the releasing buffer eluate. Figure 7 illustrates the cytotoxic effect of circulatory CD63+EVs isolated from the serum of ALS patients (n=3) and from healthy subjects (n=3). The cytotoxic sub-populations of CD63+EVs from each of these cohorts were removed as per the schematic illustration of Figure 6 giving rise to 3 different EV sub-populations for each cohort, which were then tested for cytotoxicity towards motor neurons. In this regard: “CD63-“ identifies serum that has been depleted of cytotoxic CD63+EVs; “CD63+” identifies “CD63-“ serum, to which the removed sub-population of cytotoxic CD63+EVs has been added back; “Total EVs” identifies untreated serum. For both the ALS (the three bars on the left) and healthy control, HC (the three bars on the right) groups of datapoints, the left-hand bar is for CD63-, the middle bar is for CD63+ and the right hand bar is for Total EVs. The CD63- EVs (serum) from ALS showed a significantly reduced toxicity while CD63+ and total EVs from ALS patients 39 to 46% motor neuron death 72h post-treatment. One data point = one patient. ANOVA 2F and Sidak’s Multiple comparison test: *, P<0.05, **, P<0.01. Figure 8 provides a view of commercial antibodies’ ability to link full CD63 positive vesicles. Muscle exosomes (MuEVs) were extracted from ALS patients using DAG1 antibody and were revealed with anti-CD63 TS63 or SAB4301607. The SAB4301607 anti-CD63 antibody is unable to detect all MuEVs. Pictures at 60x Figure 9: hCD63 structure. (A) Schematic of hCD63 transmembrane structure, showing extracellular loops which are the potential targets for immunization and antibody generation. (B) Clustal Omega sequence alignment of human and mouse CD63. Cytosolic regions are highlighted in yellow, transmembrane in blue and two extracellular exposed ECD are shown in green. Figure 10: Validation of clones that highly-produce antibodies specific to ECD1 peptides. (A) Validation of clones that highly-produce antibodies specific to ECD1 peptides. (B) Selection of 6 clones (highlighted in yellow) recognising human MuEVs (human CD63 positive vesicles). Figure 11 illustrates a Flow Activated Cell Sorting analysis to determine the quality of anti-CD63+ coated beads To confirm that the magnetic beads were properly paired with new anti-CD63+ antibody, they were incubated with an anti-mouse IgG1-Alexa Fluor 488. The negative control group consisted of beads that were not coupled with anti-CD63+ antibody. All of the beads demonstrated strong binding with mouse IgG1-Alexa Fluor 488. This indicates that the anti-CD63+ antibody has successfully attached to the beads. Figure 12 illustrates a Flow Activated Cell Sorting analysis to determine the capacity of anti-CD63+ coated beads to capture circulating MuEVs in serum EVs samples from the serum of both ALS and HC subjects were incubated with magnetic beads coated with anti-CD63+ antibodies. The EVs that were captured by the anti-CD63+ were then identified using the anti-DAG1 antibody and the secondary antibody anti-mouse IgG2a-Alexa fluor 488. The results showed that all three antibodies used were able to capture CD63+ EVs in either ALS or Healthy samples. Figure 13 illustrates the experimental plan of Example 26 and Figure 14 Three monoclonal antibodies (one commercially available mAB, and two proprietary mABs designated 1G3 & G8) specific to CD63+ cell surface marker were assessed for their ability to protect motor neuron survival by blocking the cytotoxic effect of EVs isolated from ALS patient serum. In parallel, one further mAB (specific to CD82+ cell surface marker) was assessed for its ability to protect motor neuron survival by blocking the cytotoxic effect of EVs isolated from ALS patient serum. “ALS exo” identifies motor neuron challenge with isolated EVs from ALS patent serum; “CD63 Co” identifies “ALS exo” challenge in the presence of a commercial CD63 mAB; “CD631G3” identifies “ALS exo” challenge in the presence of proprietary mAB 1G3; “CD63 G8” identifies “ALS exo” challenge in the presence of proprietary mAB G8; “CD82” identifies “ALS exo” challenge in the presence of a commercial CD82 mAB. Figure 14 illustrates the relative ability of 4 different mABs to protect motor neurons from the cytotoxic effect of EVs isolated from ALS patient serum Proprietary mAB “G8” provided the greatest protective effect on motor neuron survival, with proprietary mAB “1G3” providing the second best protective effect. Indeed, of the 4 different mABs assessed, only these 2 mABs provided a complete protective effect on motor neuron survival. Figure 15 - Human ALS EV and SOD1-derived murine EVs are toxic toward murine NSC-34 motor neurons. (A) Representative images of differentiated NCS-34 motor neurons. ALS vesicles extracted from patient serum were tested: French cohort (extract 1) and the Italian cohort (extract 2). Two doses were tested: 16 and 32 ug. (B) Patient ALS vesicles significantly decrease the MTT activity, suggesting a lower quantity of living cells. N=6 replicates / condition. Results of one-way ANOVA followed by Dunnett’s multiple comparisons test are shown. (C) Patient ALS vesicles significantly increase the release of LDH in the culture medium, suggesting the presence of damaged cells. N=7- 8 replicates / condition. Results of one-way ANOVA followed by Dunnett’s multiple comparisons test are shown. (D) Murine motor neurons treated with ALS vesicles from patients show a significant increase in PI confirming the presence of a damaged cell membrane. N= 4-5 replicates / condition. Results of one-way ANOVA followed by Dunnett’s multiple comparisons test are shown. (E) Representative images showing how the PI-positive cells were analysed. Each blue peak represents a nucleus (thus a cell), and a concomitant red peak shows a cell positive for PI. (F) Murine EVs from SOD1 mice are toxic to murine NCS-34 cells. N=4-8 replicates / condition. Results of one-way ANOVA followed by Dunnett’s multiple comparisons test are shown. Figure 16 - H&E analysis of TA and Gastrocnemius muscles. Left = Quantification of muscle fibres with central nuclei in the TA muscle. Right = Quantification of muscle fibres with central nuclei in the Gastrocnemius muscle. Values are mean ± SD, n=2-4 per group. Figure 17 - Neuromuscular junction analysis of TA and Gastrocnemius muscles. (A) Representative images of NMJ in EV, PBS and EV+Ab -treated TA muscles. (B) Quantification of NMJ innervation in the TA muscle. Values are mean ± SD, n=2-4 per group. This is shown as a stacked bar chart – for each bar with multiple segments, the bottom most (first) segment is for “innervated”, the second segment (directly above the bottom most segment) is for “partially denervated”, and the third segment (directed above the second segment) is for “denervated”); (C) Quantification of continuous and discontinuous NMJ in the TA muscle. Values are mean ± SD, n=2-4 per group. This is shown as a stacked bar chart – for each bar with multiple segments, the bottom most (first) segment is for “fragmented”, and the second segment (directly above the bottom most segment) is for “continuous”; (D) Quantification of NMJ innervation in the Gastrocnemius muscle. *, mean significantly different from PBS with P<0.05. Values are mean ± SD, n=2-4 per group. This is shown as a stacked bar chart – for each bar with multiple segments, the bottom most (first) segment is for “innervated”, the second segment (directly above the bottom most segment) is for “partially denervated”, and the third segment (directed above the second segment) is for “denervated”); (E) Quantification of continuous and discontinuous NMJ in the Gastrocnemius muscle. Values are mean ± SD, n=2-4 per group. This is shown as a stacked bar chart – for each bar with multiple segments, the bottom most (first) segment is for “fragmented”, and the second segment (directly above the bottom most segment) is for “continuous”. Figure 18 - EVs from ALS serum are toxic to MNs. Percentage of human iPSC MN death when treated with exosomes from ALS, PD, AD, and Healthy controls, in vitro (n=6, n=3, n=3, n=9 respectively). Each dot represents one individual, and each individual has been repeated 3 times. Statistical analysis was performed using Dunnett's multiple comparisons test, with the healthy control (HC) as the reference group. Significance levels are denoted as follows: **** (p < 0.0001), ** (p < 0.01), ns (not significant). Figure 19 - CD63-positive ALS vesicles are toxic toward MNs. (A) Western Blot probed with CD63. CD63 is enriched in immunoprecipitated EVs. The negative fractions are negative for CD63. (B) Percentage of iPSC MN death when treated with IP exosomes and comparing effects of CD63-positive, CD63-negative, and Total exosome samples. The statistical analysis used Sidak's multiple comparisons tests to compare CD63-negative, CD63-positive, and Total EVs within amyotrophic lateral sclerosis (ALS), healthy control (HC) and Parkinson’s Disease (PD) groups. Significance levels are denoted as follows: ** (p < 0.01), * (p < 0.05), ns (not significant). For each of the ALS (the three bars on the left), the HC (the three bars in the middle) and the PD (the three bars on the right) groups of datapoints, the left-hand bar is for “negative”, the middle bar is for “positive” and the right hand bar is for “Total EVs”. Figure 20 - Western Blot probed with CD81. CD81 detected in CD63-positive for HC. No detection in other fractions. Figure 21 - SOD1 murine serum-derived EVs characterization. Top panel: NTA results. Bottom panel: protein concentration. Figure 22 - Validation of the neuroprotective effect of murine anti-murine CD63 to murine MN. (A) Significant decrease in LDH release when SOD1 EVs are treated with Ab. N=4-8 / group. Y-axis shows percentage change in LDH release relative to untreated controls. Results of one-way ANOVA followed by Dunnett’s multiple comparisons test are shown. Values are mean ± SD. (B) Significant increase in MTT when SOD1 EV are treated with Ab. N=4-8 / group. Results of one-way ANOVA followed by Dunnett’s multiple comparisons test are shown. Values are mean ± SD. Figure 23 - Percentage of weight gain over the time course of treatment. N=5 mice per group. All male. *, means significantly different from SOD1 untreated with P<0.05. Values are Mean ± SD. Results of two- ANOVA followed by Tukey’s multiple comparisons test are shown. Examples Materials and Methods Serum samples from patients Blood samples were collected using silica vacutainers, then gently inverted 8-10 times. After 2h of incubation on ice to allow clotting, samples were centrifugated at 1,500g for 15mn. Aliquots of 100ml of serum were transferred to cryovials and stored at -80°C. EV extraction from serum samples 150 to 200 microliters of serum from ALS, SBMA, SMA, and healthy human subjects (n=10 of each) were thawed on ice and centrifuged at 2,000g for 30 min at 4°C. The supernatant was transferred to a clean tube on ice.30 microliters (or 10 microliters for 50 microliters of serum) of Total Exosome Isolation (from serum) Life Technologies® was added to the supernatant, and the sample vortexed. The sample was incubated on ice for 30 min, and then centrifuged at 10,000g for 10 min at room temperature. The supernatant was removed carefully, and the pellets were re-suspended in 50 microliters of clean PBS and stored at -80⁰C until processed for mass spectrometry analysis. Protein extraction from exosomes EV samples were precleared before dot blot analysis. Briefly 22.5μl of Dynabeads Protein A / G (Invitrogen) were washed twice with TBST 0.05% Tween 20, and were then added to each EV samples. After 2 h of incubation at room temperature on a handshaker, the supernatants depleted in IgG were collected. The EVs from the clear supernatant were then reprecipitated using the isolation kit (two precipitations using 1 / 3 of the kit). The clear EV pellets were resuspended in 27μl of urea 8M-SDS 2%-protease inhibitor cocktail RIPA 1x (1:1). Samples were then incubated 30 min on ice before centrifugation at 14,000g for 10 min at 4°C. The supernatants containing proteins were collected for dot blot analysis. Nupage sample buffer (Invitrogen ®) with reducing agent (Invitrogen®) were added to protein extract. EV protein extracts were heated at 70°C for 10 min. PVDF membrane was reactivated 2 min in methanol and washed with water before to be set up between a sponge and a glass frame from the Protein Detector™ Microarray Dot Blot system.1μl of was loaded on the membrane and let to dry. The membrane was reactivated, and loading was assessed with ponceau coloration (Ponceau S solution Sigma). Membranes were then blocked in 5% milk TBST1X overnight at 4°C and probed with either ERP57 (1:1000; rabbit), CCDC80 (1:1000; rabbit), NCL (1:1000; rabbit). All primary antibodies were coupled with biotin using Zenon TM BiotinXX rabbit IgG labelling kit or Zenon TM BiotinXX mouse IgG1 labeling kit (LifeTechnologies™). Briefly 5μl of labelling reagent per μg of antibody were incubated for 5 min at room temperature, followed by 5μl of blocking reagent per μg antibody. The biotin-coupled antibody was then probed on the membrane in milk 5% TBST for 45 min at room temperature. Membranes were washed thrice with TBST for 5 min before probing with streptavidine-HRP (1:250, Invitrogen®) for 45 min at room temperature. Membranes were incubated in the dark and revealed with ECL Prime Western Blotting Detection Reagents (Amersham cytiva) or SuperSignal TM West Pico PLUS Chemiluminescent Substrate (Thermoscientific TM). Chemiluminescent signal was captured using UVP chemidoc It2 Imager and pictures analysed with ImageJ. miRNA extraction from exosomes The exosome pellets were re-suspended with 1ml of trizol. After adding 0.2 mL of chloroform, the samples were incubated for 3 minutes at room temperature, then centrifugated for 15 minutes at 12,0003 g at 4°C. The aqueous upper phase was then mixed with 1 / 3 volume of 100% ethanol and mixed thoroughly. The samples were then placed on place a filter cartridge into a collection tube of total RNA and protein isolation kit from Invitrogen™ (LifeTechnologies™). The miRNA extraction was performed following the manufacturer’s instruction. RNA quantity was determined using nanodrop, each in accordance with the manufacturer’s instructions. Real Time qRT-PCR for miRNA cDNAs were synthesized from small RNA using a TaqMan Advanced miRNA cDNA synthesis Kit which involves four steps such as poly(A) tailing, ligation, reverse transcription reaction comes with universal RT primers and miR-Amp reaction. cDNA was amplified using Taqman Fast Advanced Master Mix and Taqman Advanced miRNA assay (Applied Biosystems) for hsa-miR-3663-5p ID479699_mir. Quantification of DAG1 in circulating EVs – see Example 3 & Figure 4B DAG1 expression levels in circulating samples were determined using Human Dystroglycan 1 (Dystrophin-Associated Glycoprotein 1) (DAG1) ELISA Kit (Cusabio®) following the manufacturer instruction. Quantification of circulating MuEVs Lipid assay to quantify the EVs. Total EVs were quantified using total lipid assay. Briefly, 50 μl of exosome resuspension in PBS were used for lipid assay. The standard curve was prepared from a stock solution at a concentration 2 mg / ml olive oil in chloroform and serial dilutions were realized. Sample tubes were also coated and pre- treated with chloroform. All Eppendorf Tubes™ were incubated at 90°C for 20 min to let the chloroform evaporate. Fifty μl of samples or PBS as well as 250 μl of 96-98% sulfuric acid per replicate respectively were then added to each tube. After 40 min of incubation at 90°C, 110μl of 0.2 mg / ml phosphovanilin in 17% phosphoric acid was added to each tube. Three hundred and thirty μl of samples or standards were loaded on 96 well plate. Absorbance was read at 540 nm on Epoch microplate Spectrophotometer (Biotek Instruments). MuEVs immunoprecipitation. Ten μg of dystroglycan DAG1 antibody were coupled to 1 mg of M-270 epoxy magnetic beads following the manufacturer instruction. EVs extracted from 200 μl of serum were incubated with 2mg of coupled beads overnight with end over end rotation at 4 °C. The beads were captured using a magnet and the supernatant was discarded. The beads were washed three with pbs. The MuEVs were eluted from the beads by incubating with 0.2M glycine, pH 2.5, for a minimum of 1 hour at 4°C. The pH of the eluate was equilibrated by adding 1M Tris-HCL, pH 7.5. The quantity of lipid from the eluted MuEVs was quantified as described above. The proportion of circulating MuEVs was obtained from the ratio of MuEVs lipid versus Total EVs lipid. CD63+ level in MuEVs. MuEVs were extracted by immunoprecipitation as described above. The protein from the MuEVs were extracted as described in section “Protein extraction from exosomes” and the CD63 expression level was determined by dot-blot as described in “Protein extraction from exosomes” using an anti-CD63 clone TS63 biotinylated using Zenon TM BiotinXX use IgG1 labelling kit (LifeTechnologies™) and streptavidin HRP. Testing the toxicity of EVs on iPSC motor neurons - see Example 4 & Figure 5 Human iPSC-derived motor neuron progenitors were differentiated into motor neurons as previously described (Le Gall et al., 2022, Le Gall et al, 2020, Anakor et al.2022). Briefly, µ-Slide 8-well tissue culture treated (Ibidi®) were first coated with 20 µg.mL−1poly-L-ornithine then with 5µg.mL−1laminin. Human neuron progenitors were then plated and maintained in N2B27 media containing Neurobasal, DMEM / F12-Glutamax, N2 (1X), B27 (1X), Pen / Strep 1%, 0.25 mM 2-mercaptoethanol and 0.1% Glutamax®and supplemented with 100 nM Rock Inhibitor (RI), 100 nM Retinoic Acid (RA), 500 nM SAG, 100 nM DAPT, 10 ng.mL−1BDNF and 2.5 µg.mL−1laminin. Two days later, the media was renewed with N2B27 media containing 200 nM RA, 1 µM SAG, 200 nM DAPT, 20 ng.mL−1BDNF. After 3 days, the culture media was renewed with N2B27 media containing 200 nM RA, 200 nM DAPT, 20 ng.mL−1BDNF and 20 ng.mL−1GDNF. Two days later, the media was renewed with N2B27 media containing 20 ngmL−1BDNF and 20 ng.mL−1GDNF. At this point, progenitors were fully differentiated into motor neurons and ready for functional studies involving extracellular vesicles. EVs were then added to the culture medium for 72h. Extraction of CD63+ and CD63- EVs – see Example 5 & Figure 7 Ten μg of anti-CD63+ antibody were coupled to 1 mg of M-270 epoxy magnetic beads following the manufacturer’s instruction. EVs extracted from 200 μl of serum were incubated with 2mg of coupled beads overnight with end over end rotation at 4 °C. The beads were captured using a magnet and the supernatant was discarded. The beads were washed three with PBS. The CD63+EVs were eluted from the beads by incubating with 0.2M glycine, pH 2.5, for a minimum of 1 hour at 4°C. The pH of the eluate was equilibrated by adding 1M Tris-HCL, pH 7.5. EVs depleted in CD63+ EVs and EVs enriched in CD63+ EVs were then applied to human iPC-derived motor neurons to test their neurotoxicity. Proprietary antibodies capture MuEVs from serum – see Example 23 & Figures 11-12 The newly generated anti-CD63+ antibodies were coupled to 1 mg of M-270 epoxy magnetic beads following the manufacturer’s instruction. EVs were extracted from 200 μl of serum and were incubated with magnetic beads as described above. The EVs captured onto the CD63-beads were then incubated with DAG-1 clone 6F4 (DSHB) antibody for 2h at room temperature. beads were washed three with PBS and incubated with anti-mouse IgG2a-Alexa fluor 488 for 1 hr at room temperature. After 3 PBS washes, beads were analysed by flow cytometry using BD FACSAria™ III. Briefly, to determine the acquisition window, beads conjugated CD63 antibodies (all anti-CD63 used were IgG1) and incubated with anti-mouse IgG2a-Alexa fluor were used as negative controls, beads conjugated CD63 antibodies and incubated with anti-mouse IgG1-Alexa fluor were used as positive controls. Immunoblockade of EVs – see Example 26 & Figures 13-14 EVs were extracted from serum as described above. EVs were then incubated for 1 hr at room temperature with an anti-CD63+ antibody (1 commercial clone TS63 and 2 proprietary antibodies) or an anti-CD82+ antibody at a ratio of 1:1 protein. EVs were then washed to remove the excess of antibodies. Coated EVs were then applied to differentiated iPSC-motor neurons for 72h. The commercial clone TS63 is available from Invitrogen (ThermoFisher Scientific), e.g. under Catalog # 10628D. Example 1 – biomarker and miR composition of circulating EVs in neuromuscular disorder (NMD) patients (e.g. SBMA & SMA patients) and neurodegenerative (NDD) patients (e.g. ALS & PD patients) To investigate if there are differences in the circulating extracellular vesicles (EVs) extracted from the serum of patients with different conditions (ALS, SMA, SBMA, and PD) we measured the expression level of various protein candidates. Specifically, we focused on proteins associated with the endoplasmic reticulum and involved in protein homeostasis (ERP57 and CCDC80), proteins implicated in amyloid and tau pathology (NCL), and proteins involved in RNA homeostasis. We found that these proteins were differentially expressed in EVs when compared across different conditions (see Figure 1). For example, ERP57 was enriched in ALS and SMA EVs (Figure 1A), while CCDC80 and NCL were enriched in ALS, PD and SMA EVs (Figure 1B and C). Additionally, we investigated the miRNA profile of EVs and found that 14 miRNA candidates were differentially expressed in ALS and healthy EVs in vitro. We also observed that one candidate, MiR-3663, was differentially expressed between PD and ALS (Figure 2). In conclusion, our findings suggest that EVs originating from different conditions have different cargo compositions and may have varying effects on recipient cells. Example 2 – serum MuEVs from NDD ALS & PD) patients show elevated levels of neuronal toxicity relative to subjects Muscle cell origin extracellular EVs (MuEVs), a subpopulation of extracellular vesicles (EVs), were extracted from serum from patients with amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) and compared with MuEVs obtained from healthy patients to investigate any potential harmful effects on motor neurons. ALS and PD MuEVs caused a significant death rate of motor neurons, which was 35% and 14% respectively (Figure 3). These results suggest that circulating MuEVs from ALS and PD patients carry toxic substances that can harm motor neurons. Example 3 – analysing the total population of circulating EVs present in NMD and NDD patients to determine what proportion has muscle cell origin The total population of circulating EVs (isolated from serum) were analysed from three different patient cohorts (ALS, SBMA & SMA) to ascertain what proportion of these EVs have a muscle cell origin. The ALS cohort of patients demonstrated the highest proportion of MuEVs (4-11%) present in circulating EVs, whereas, the SMBA & SMA cohorts demonstrated a much lower proportion of MuEVs (1-5%) - see Fig.4A. DAG-1 is regarded as a reliable biomarker for detecting the presence of MuEVs, and these data demonstrate that there is a higher proportion of MuEVs present in the total circulating EVs of a patient suffering from ALS than there is in a patient suffering from SBMA (or indeed in a heathy patient control) - see Fig.4B. Total circulating MuEVs were extracted in three different patient cohorts (ALS, PD & heathy patient control) and quantified by measuring the expression level of CD63+. The results indicate a higher proportion of MuEVs present in the total circulating EVs of a patient suffering from ALS compared to a patient suffering from PD or a healthy control - as shown in Figure 4C. Example 4 – Serum-derived EVs from ALS & PD patients demonstrate a cytotoxic effect on motor neurons Afterward, we investigated the impact of extracellular vesicles (EVs) from various conditions (ALS, and PD) on healthy human cortico-spinal motor neurons derived from iPSCs. Our findings revealed that EVs derived from ALS patients caused motor neuron cell death at a rate of approximately 44% (see Figure 5). Similarly, EVs from PD patients also led to motor neuron cell death, although to a lesser extent, with a rate of approximately 20% (Figure 5). These results suggest that EVs from ALS and PD conditions carry toxic substances that can motor neurons, while EVs from healthy donors do not affect motor neurons. Example 5 – Serum-derived EVs from ALS patients demonstrate a reduced cytotoxic effect on motor neurons following depletion of the CD63+ sub- population of EVs The first step involved extracting the total population of circulating extracellular vesicles (EVs) from serum of both ALS and HC subjects. The EVs were incubated with magnetic beads coated with anti-CD63+ antibodies, and then the CD63+ EVs eluted from the beads (see Figure 6). Both CD63+ and CD63- fractions of the EVs were kept and then applied to healthy human cortico-spinal motor neurons derived from iPSCs. The results showed that there was a significant reduction in toxicity when the CD63+ subpopulation of EVs were depleted (see Figure 7). Moreover, the CD63+ sub-population of EVs were found to have a toxic effect comparable to that observed with total EVs suggesting toxicity is associated with the CD63+ sub-population of EVs. Example 6 - Human ALS EV are toxic toward murine NSC-34 motor neurons A CD63+ sub-population of EVs were extracted from pooled serum samples from ALS patients according to methods described above. It was then tested whether human EVs have an effect on murine NSC-34 motor neuron survival. NSC-34 cells were converted to motor neuron-like cells according to methods described in Nango et al (Cells 2020, 9(7), 1741) with suitable adaptation. Initially, 5,000 cells were plated in a 96-well plate. Cells were treated with 10 μM retinoic acid (RA) similarly to the PGE2 treatment described in said Nango et al, abd they survived and exhibited projection (see Figure 15A), but they continued to proliferate, dividing once every 24 hours. Based on these observations, we plated 750 cells per well in medium containing 10uM RA and treated the cells with 16 and 32 ug of EVs to compensate for their proliferation rate. NSC-34 cells were treated with 16 and 32 μg of extracellular vesicles (EVs) for 72 hours. We employed three different methods to measure cell death: 1. MTT Assay: This method assesses the number of viable cells by measuring metabolic activity, specifically through (P)H-dependent cellular oxidoreductase enzyme activity. 2. Lactate Dehydrogenase (LDH) Release: The release of LDH into the cell culture medium indicates damage to the plasma membrane and serves as a marker of cell death. 3. Propidium Iodide (PI) Absorption: The absorption of PI by cells indicates membrane damage and is also a marker of cell death. We observed a significant decrease in MTT activity in treated cells with human EV extracts 1 and 2 (Figure 15B), alongside a significant increase in LDH (Figure 1C) release and PI absorption (Figure 15D-E). These data suggest that human extracellular vesicles (EVs) can be toxic to murine motor neurons. Additionally, we found that the toxicity of SOD1 murine EVs to NCS-34 cells is greater than that of human EVs, indicating a species specificity in toxicity (Figure 15F). Example 7 – Effects of human CD63+ EVs from ALS patients in vivo (mouse) and suppression of their toxicity with anti-CD63 antibody Mice were administered with CD63+ EVs extracted from ALS patient samples (“EVs”) according to methods described above. To investigate the ability of anti-CD63 antibody to suppress the cytotoxic effect (in vivo) of such EVs, another cohort of mice were instead injected with such EVs that were first coated with (e.g. neutralised) an anti-CD63 antibody (“EV+Ab”), in this case clone 1G8 described below. A control cohort was injected with phosphate buffered saline buffer (“PBS”) only. The injections of EV (n=4), or PBS (n=4) occurred weekly for 4 months, and EV+Ab (n=2) weekly for 3 months. Hematoxylin and Eosin (H&E) histological analysis was then performed on the Tibialis anterior (TA) muscle and gastrocnemius muscle to investigate centralised nuclei, which was increased in the EV injected cohort (vs PBS), whereas such centralised nuclei were suppressed by anti-CD63 antibody (EV+Ab) – see Figure 16. In addition, neuromuscular junction (NMJ) analysis of TA and Gastrocnemius muscles was performed on these mice at 4 months. The neuromuscular junction shape and innervation status were then assessed. A lower percentage of innervated NMJ combined with a greater percentage of denervated NMJ (Figure 17A and B) and fragmented NMJ (Figure 17C) was observed in the EV-treated TA muscles. A significantly lower percentage of fibres and a significantly greater percentage of partially denervated fibres were observed in the EV-treated gastrocnemius muscle (Figure 17D). This was accompanied by a greater percentage of fragmented NMJ in the gastrocnemius muscle (Figure 17E). No denervated NMJ and no increase in fragmented NMJ was observed in the EV+Ab treated group in both TA and Gastrocnemius muscles. Example 8 – The cytotoxic effect of ALS CD63+ EVs is also seen for PD CD63+ EVs in vitro This examples investigated the effects of serum-derived exosomes from ALS, Parkinson’s Disease (PD), and Alzheimer’s Disease (AD) patients, and healthy control human subjects (HCs) on human iPSC-derived MNs. ALS EVs significantly increased MN death, with an increase was also observed in PD- EV treated MNs. No significant effect was seen with AD exosomes. See Figure 18. Noting AD is not typically associated with motor neuron degeneration (whereas both AD and PD are), this demonstrates the ability of the claimed invention to suppress neurological disorders that are associated with motor neuron degeneration. CD63 was observed to be enriched in immunoprecipitated EVs and was not detected in the negative fractions, suggesting that the IP has extracted all CD63-positive EVs (Figure 19A). MNs treated with ALS CD63-positive exosomes showed a significant increase in cell death compared to the CD63-negative samples and showed no difference compared to the total exosome fraction (Figure 19B). The MNs treated with the exosomes from HCs showed no significant difference in cell death when treated with CD63-positive or -negative. The small toxic effect of PD EV was not observed in the CD63-positive and negative fractions. Example 9 – CD81 is not detected in ALS or PD EVs Co-expression of CD81 and CD63 was observed in healthy control subject (HC) EVs, indicating a classical exosomal nature. The isolation method effectively captures exosomes (Figure 20). The absence of CD81 in ALS and PD EVs might suggest a difference in the exosomal population compared to HCs. This could imply that ALS and PD exosomes either do not express CD81 at detectable levels or that their exosomal population may have distinct characteristics from those of HCs. Example 10 – Murine anti- mouse suppresses the toxicity of SOD1 EVs in vitro The SOD1 mouse (e.g. B6SJL-Tg(SOD1*G93A)1Gur / J. e.g. Strain #:002726 of The Jackson Laboratory) has been used for studying neuromuscular disorders such as Amyotrophic Lateral Sclerosis. CD63+ EVs were extracted from the serum of SOD1 mice. Murine SOD Murine SOD1 serum derived EVs were characterised using nanoparticle tracking analysis (NTA) and bicinchoninic assay (BCA) – see Figure 21. These EVs that were extracted from SOD1 mice were tested for cytotoxicity against NSC-34 cells, and whether cytotoxicity could be suppresses by anti-CD63 antibody. A number of anti-CD63 were screened as potential candidates for binding murine SOD1 EVs (via FACS based analysis), and the sequences of the chosen candidate Ab (a mouse monoclonal Ab) are shown in SEQ ID NOs: 41-52 which can be inserted into a suitable plasmid and transfected into HEK293 cells to produce the antibody. NSC-34 cells are a murine neuroblastoma x spinal cord cell line that are widely used to model murine motor neurons. These cells were seeded into 96-well plates at 750 cells / well and differentiated into mature murine motor neurons. The cells were then incubated for 72 hours at 37oC, 5% CO2, with 32ug of murine SOD1 EVs. The cells were then analysed for viability using the MTT assay and for cytotoxicity using the lactose dehydrogenase (LDH) assay. Whereas LDH release was observed to be increased by more than 100% in NCS34 treated with SOD1 EVs compared to untreated controls, this was largely abolished with antibody treatment (Figure 22A). This was accompanied by a significant rescue of MTT metabolic activity (Figure 22B). Example 11 - Administration anti-CD63 antibody to SOD1 mice As shown in Example 10, SOD1 mice harbour cytotoxic EVs that can be suppressed by anti-CD63 antibody. The same anti-CD63 antibody (a mouse monoclonal Ab) was then administered directly to SOD1 mice. The concentration of circulating CD63 in SOD1 mice was measured using murine CD63 ELISA kit. A concentration of 0.048ng / ml was observed. A previous paper using the anti-SOD1 antibody in SOD1 mice injected 70µg of antibody per mouse via the intraperitoneal route, and as ~5-10% of diffuses from the peritoneum to the blood, suggesting up to ~7ug per mouse be tolerated. It was decided to increase the dose overtime toward avoiding adaptation (e.g. resistance) from the mice, beginning from 108ng (3,000 x ratio against endogenous CD63), ramping up to 6,480ng (180,000 x ratio against endogenous CD63). The antibody was injected weekly as follows: The percentage weight gain was measured twice a week. The treated (with Ab) mice have a greater percentage weight gain than the untreated mice – see Figure 23. Example 12 – Effects of human CD63+ EVs from PD patients in vivo (mouse) and suppression of their toxicity with anti-CD63 antibody Noting results of example 8 (for EVs of disorders beyond ALS), the in vivo (mouse) experiment of example 7 is repeated, but involving administration CD63+ EVs from PD patients (instead of from ALS patients). Mice are administered with CD63+ EVs extracted from PD patient samples (“EVs”) according to methods described above. To investigate the ability of anti-CD63 antibody to suppress the cytotoxic effect (in vivo) of such EVs, another cohort of mice are instead injected with such EVs that are first coated with (e.g. neutralised) an anti-CD63 antibody (“EV+Ab”). A control cohort is injected with phosphate buffered saline buffer (“PBS”) only. The histological analysis described in example 7 is performed, showing a similar effect for administration of PD EVs, an effect which is suppressed by first coating the PD EVs in anti-CD63 antibody (EV+Ab). The neuromuscular junction (NMJ) analysis described in example 7 is performed, where the neuromuscular junction shape and innervation status are assessed in mice administered PD EVs. This shows a similar effect (as per example 7) for administration of PD EVs, an effect which is suppressed by first coating the PD EVs in anti-CD63 antibody (EV+Ab). Example 13 – Effects of human CD63+ EVs from SMA, SBMA, PMA and PLS patients in vivo (mouse) and suppression of their toxicity with anti-CD63 antibody Noting results of example 8 (for EVs of disorders beyond ALS), the in vivo (mouse) experiment of example 7 is repeated, but involving administration CD63+ EVs from either SMA, SBMA, PMA or PLS patients (instead of from ALS patients). Mice are administered with CD63+ EVs extracted from SMA, SBMA, PMA or PLS patient samples (“EVs”) according to methods described above. To investigate the ability of anti-CD63 antibody to suppress the cytotoxic effect (in vivo) of such EVs, another cohort of mice are instead injected with such EVs that are first coated with (e.g. neutralised) an anti-CD63 antibody (“EV+Ab”). A control cohort is injected with phosphate buffered saline buffer (“PBS”) only. The histological analysis described in example 7 is performed, showing a similar effect for administration of SMA, SBMA, PMA and PLS EVs, an effect which is suppressed by first coating the SMA, SBMA, PMA and PLS EVs in anti-CD63 antibody (EV+Ab). The neuromuscular junction (NMJ) analysis described in example 7 is performed, where the neuromuscular junction shape and innervation status are assessed in mice administered SMA, SBMA, PMA or PLS EVs. This shows a similar effect (as per example 7) for administration of SMA, SBMA, PMA and PLS EVs, an effect which is suppressed by first coating the SMA, SBMA, PMA and PLS EVs in anti-CD63 antibody (EV+Ab). Example 14 – clinical example 1 A patient with sporadic or familial ALS is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. Since apheresis is performed on plasma, the plasma component must first be separated from the corpuscular blood components, which can be achieved by any conventional means. The plasma component is then allowed to flow across a surface on to which has been immobilised a coating of anti-CD63+ antibodies, which sequesters the CD63+ sub- population of EVs from the serum. The plasma thus depleted in CD63+ EVs is reconstituted to blood ex vivo and re-infused into the patient. As is common procedure in apheresis applications to purify blood this procedure can be repeated a number of times to diminish the total amount of circulating CD63+ EVs (and thereby reduce the body’s “total cytotoxic EV burden”. Example 15 – clinical example 2 A patient with sporadic or familial Parkinson’s disease is shown to carry CD63-positive exosomes, which exert a cytotoxic effect on motor neurons in vitro. The patient’s blood is subjected to systemic apheresis using a column with bound anti-CD63- antibodies that clear the plasma after separation from corpuscular blood components as is standard procedure. The plasma thus cleared from CD63-positive exosomes is reconstituted to blood ex vivo and re-infused into the patient. As is common procedure in apheresis applications to purify blood this procedure can be repeated a number of times to diminish the total amount of circulating CD 63-positive exosomes. Example 16 – clinical example 3 A patient with sporadic or familial ALS or with sporadic or familial Parkinson’s disease is shown to carry CD63-positive exosomes, which exert a cytotoxic effect on motor neurons in vitro. The patient’s blood is subjected to systemic apheresis using a column with bound aptamers that clear the plasma after separation from corpuscular blood components from CD 63-positive exosomes as is standard procedure. The plasma thus cleared from CD63-positive exosomes is reconstituted to blood ex vivo and re-infused into the patient. As is common procedure in apheresis applications to purify blood this procedure can be repeated a number of times to diminish the total amount of circulating CD 63-positive exosomes. Example 17 – clinical example 4 A patient with sporadic or familial ALS or sporadic or familial Parkinson’s disease is shown to carry CD63-positive exosomes, which exert a cytotoxic effect on motor neurons in vitro. The patient’s blood is subjected to systemic apheresis using a column with bound aptamers or using a column with anti-CD 63-antibodies to clear the plasma after separation from corpuscular blood components from CD 63-positive exosomes as is standard procedure. The plasma thus cleared from CD63-positive exosomes is reconstituted to blood ex vivo. Whilst reconstituting the blood, the CD-63-exosome depleted plasma is enriched by CD63-positive exosomes from a healthy donor and re- infused into the patient (either with the reconstituted blood or via separate infusion). Example 18 – clinical example 5 A patient with sporadic or familial ALS is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. The patient is administered with an anti-CD63 aptamer that was demonstrated to suppress said in vitro cytotoxic effect. Once administered to the patient, a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject is formed in a targeted manner. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the patient’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. An alternative subpopulation of CD63-CD81+ EVs remains substantially unbound (by antibody) in the patient’s blood. Example 19 – clinical example 6 A patient with sporadic or familial ALS is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. The patient is administered with an anti-CD63 antibody that was demonstrated to suppress said in vitro cytotoxic effect. Once administered to the patient, a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject is formed in a targeted manner. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the patient’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. An alternative subpopulation of CD63-CD81+ EVs remains substantially unbound (by antibody) in the patient’s blood. Example 20 – clinical example 7 A patient with Parkinson’s Disease is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. The patient is administered with an anti-CD63 that was demonstrated to suppress said in vitro cytotoxic effect. Once to the patient, a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject is formed in a targeted manner. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the patient’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. An alternative subpopulation of CD63-CD81+ EVs remains substantially unbound (by antibody) in the patient’s blood. Example 21 – clinical example 8 A patient with Parkinson’s Disease is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. The patient is administered with an anti-CD63 antibody that was demonstrated to suppress said in vitro cytotoxic effect. Once administered to the patient, a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject is formed in a targeted manner. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the patient’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. An alternative subpopulation of CD63-CD81+ EVs remains substantially unbound (by antibody) in the patient’s blood. Example 22 – clinical example 9 A patient with SMA, SBMA, PMA or PLS is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. The patient is administered with an anti-CD63 aptamer that was demonstrated to suppress said in vitro cytotoxic effect. Once administered to the patient, a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject is formed in a targeted manner. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker from the patient’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. An alternative subpopulation of CD63-CD81+ EVs remains substantially unbound (by antibody) in the patient’s blood. Example 23 – clinical example 10 A patient with SMA, SBMA, PMA or PLS is shown to carry a CD63+sub-population of extracellular vesicles, which exerts a cytotoxic effect on motor neurons in vitro. The patient is administered with an anti-CD63 antibody that was demonstrated to suppress said in vitro cytotoxic effect. Once administered to the patient, a bound complex with extracellular vesicles having a CD63+ cell surface marker present in the subject is formed in a targeted manner. The bound complex sequesters extracellular vesicles having a CD63+ cell surface marker patient’s blood and thereby suppresses cellular uptake of said extracellular vesicles by the subject. An alternative subpopulation of CD63-CD81+ EVs remains substantially unbound (by antibody) in the patient’s blood. Example 24 – Generation of anti-CD63 antibodies For completeness, having demonstrated clinical utility in the examples above, we now provide an example to demonstrate how the proprietary antibodies were generated. To successfully capture exosomes or block their uptake, the antibody should recognise the native conformation of CD63. Commmercial antibodies worked, e.g. with a denaturation step in order to bind to CD63 (see figure 8). But it would be preferably that a first denaturation of the exosomes can suitably be avoided. We achieved this by generative bespoke antibodies. To generate new anti-CD63, a 3D model of the human CD63 protein was generated and used to design recombinant protein antigens (Fig.9). A specific motif was identified (ECD1) as an ideal target for generation of an antibody specific to CD63: LIAVGVGAQLVLSQTIIQGATPGS. This sequence was short enough to be represented as a synthetic peptide. An antigen display technology was used to generate a protein framework in which the antigen sequence was grafted into a stable immunologically- neutral loop formation. The peptide was held in a loop conformation and aligned in silico to confirm close match to the native presentation of the sequence. Antigens were isolated and used to immunise a colony of mice, taking regular test bleeds over an 11-week period. Test bleeds were screened against the screening protein to assess immune response of mice. Upon identification of positive mice, a fusion was performed and supernatant from hybridoma clones was then validated. The specific antibodies then underwent limiting dilution and cloning to produce several stable cell lines (Fig.10). Among the 28 hybridoma clones generated, we tested their efficacy to recognise muscle exosome by sandwich dot-blot. Six hybridoma lines (highlighted in yellow in Fig 10b) have been selected for their strong or medium capacity to capture MuEVs. Clones of interest were then PCR & Sanger sequencing method. Below the sequences of heavy and light of four antibodies are given. Example 25 confirmation that the proprietary anti-CD63+ antibodies can capture EVs from ALS and HC serum samples The total population of circulating extracellular vesicles (EVs) was extracted from serum of both ALS and HC subjects. To capture these EVs, magnetic beads were coated with one of three different anti-CD63 antibodies. All the beads were coupled with anti-cd63 as shown after by incubating them anti-mouse IgG1-Alexa fluor 488 (see Figure 11). The anti-CD63+ coated magnetic beads were then incubated with total EVs from either ALS or HC samples. The EVs captured by anti-CD63+ antibody coated beads binding were then revealed with anti-DAG1 antibody and secondary antibody anti-mouse IgG2a-Alexa fluor 488. The results showed that the EVs captured by each of the three antibodies tested positive for DAG1, confirming said EVs were, in fact, MuEVs, and which are known to possess the CD63+ cell surface marker (see Figure 12). Example 26 validation of the proprietary anti-CD63+ antibodies as immunoblocking agents that bind to cytotoxic EVs (via the CD63+ cell surface marker) and, in doing so, neutralise the binding capability of the cytotoxic EVs for neurons. Total EVs were extracted from ALS serum samples. EVs were pre-incubated for 1 hr at room temperature with different anti-CD63 (one commercial CD63, and two newly generated anti-CD63) or with anti-CD82, another EVs membrane marker. After removing the excess of antibodies, the EVs coated with anti-CD63 antibodies were added to the culture medium of healthy human cortico-spinal motor neurons derived from iPSCs (See Figure 13). A significant reduction in iPSC-derived motor neuron death was observed when EVs were incubated with anti-CD631G8 (see Figure 14).

[0002] SEQUENCES 1G8 sequences: SEQ ID NO: 1 (HCDR1) GYTFTDYA SEQ ID NO: 2 (HCDR2) ISTYNGNT SEQ ID NO: 3 (HCDR3) AKSTTDWYFDV SEQ ID NO: 4 (LCDR1) QDINKY SEQ ID NO: 5 (LCDR2) YTS SEQ ID NO: 6 (LCDR3) LQYDNLWT SEQ ID NO: 7 (1G8 variable heavy chain, protein) – CDR sequences underlined QVQLQQSGPEVVRPGVSVKISCKGSGYTFTDYAIHWVKQSHAKSLEWIGVISTYNGN TNYNQKFKGKATVTVDKSSSTAYMELARLTSEDSAIYYCAKSTTDWYFDVWGAGTT VTVSS SEQ ID NO: 8 (1G8 variable light chain, protein) – CDR sequences underlined DIQMTQSPSSLSASLGGKVTITCKASQDINKYIAWYQHKPGKGPRLLIHYTSTLQPGIP SRFSGSGSGRDFSFSISNLEPEDITTYYCLQYDNLWTFGGGTKLEIK SEQ ID NO: 9 (1G8 variable heavy chain, DNA, sequences encoding CDRs underlined) CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGT GAAGATTTCCTGCAAGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGG GTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAGTACTTACA ATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAGGCCACAGTGACTGTAGA CAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGGATTCT GCCATCTATTACTGTGCAAAATCTACGACCGACTGGTACTTCGATGTCTGGGGCG CAGGGACCACGGTCACCGTCTCCTCAG SEQ ID NO: 10 (1G8 variable light chain, DNA, sequences encoding CDRs underlined) GACATCCAGATGACACAGTCTCCATCCTCACTGTCTGCATCTCTGGGAGGCAAA GTCACCATCACTTGCAAGGCAAGCCAAGACATTAACAAGTATATAGCTTGGTACC AACACAAGCCTGGAAAAGGTCCTAGGCTGCTCATACATTACACATCTACATTACA ACCAGGCATCCCATCAAGGTTCAGTGGAAGTGGGTCTGGGAGAGATTTTTCCTT GATAATCTGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAGC 1G3 sequences: SEQ ID NO: 11 (HCDR1) GYTFTDYA SEQ ID NO: 12 (HCDR2) ISTYNGNT SEQ ID NO: 13 (HCDR3) AKSTTDWYFDV SEQ ID NO: 14 (LCDR1) QDINKY SEQ ID NO: 15 (LCDR2) YTS SEQ ID NO: 16 (LCDR3) LQYDNLWT SEQ ID NO: 17 (1G3 variable heavy chain, protein) – CDR sequences underlined QVQLQQSGPEVVRPGVSVKISCKGSGYTFTDYAIHWVKQSHAKSLEWIGVISTYNGN TNYNQKFKGKATVTVDKSSSTAYMELARLTSEDSAIYYCAKSTTDWYFDVWGAGTT VTVSS SEQ ID NO: 18 (1G3 variable light chain, protein) – CDR sequences underlined DIQMTQSPSSLSASLGGKVTITCKASQDINKYIAWYQHKPGKGPRLLIHYTSTLQPGIP SRFSGSGSGRDFSFSISNLEPEDITTYYCLQYDNLWTFGGGTKLEIK SEQ ID NO: 19 (1G3 variable heavy chain, DNA, sequences encoding CDRs underlined) CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGT GAAGATTTCCTGCAAGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGG GTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAGTACTTACA ATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAGGCCACAGTGACTGTAGA CAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGGATTCT GCCATCTATTACTGTGCAAAATCTACGACCGACTGGTACTTCGATGTCTGGGGCG CAGGGACCACGGTCACCGTCTCCTCAG SEQ ID NO: 20 (1G3 variable light chain, DNA, sequences encoding CDRs underlined) GACATCCAGATGACACAGTCTCCATCCTCACTGTCTGCATCTCTGGGAGGCAAA GTCACCATCACTTGCAAGGCAAGCCAAGACATTAACAAGTATATAGCTTGGTACC AACACAAGCCTGGAAAAGGTCCTAGGCTGCTCATACATTACACATCTACATTACA ACCAGGCATCCCATCAAGGTTCAGTGGAAGTGGGTCTGGGAGAGATTTTTCCTT CAGCATCAGCAACCTGGAGCCTGAAGATATTACAACTTATTATTGTCTACAGTAT GATAATCTGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAGC 2G10 sequences: SEQ ID NO: 21 (HCDR1) GYTFTDYA SEQ ID NO: 22 (HCDR2) ISTYNGNT SEQ ID NO: 23 (HCDR3) AKSTTDWYFDV SEQ ID NO: 24 (LCDR1) SSVSY SEQ ID NO: 25 (LCDR2) ATS SEQ ID NO: 26 (LCDR3) QQWSSNPPT SEQ ID NO: 27 (2G10 variable heavy chain, protein) – CDR sequences underlined QVQLQQSGPEVVRPGVSVKISCKGSGYTFTDYAIHWVKQSHAKSLEWIGVISTYNGN TNYNQKFKGKATVTVDKSSSTAYMELARLTSEDSAIYYCAKSTTDWYFDVWGAGTT VTVSS SEQ ID NO: 28 (2G10 variable light chain, protein) – CDR sequences underlined QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQQKPGSSPKPWIYATSNLASG VPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSSNPPTFGGGTKLEIK SEQ ID NO: 29 (2G10 variable heavy chain, DNA, sequences encoding CDRs underlined) CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGT GAAGATTTCCTGCAAGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGG GTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAGTACTTACA ATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAGGCCACAGTGACTGTAGA CAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGGATTCT CAGGGACCACGGTCACCGTCTCCTCAG SEQ ID NO: 30 (2G10 variable light chain, DNA, sequences encoding CDRs underlined) CAAATTGTTCTCTCCCAGTCTCCAGCAATCCTGTCTGCATCTCCAGGGGAGAAGG TCACAATGACTTGCAGGGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGC AGAAGCCAGGATCCTCCCCCAAACCCTGGATTTATGCCACATCCAACCTGGCTT CTGGAGTCCCTGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCA CAATCAGCAGAGTGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCAGTGGA GTAGTAACCCACCCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAAC 1E12 sequence: SEQ ID NO: 31 (HCDR1) GYTVTEYI SEQ ID NO: 32 (HCDR2) FYFGSGGI SEQ ID NO: 33 (HCDR3) ARHEDDYGEY SEQ ID NO: 34 (LCDR1) QSLLDSDGKTY SEQ ID NO: 35 (LCDR2) LVS SEQ ID NO: 36 (LCDR3) WQGTHFPIT SEQ ID NO: 37 (1E12 variable heavy chain, protein) KVQLQQSGAELVKPGASVKLSCKASGYTVTEYIIHWVKQRSGQGLEWIGFFYFGSG GIKYNERFKDKATLSADKSSSTVYLELSRLTSEDSAVYFCARHEDDYGEYWGQGTS VTVSS SEQ ID NO: 38 (1E12 variable light chain, protein) DVMMTQTSLILSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSK VDSGVPDRFTGSGSGTDFTLKISSVEAEDLGVYYCWQGTHFPITFGAGTKLELK SEQ ID NO: 39 (1E12 variable heavy chain, DNA, sequences encoding CDRs underlined) AAGGTCCAGTTGCAGCAGTCTGGAGCTGAGCTGGTGAAACCCGGGGCATCAGT GAAGCTGTCCTGCAAGGCTTCTGGCTACACCGTCACTGAATATATTATACACTGG GTAAAGCAGAGGTCTGGACAGGGTCTTGAGTGGATTGGGTTTTTTTATTTTGGAA GTGGTGGTATAAAGTACAATGAGAGATTCAAGGACAAGGCCACACTGAGTGCGG ACAAATCCTCCAGCACAGTCTATCTGGAGCTTAGTAGATTGACATCTGAAGACTC TGCGGTCTATTTCTGTGCAAGACACGAGGACGACTATGGGGAGTACTGGGGTCA AGGAACCTCAGTCACCGTCTCCTCAG SEQ ID NO: 40 (1E12 variable light chain, DNA, sequences encoding CDRs underlined) GATGTTATGATGACCCAGACTTCACTCATTTTGTCGGTTACCATTGGACAACCAG CCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATA TTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTG GTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGG ACAGATTTCACACTGAAAATCAGCAGTGTGGAGGCTGAGGATTTGGGAGTTTATT ATTGTTGGCAAGGGACACATTTTCCGATCACGTTCGGTGCTGGGACCAAGTTGG AGCTGAAAC SEQ ID NO: 41 – Murine anti-CD63 antibody variable heavy chain (VH), protein EVQLQQSGPELIKPGASVKMSCKASGYTFTTYVMHWVKQRPGQGLEWIGYITPYND GTKYNEKFKGKATLTSDTSSSTAYMELSSLTSEDSAVYYCTTGRAYYYVMDYWGQG TSVTVSS SEQ ID NO: 42 – Murine anti-CD63 antibody constant heavy chain (CH), protein AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAV LQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPE VSSVFIFPPKPKDVLMISLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTKPREE QINSTFRSVSELPILHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPP PKEQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSK LNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPG SEQ ID NO: 43 – Murine anti-CD63 variable heavy chain (VH) and constant heavy chain (CH), protein EVQLQQSGPELIKPGASVKMSCKASGYTFTTYVMHWVKQRPGQGLEWIGYITPYND GTKYNEKFKGKATLTSDTSSSTAYMELSSLTSEDSAVYYCTTGRAYYYVMDYWGQG TSVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSG VHTFPAVLQSDLYTLSSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRDCGCKP CICTVPEVSSVFIFPPKPKDVLMISLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTA QTKPREEQINSTFRSVSELPILHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKA PQVYTIPPPKEQMAKDKVSLTCMITNFFPEDITVEWQWNGQPAENYKNTQPIMDTD GSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPG SEQ ID NO: 44 – Murine anti-CD63 antibody variable heavy chain (VH), DNA GAAGTCCAGCTCCAACAGTCAGGCCCAGAACTTATTAAGCCCGGCGCATCAGTA AAAATGAGCTGTAAGGCATCCGGCTACACTTTCACCACTTACGTCATGCACTGGG TGAAGCAACGACCAGGACAAGGGCTGGAGTGGATCGGTTACATAACACCGTACA ACGACGGAACCAAGTACAATGAGAAGTTCAAGGGAAAGGCAACCCTCACCAGTG ACACTTCATCTAGTACCGCCTACATGGAGCTGTCCTCCCTCACATCTGAAGACT CTGCCGTTTATTACTGCACCACGGGCCGGGCCTACTATTACGTCATGGACTACT GGGGACAGGGCACAAGTGTGACAGTGAGCTCT SEQ ID NO: 45 – Murine anti-CD63 antibody constant heavy chain (CH), DNA GCTAAAACAACCCCTCCATCTGTGTATCCCCTTGCCCCCGGAAGTGCCGCTCAG ACAAATAGTATGGTGACCCTGGGTTGCTTGGTTAAAGGGTACTTTCCCGAACCTG TTACCGTGACTTGGAACTCCGGGAGTTTGTCCAGTGGAGTGCACACCTTCCCCG CCGTATTGCAGTCTGATCTCTATACTCTGTCAAGCTCTGTCACGGTGCCCTCATC AACATGGCCCAGTCAGACTGTCACTTGCAATGTGGCCCATCCCGCCTCATCTACT AAAGTGGACAAGAAAATTGTTCCGCGAGATTGTGGATGCAAACCTTGTATCTGTA CAGTGCCAGAAGTGTCCAGTGTGTTCATCTTTCCCCCCAAGCCAAAAGATGTCCT GATGATTAGCCTCACGCCTAAAGTGACATGTGTCGTCGTGGACATCTCAAAGGA CGACCCTGAAGTCCAATTCTCCTGGTTCGTGGATGACGTTGAGGTTCATACCGC ACAGACCAAACCCAGGGAGGAACAGATCAACTCCACCTTCCGATCAGTTAGCGA GCTCCCCATTCTGCACCAGGATTGGCTGAATGGCAAAGAGTTTAAGTGCAGAGT CAATAGCGCTGCATTTCCGGCTCCCATCGAAAAGACCATCTCTAAAACGAAAGG GCGCCCAAAAGCCCCTCAGGTGTATACAATCCCGCCACCTAAAGAGCAAATGGC GAAGGATAAAGTGTCCCTGACATGCATGATTACTAACTTTTTCCCAGAGGACATT ACGGTTGAGTGGCAATGGAATGGACAGCCCGCCGAAAACTACAAGAATACACAG AGTCTAACTGGGAGGCTGGGAATACTTTCACCTGCTCAGTGCTCCATGAAGGGT TGCACAATCACCACACAGAGAAGAGTCTGTCACATTCCCCAGGGTAA SEQ ID NO: 46 – Murine anti-CD63 antibody variable heavy chain (VH) and constant heavy chain (CH), DNA GAAGTCCAGCTCCAACAGTCAGGCCCAGAACTTATTAAGCCCGGCGCATCAGTA AAAATGAGCTGTAAGGCATCCGGCTACACTTTCACCACTTACGTCATGCACTGGG TGAAGCAACGACCAGGACAAGGGCTGGAGTGGATCGGTTACATAACACCGTACA ACGACGGAACCAAGTACAATGAGAAGTTCAAGGGAAAGGCAACCCTCACCAGTG ACACTTCATCTAGTACCGCCTACATGGAGCTGTCCTCCCTCACATCTGAAGACTC TGCCGTTTATTACTGCACCACGGGCCGGGCCTACTATTACGTCATGGACTACTG GGGACAGGGCACAAGTGTGACAGTGAGCTCTGCTAAAACAACCCCTCCATCTGT GTATCCCCTTGCCCCCGGAAGTGCCGCTCAGACAAATAGTATGGTGACCCTGGG TTGCTTGGTTAAAGGGTACTTTCCCGAACCTGTTACCGTGACTTGGAACTCCGGG AGTTTGTCCAGTGGAGTGCACACCTTCCCCGCCGTATTGCAGTCTGATCTCTATA CTCTGTCAAGCTCTGTCACGGTGCCCTCATCAACATGGCCCAGTCAGACTGTCA CTTGCAATGTGGCCCATCCCGCCTCATCTACTAAAGTGGACAAGAAAATTGTTCC GCGAGATTGTGGATGCAAACCTTGTATCTGTACAGTGCCAGAAGTGTCCAGTGT GTTCATCTTTCCCCCCAAGCCAAAAGATGTCCTGATGATTAGCCTCACGCCTAAA GTGACATGTGTCGTCGTGGACATCTCAAAGGACGACCCTGAAGTCCAATTCTCC TGGTTCGTGGATGACGTTGAGGTTCATACCGCACAGACCAAACCCAGGGAGGAA CAGATCAACTCCACCTTCCGATCAGTTAGCGAGCTCCCCATTCTGCACCAGGATT GGCTGAATGGCAAAGAGTTTAAGTGCAGAGTCAATAGCGCTGCATTTCCGGCTC CCATCGAAAAGACCATCTCTAAAACGAAAGGGCGCCCAAAAGCCCCTCAGGTGT ATACAATCCCGCCACCTAAAGAGCAAATGGCGAAGGATAAAGTGTCCCTGACAT GCATGATTACTAACTTTTTCCCAGAGGACATTACGGTTGAGTGGCAATGGAATGG ACAGCCCGCCGAAAACTACAAGAATACACAGCCTATCATGGACACCGATGGTTC CTATTTCGTATATTCAAAGCTGAACGTTCAGAAGTCTAACTGGGAGGCTGGGAAT ACTTTCACCTGCTCAGTGCTCCATGAAGGGTTGCACAATCACCACACAGAGAAGA GTCTGTCACATTCCCCAGGGTAA SEQ ID NO: 47 – Murine anti-CD63 antibody variable light chain (VL), protein NIMMTQSPSSLAVSAGEKVTMSCKSSQSVFYSSNQKNYLAWYQQKPGQSPKLLIYW ASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYFSSYTFGGGTKLEIK SEQ ID NO: 48 – Murine anti-CD63 constant light chain (CL), protein RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWT DQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC SEQ ID NO: 49 – Murine anti-CD63 antibody variable light chain (VL) and constant light chain (CL), protein NIMMTQSPSSLAVSAGEKVTMSCKSSQSVFYSSNQKNYLAWYQQKPGQSPKLLIYW ASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYFSSYTFGGGTKLEIKR ADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTD QDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC SEQ ID NO: 50 – Murine anti-CD63 antibody variable light chain (VL), DNA AACATCATGATGACCCAGTCCCCTAGTTCTCTCGCAGTGTCAGCCGGCGAGAAG GTCACCATGAGTTGTAAGAGCAGCCAGAGCGTGTTTTACAGTAGTAACCAGAAG AACTATCTGGCTTGGTATCAGCAGAAACCAGGCCAGAGCCCTAAACTCTTGATCT ACTGGGCTTCCACTAGAGAGTCTGGCGTACCTGACAGATTCACTGGATCTGGGT CCGGCACTGACTTTACACTTACCATATCAAGCGTGCAAGCCGAAGATCTGGCCG TCTATTATTGTCACCAATACTTCAGCAGCTATACCTTTGGTGGTGGGACTAAACTG GAGATAAAG SEQ ID NO: 51 – Murine anti-CD63 antibody constant light chain (CL), DNA CGGGCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAA CATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTCTACCCCAAAGACAT CAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGCGTCCTGAACAG TTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCAC GTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCA CAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGAATGAGTGTTAA SEQ ID NO: 52 – Murine anti-CD63 antibody variable light chain (VL) and constant light chain (CL), DNA AACATCATGATGACCCAGTCCCCTAGTTCTCTCGCAGTGTCAGCCGGCGAGAAG GTCACCATGAGTTGTAAGAGCAGCCAGAGCGTGTTTTACAGTAGTAACCAGAAG AACTATCTGGCTTGGTATCAGCAGAAACCAGGCCAGAGCCCTAAACTCTTGATCT ACTGGGCTTCCACTAGAGAGTCTGGCGTACCTGACAGATTCACTGGATCTGGGT CCGGCACTGACTTTACACTTACCATATCAAGCGTGCAAGCCGAAGATCTGGCCG TCTATTATTGTCACCAATACTTCAGCAGCTATACCTTTGGTGGTGGGACTAAACTG GAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTCTACC CCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGCG TCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCA GCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTG AGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGAATGA GTGTTAA SEQ ID NO: 53 - ECD1 target for generation of an antibody specific to CD63 LIAVGVGAQLVLSQTIIQGATPGS SEQ ID NO: 54 - Mouse CD63 MAVEGGMKCVKFLLYVLLLAFCACAVGLIAIGVAVQVVLKQAITHETTAGSLLPVVIIAV GAFLFLVAFVGCCGACKENYCLMITFAIFLSLIMLVEVAVAIAGYVFRDQVKSEFNKSF QQQMQNYLKDNKTATILDKLQKENNCCGASNYTDWENIPGMAKDRVPDSCCINITV GCGNDFKESTIHTQGCVETIAIWLRKNILLVAAAALGIAFVEVLGIIFSCCLVKSIRSGYE V SEQ ID NO: 55 - Human CD63 (preferably epitope underlined) MAVEGGMKCVKFLLYVLLLAFCACAVGLIAVGVGAQLVLSQTIIQGATPGSLLPVVIIA VGVFLFLVAFVGCCGACKENYCLMITFAIFLSLIMLVEVAAAIAGYVFRDKVMSEFNNN FRQQMENYPKNNHTASILDRMQADFKCCGAANYTDWEKIPSMSKNRVPDSCCINVT VGCGINFNEKAIHKEGCVEKIGGWLRKNVLVVAAAALGIAFVEVLGIVFACCLVKSIRS GYEVM

Claims

CLAIMS:

1. A method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: administering to the subject a therapeutically effective amount of a CD63+ complementary binding partner, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63- CD81+ EVs present in the subject remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder.

2. A CD63+ complementary binding partner for use in a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: administering to the subject a therapeutically effective amount of the CD63+ complementary binding partner, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63- CD81+ EVs present in the subject remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder.

3. A method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, the method comprising: a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from a blood sample (e.g. whole blood, plasma or serum), byi. contacting ex vivo blood obtained from the subject) with a CD63+ complementary partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged; and iii. removing bound complex from said blood; thereby providing a blood preparation that is substantially free from a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons; and b) administering the blood preparation to a subject having said neurological disorder; preferably wherein the blood sample is obtained from a subject having a neurological disorder (e.g. associated with motor neuron degeneration); more preferably wherein the blood sample is obtained from the subject undergoing treatment, e.g. wherein step b) comprises reinfusing the blood preparation (subsequent to step a)) to the subject.

4. A CD63+ complementary binding partner for use in a method for suppressing progression of a neurological disorder associated with motor neuron degeneration in a subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from a blood sample (e.g. whole blood, plasma or serum), by i. contacting ex vivo blood (preferably obtained from the subject) with a CD63+ complementary binding partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged; and iii. removing bound complex from said blood;thereby providing a blood preparation that is substantially free from a subpopulation extracellular vesicles (EVs) that are cytotoxic to motor neurons; and b) administering the blood preparation to a subject having said neurological disorder; preferably wherein the blood sample is obtained from a subject having a neurological disorder (e.g. associated with motor neuron degeneration); more preferably wherein the blood sample is obtained from the subject undergoing treatment, e.g. wherein step b) comprises reinfusing the blood preparation (subsequent to step a)) to the subject.

5. A blood preparation (e.g. selected from whole blood, serum and plasma) substantially free from a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, and wherein said blood preparation comprises a subpopulation of CD63-CD81+EVs; and optionally wherein said blood preparation is substantially free from a subpopulation of CD82+ EVs that are cytotoxic to motor neurons.

6. A blood preparation according to claim 5, for use in a method of suppressing a neurological disorder associated with motor neuron degeneration in a subject having said disorder, wherein the subject has a blood supply system that feeds all major organs and connects surrounding tissues, and which collectively defines a reservoir of circulatory EVs, said method comprising: a. administering the blood preparation to said subject in which a sub- population of cytotoxic circulatory EVs having a CD63+ cell surface marker has been depleted from said reservoir of circulatory EVs with a complementary binding partner that forms a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged in the subject.

7. A method of suppressing a neurological disorder associated with motor neuron degeneration in a subject having said disorder, wherein the subject has a blood supply system that feeds all major organs and connects surroundingtissues, and which collectively defines a reservoir of circulatory EVs, the method comprising a. administering the blood preparation of claim 5 to said subject in which a subpopulation of cytotoxic circulatory EVs having a CD63+ cell surface marker has been depleted from said reservoir of circulatory EVs with a complementary binding partner that forms a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged in the subject.

8. The method or CD63+ complementary binding partner for use according to claim 3 or 4, wherein step i) comprises contacting ex vivo blood (preferably obtained from the subject) with a solid phase support comprising said CD63+ complementary binding partner immobilised thereon, and optionally contacting ex vivo blood (preferably obtained from the subject) with a solid phase support comprising an immobilised CD82+ complementary binding partner.

9. The method or CD63+ complementary binding partner for use according to any one of claims 3, 4, or 8, wherein step (a) is performed on a serum or plasma component of the subject’s blood; and / or wherein step (a) comprises aphaeresis of the subject’s blood.

10. The method according to claim 1 or CD63+ complementary binding partner for use according to claim 2, wherein prior to administering said CD63+ complementary binding partner the total population of (e.g. unbound / non- complexed) extracellular vesicles present in the subject’s blood comprises at most 30% muscle-derived extracellular vesicles; and / or wherein prior to administering said CD63+ complementary binding partner the total population of extracellular vesicles present in the subject’s blood comprises at least 70% extracellular vesicles derived from a non-muscle source.

11. The method, or CD63+ complementary binding partner for use, or blood preparation for use according to any of claims 3-4 or 6-9, wherein prior to step (a) the total population of extracellular vesicles present in the subject’s blood comprises at most 30% muscle-derived extracellular vesicles; and / orwherein prior to step (a) the total population of extracellular vesicles present in the subject’s blood at least 70% extracellular vesicles derived from a non-muscle source.

12. The method, CD63+ complementary binding partner for use, or blood preparation for use according to claim 10 or claim 11, wherein said non-muscle source is selected from: brain, gut, or liver; optionally wherein said non-muscle source comprises EVs derived from brain, or liver.

13. The method, the CD63+ complementary binding partner for use, or blood preparation for use according to any preceding claim, wherein the subject is carrying CD63+ cytotoxic EVs but is asymptomatic for the neurological disorder; or wherein the subject is carrying CD63+ cytotoxic EVs and has at least one symptom associated with the neurological disorder.

14. The method, the CD63+ complementary binding partner for use, or blood preparation for use according to any preceding claim, wherein the neurological disorder is selected from the group consisting of: Amyotrophic Lateral Sclerosis (ALS) (such as familial ALS (fALS), sporadic ALS (sALS), Fast progression ALS, Slow progression ALS, Severe disease ALS, Mild disease ALS, and / or a neurological disorder the ALS-FTD disease spectrum), Primary Lateral Sclerosis, Spinal-Bulbar Muscular Atrophy (SBMA), Spinal Muscular Atrophy (SMA), Spinal Muscular Atrophy type II (SMAII), Spinal Muscular Atrophy type III / IV (SMAIII / IV), Parkinson’s disease (PD), and Progressive Muscular Atrophy (PMA).

15. The method or blood preparation for use according to any one of claims 3-4, 6-9 or 11-14, said method further comprising administering to the subject a CD63+ complementary binding partner, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63- CD81+ EVs present in the subject remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs and, when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of theneurological disorder, optionally wherein said CD63+ complementary binding partner is infused ex vivo into the blood; and optionally further comprising administering to the subject a CD82+ complementary binding partner that forms a bound complex with extracellular vesicles having a CD82+ cell surface marker present in the subject, wherein the CD82+ complementary binding partner selectively binds to the CD82+ EVs and, when so bound, the CD82+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder; optionally wherein said CD82+ complementary binding partner is infused ex vivo into the patient’s blood.

16. A method for monitoring responsiveness to therapeutic intervention by a subject having a neurological disorder associated with motor neuron degeneration, said subject having a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method comprising: a. determining the total number of CD63+ extracellular vesicles per unit volume present in a biological sample obtained from said subject at a time point after therapeutic intervention; and optionally determining the total number of CD82+ extracellular vesicles per unit volume present in a biological sample obtained from said subject at a time point after therapeutic intervention; b. comparing said total number with that of a reference sample obtained from the subject by otherwise comparable means at an earlier time point; and c. wherein a decrease in the total number of CD63+ extracellular vesicles (and optionally a decrease in the total number of CD82+ extracellular vesicles) is indicative the subject has responded positively to the therapeutic intervention, whereas an increase in the total number of CD63+ extracellular vesicles (and optionally an increase in the total number of CD82+ extracellular vesicles) is indicative the subject has not responded positively to the therapeutic intervention.

17. An ex vivo method for depleting cytotoxic circulatory EVs from a blood sample (e.g. whole blood, plasma or serum) obtained from a subject having a neurological disorder associated with motor neuron degeneration, the subjecthaving a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons, said method a) an ex vivo step of removing extracellular vesicles having a CD63+ cell surface marker from the blood sample by: i. contacting said ex vivo blood sample with a CD63+ complementary binding partner; ii. allowing said complementary binding partner to form a bound complex with EVs having a CD63+ cell surface marker, wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged; and iii. removing bound complex from said blood; thereby providing a blood preparation that is substantially free from a subpopulation of CD63+ extracellular vesicles (EVs) that are cytotoxic to motor neurons; and b) optionally an ex vivo step of removing extracellular vesicles having a CD82+ cell surface marker from the blood sample thereby providing a blood preparation that is substantially free from a subpopulation of CD63+ EVs and substantially free from a subpopulation of CD82+ EVs that are cytotoxic to motor neurons.

18. A blood preparation obtainable by the method of claim 17.

19. An anti-CD63 antibody (or antigen binding portion thereof) that comprises: a. a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; or b. a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively; or c. a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 21, SEQ ID NO: 22,SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26, respectively; or d. a HCDR1, a HCDR2, a HCDR3, a LCDR1, LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, respectively.

20. The anti-CD63 antibody (or antigen binding portion thereof) of claim 19, comprising: a. (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 7, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 8, or a functional variant thereof; or b. (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 17, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (preferably 100%) sequence identity to the amino acid sequence of SEQ ID NO: 18, or a functional variant thereof; or c. (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g.100%) sequence identity to the amino acid sequence of SEQ ID NO: 27, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g. 100%) sequence identity to the amino acid sequence of SEQ ID NO: 28, or a functional variant thereof; or d. (i) a variable heavy chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g.100%) sequence identity to the amino acid sequence of SEQ ID NO: 37, or a functional variant thereof; and (ii) a variable light chain comprising an amino acid sequence having at least 70%, 75%, 80%, 90%, 95% or 100% (e.g. 100%)sequence identity to the amino acid sequence of SEQ ID NO: 38, or a functional variant thereof.

21. A solid phase support comprising an immobilised capture means for removing cytotoxic EVs having a CD63+ cell surface marker, and optionally cytotoxic EVs having a CD82+ cell surface marker, from a blood sample, the capture means comprising: a. a CD63+ complementary binding partner (e.g. of claim 19 or claim 20), wherein the CD63+ complementary binding partner does not bind to CD63- EVs such that a subpopulation of CD63-CD81+ EVs present in the blood sample remains unchanged, wherein the CD63+ complementary binding partner selectively binds to the CD63+ EVs (e.g. and when so bound, the CD63+ EVs have diminished cytotoxic effect on motor neurons); b. and optionally a CD82+ complementary binding partner, wherein the CD82+ complementary binding partner selectively binds to the CD82+ EVs (e.g. and when so bound, the CD82+ EVs have diminished cytotoxic effect on motor neurons); optionally wherein the solid phase support is provided in the form of beads (e.g. magnetic beads) having a surface on which the capture means is immobilised; and / or optionally wherein the solid phase support is provided in the form of a column (e.g. exchange column) having a surface on which the capture means is immobilised.

22. An extracorporeal blood processing system adapted for depleting a sub- population of cytotoxic extracellular vesicles (EVs) having a CD63+ cell surface marker (and optionally for depleting cytotoxic EVs having a CD82+ cell surface marker) from blood, the system comprising: a density-based separation device (e.g. a centrifuge or rotating belt) configured to separate the blood’s fractions into density-separated phases, including a distinct phase comprising plasma and / or a distinct phase comprising serum; and a fluid connection configured to fluidly connect said distinct phase comprising plasma and / or said distinct phase comprising serum to a solid phase support of claim 21, the solid phase support being provided within a flow path along which the plasma and / or serum will travel at a flow ratecontrolled to allow for the immobilised capture means to bind (and sequester) cytotoxic EVs in the plasma, to provide cleaned plasma and / or cleaned serum substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker, and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker.

23. The extracorporeal blood processing system of claim 22, further comprising: means to combine the cleaned plasma and / or cleaned serum with the remaining density-separated phases (e.g. blood fractions), thereby providing a reconstituted blood supply substantially free from cytotoxic circulatory EVs having a CD63+ cell surface marker, and optionally substantially free from cytotoxic circulatory EVs having a CD82+ cell surface marker.

24. The method, the CD63+ complementary binding partner, the blood preparation for use, the solid phase support, or the blood processing system of any of the preceding claims, wherein the CD63+ complementary binding partner comprises the anti-CD63 antibody (or antigen binding portion thereof) of any of claims 19-20.

25. The method for suppressing a neurological disorder or CD63+ complementary binding partner according to any one of the preceding claims, further comprising administering to the subject a therapeutically effective amount of a CD82+ complementary binding partner, wherein the CD82+ complementary binding partner selectively binds to CD82+ EVs in the subject and, when so bound, the CD82+ EVs have diminished cytotoxic effect on motor neurons, thereby suppressing disease progression of the neurological disorder.

26. The method or CD63+ complementary binding partner for use according to claim 3 or claim 4, wherein step a) comprises an ex vivo step of removing extracellular vesicles having a CD82+ cell surface marker from said blood sample, thereby providing a blood preparation that is substantially free from extracellular vesicles having a CD63+ cell surface marker, and that issubstantially free from extracellular vesicles having a CD82+ cell surface marker; preferably wherein the blood is obtained from a subject having a neurological disorder.

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