DEVICE FOR THE COMBINED EXTRACTION OF A METALLICATION AND A TARGET MOLECULE

Description

technical field

[0001] The present invention relates to the field of medical devices, more particularly to devices that allow the simultaneous extraction from an organism of at least one metal cation and at least one target molecule. The use of these devices makes it possible, for example, to prevent and / or treat pathologies related to a dysregulation of the homeostasis of metals and / or target molecules in the body, such as neurological diseases and / or proteinopathies. Previous technique

[0002] Maintaining homeostasis in the body's internal environment—that is, the balance of all the body's biological fluids—is essential for its proper functioning. In many pathologies, systemic or local dysregulations of metal and / or peptide or protein homeostasis have been demonstrated.

[0003] Regarding metals, chelation therapies, aimed at reducing the concentration of metal ions, have been used for many years in cases of acute poisoning. A number of chelating agents are already accepted for human use, each associated with a particular group of metals (G. Crisponi et al., Coordination Chemistry Reviews, 2015).

[0004] A growing body of scientific research highlights the significant role that metals may play in a number of neurological disorders, particularly iron, but also copper, zinc, manganese, and even aluminum and lead (EJ McAllum et al., J. Mol. Neurosci., 2016). This is especially true for iron overload neurodegeneration, a rare disease associated with a genetic abnormality linked to iron accumulation in certain brain regions, and which currently only benefits from palliative treatments (S. Wiethoff et al., Handb. Clin. Neurol., 2017). Furthermore, numerous studies have shown that iron tends to accumulate in the brain with age (J. Acosta-Cabronero et al., Journal of Neuroscience, 2016). Wilson's disease is also a genetic disorder that causes copper to accumulate in the body, leading to various problems, particularly liver and / or neurological issues (Anna Cz). onkowskal et al., Nature Rev., 2018).

[0005] Several neurological diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, are also associated with increased iron levels in specific areas, leading to cellular damage and oxidative stress (AA Belaidi et al., Journal of Neurochemistry, 2016). For example, Huntington's disease is a neurodegenerative disorder characterized by movement disorders, cognitive decline, and psychiatric problems. In this condition, numerous markers of oxidative stress are observed in the brain, which may be linked to a dysregulation of iron homeostasis (SJA van den Bogaard et al., International Review of Neurobiology, 2013). Increased iron levels in several brain regions (putamen, caudate nucleus, and globus pallidus) have been validated by several MRI studies, including that of Bartzorkis (G. Bartzorkis et al., Archives of Neurology, 1999).

[0006] In these same pathologies, the homeostasis of other biological compounds is also disrupted. In Alzheimer's disease, for example, the A-β (amyloid-beta) peptide, a peptide of approximately 42 amino acids (39 to 43), accumulates, forming beta-amyloid aggregates. Treatments for amyloid diseases have been proposed involving the extraction of the A-β peptide from biological fluids (US2013 / 0045216 A1; M. Menendez-Gonzalez et al., Hypothesis and Theory, 2018). Also with the aim of treating or slowing the progression of Alzheimer's disease, dilution of cerebrospinal fluid by replacement and filtration has been proposed to reduce levels of abnormally phosphorylated A-β peptide and Tau protein (phospho-Tau) (MM Gonzalez, Cureus, 2017).

[0007] In addition to Alzheimer's disease, a conformational conversion of normal soluble proteins into insoluble proteins, leading to the formation of amyloid plaques or fibrils, has been demonstrated in numerous other amyloid pathologies such as Parkinson's disease and prion disease. Therefore, antibodies or small molecules specifically targeting these proteins are being studied with the aim of inhibiting key steps in the aggregation process of these abnormal proteins, reducing the conversion of proteins to their pathological conformation, reducing the toxicity of pathological proteins, or increasing the selective clearance of abnormal proteins (N. Cremade et al., Neurobiol Dis., 2018).

[0008] In addition, in Alzheimer's disease in particular, interactions have been shown between certain metal ions, especially ions from metals such as zinc, iron or copper, with Aβ peptides that can lead to increased protein aggregation (Tougu et al. Metallomics, 2010).

[0009] It is thus accepted that in many proteinopathies, metal cations play a significant role in the formation of abnormal configurations of certain proteins; in particular, some promote the formation of aggregates, fibrils, or other solid deposits. In proteinopathies, there would therefore be a local, dual dysregulation of homeostasis: dysregulation of the homeostasis of certain metals and dysregulation of the homeostasis of target molecules such as proteins, which are the origin of the aggregates and other solid deposits.

[0010] Although scientific knowledge regarding these various pathologies is progressing (Pfaender S et al., 2014; Boland B et al., 2018; Ladanza MG et al., 2018), there is currently no effective treatment for Alzheimer's disease or Parkinson's disease, and more generally, for neurodegenerative diseases and, more broadly, for diseases involving multiple dysregulations leading to dyshomeostasis. Document US2011 / 0158986 is considered to be part of the prior art. Technical problem

[0011] Therefore, there is currently a need to develop new methods to prevent and / or treat pathologies involving multiple dysregulations that lead to dyshomeostasis and the formation of aberrant protein conformations, resulting in the formation of deposits, aggregates, fibrils, or plaques containing these proteins. These methods would thus offer one or more of the following advantages: targeted and combined extraction of these compounds (target metals and proteins) within the body, whether they are present in high or low quantities, absence of toxicity when these compounds are co-aggregated in the body, absence of release of either compound in isolation that may occur during the extraction process, a determined duration of local efficacy not linked to the biodistribution of an administered drug, local action even accessible beyond the blood-brain barrier, in the case of the treatment of neurological diseases, an application suitable for the prevention and / or treatment of any pathology linked to a dysregulation of the homeostasis of target compounds, in particular combining metals and target molecules likely to co-aggregate.

[0012] These benefits and many others are described in this disclosure. Description of the invention

[0013] A device is proposed for the joint extraction of at least one metallic cation and at least one target molecule from a biological fluid, biological aggregate, organ or tissue for diagnostic or therapeutic purposes, characterized in that it comprises: a. at least one ligand exhibiting a specific affinity for the target molecule; b. at least one means for extracting the metal cation, said means being a perfusion fluid comprising at least one chelating agent, said perfusion fluid being contained in a dialysis or microdialysis system.

[0014] A microdialysis system is also proposed, comprising said extraction device and such that said system comprises at least: an perfusion reservoir 7 comprising the perfusion fluid 11 and a collection reservoir 8 comprising the perfusion fluid comprising the extracted compounds 12; or a mixed reservoir 22 comprising the perfusion fluid 11, 12; a bidirectional catheter 3 connecting the microdialysis probe 1 to the perfusion reservoir 7 and the collection reservoir 8 or to the mixed reservoir 22; a microdialysis probe 1 comprising a first lumen 4 allowing the passage of the perfusion fluid 11 to a second lumen 5, said second lumen 5 allowing the evacuation of the perfusion fluid comprising the extracted compounds 12 and a microdialysis membrane 2 comprising between the second lumen 5 and the outside of the microdialysis probe 1 in contact with the biological fluid.

[0015] According to an alternative embodiment, a dialysis system is proposed comprising said extraction device and such that it comprises at least: a separate lumen probe 17, comprising a second catheter 5bis allowing the entry of the biological fluid into the dialysis system and a first catheter 4bis allowing the exit of the biological fluid from the dialysis system; a reservoir 23 comprising i) the perfusion fluid 11; ii) a dialysis compartment comprising a dialysis membrane 18 separating the perfusion fluid 11 from the biological fluid, the biological fluid entering said dialysis compartment via the second catheter 5bis and exiting via the first catheter 4bis.

[0016] The features described in the following paragraphs may optionally be implemented. They may be implemented independently or in combination with each other.

[0017] The means of extracting the metal cation may be a perfusion fluid used in a dialysis or microdialysis system, said perfusion fluid further comprising said ligand having a specific affinity for the target molecule.

[0018] Advantageously, the complexation constant log(KC1) of the chelating agent for at least one metal cation is greater than 10, preferably greater than or equal to 15, and said at least one cation is chosen from among the metal cations Cu, Fe, Zn, Hg, Cd, Pb, Mn, Co, Gd and Al, taken alone or in association, and more particularly Cu, Fe and Zn, taken alone or in association.

[0019] According to a preferred embodiment, the extraction means allows the cations to be extracted from a biological fluid, a biological aggregate, an organ or a tissue when the content of said metallic cations is less than 1 ppm, preferably less than 0.1 ppm, more preferably less than 0.01 ppm and, even more preferably, less than 1 ppb.

[0020] The extraction method can allow the extraction of a quantity of metallic cations representing at least 1% of its mass and, preferably, more than 10% of its mass.

[0021] The device is advantageously an infusion fluid included in a dialysis system comprising a dialysis membrane and a reservoir containing the infusion fluid, said infusion fluid being selected from: a nanoparticle solution comprising, as an active ingredient, at least one chelating agent and a solution of at least one ligand having a specific affinity for the target molecule, the average diameter of said nanoparticles and that of the ligand being greater than the pores of the dialysis or microdialysis membrane; or a polymer solution, said polymers being grafted to at least one active ingredient which is a chelating agent and a solution of at least one ligand having a specific affinity for the target molecule, the average diameter being greater than the pores of said dialysis or microdialysis membrane.

[0022] Preferably, the device comprises a dialysis system including a dialysis membrane and a reservoir containing an perfusion fluid, said perfusion fluid being selected from: a nanoparticle solution comprising as an active ingredient at least one chelating agent and a solution of at least one ligand having a specific affinity for the target molecule, the average diameter of said nanoparticles and that of the ligand being greater than the pores of the dialysis membrane, a polymer solution, said polymers being grafted to at least one active ingredient which is a chelating agent and a solution of at least one ligand having a specific affinity for the target molecule, the average diameter being greater than the pores of said dialysis membrane.

[0023] According to an advantageous embodiment, the chelating agents are obtained by grafting onto the nanoparticles or onto the polymer one of the following complexing molecules or its derivatives: DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA, DFO, DOTAM, NOTAM, DOTP, NOTP, TETA, TETAM, TETP and DTPABA, or mixtures thereof.

[0024] Preferably, the nanoparticles are polysiloxane-based nanoparticles with an average diameter between 3 and 50 nm, comprising the chelating agent obtained by grafting DOTA, DOTAGA, EDTA or DTPA onto the nanoparticles.

[0025] According to a particular embodiment, the chelating agent contains at least one alkaline earth cation, preferably a cation of metals chosen from Ca and Mg.

[0026] Advantageously, at least 10% of the chelating agents of said device are pre-complexed with an alkaline earth cation, preferably 20%, more preferably 30% and more preferably still more than 50% of the chelating agents of said device are pre-complexed with an alkaline earth cation.

[0027] According to one embodiment, the nanoparticles or polymers, comprising the chelating agent obtained by grafting DOTA, DOTAGA, EDTA or DTPA, have an average diameter greater than 20 kDa and less than 1 MDa.

[0028] Advantageously, the nanoparticles are based on polysiloxane or the polymers are based on chitosan or polyethylene glycol or polyvinyl alcohols.

[0029] According to one embodiment, the target molecule is chosen from proteins, peptides, and glycoproteins. Advantageously, the target molecule is chosen from amyloidogenic proteins and components of amyloid structures (in native monomeric form, or as oligomers, fibrils, aggregates, or molecules responsible for their formation or accumulation).

[0030] According to a preferred embodiment, the target molecule is chosen from among the molecules involved in amyloidosis, tauopathies or any pathology presenting a deposit based on one or more proteins. Advantageously, the target molecule is chosen from proteins and / or their precursors such as light and heavy immunoglobulin chains, serum amyloid protein, transthyretin, apolipoprotein AI, All, AVI, CII or CIII, beta 2 microglobulin, gelsolin, lysozyme, fibrinogen, cystatin C, atrial natriuretic factor, calcitonin, amylin, insulin, prolactin, lactoferrin, cadherin, A-Bri, A-Dan, beta amyloid peptide, prion protein, alpha-synuclein, Tau protein, superoxydismutase, huntingtin, neuroserpin, actin, ferritin or mixtures thereof.

[0031] Preferably, the ligand is an antibody or an artificial protein ligand of the target molecule. Advantageously, the ligand is chosen from: antibodies targeting beta-amyloid protein, preferably Solanezumab, Aducanumab, Crenezumab, Ponezumab, GSK933776, Gantenerumab, AAB-003, AAB-001, BAN2401, LY2599666, LY3002813, LY3372993, MEDI1814, SAR228810; antibodies targeting alpha-synuclein, preferably BII054 or PRX002; antibodies targeting tau protein, preferably BII076, BII092, ABBV-8E12, JNJ-63733657, LY3303560, RG7345, RO7105705, UCB0107; antibodies targeting serum amyloid protein, preferably: Dezamizumab or GSK2398852, Miridesap or GSK2315698, GSK3039294; antibodies targeting transthyretin, preferably PRX004; aptamers; artificial protein ligands exhibiting specific affinity for at least one of the molecules, optionally chosen from: ABD, Adhiron, Adnectin, Affibody, Affilin, Affimer, Affitin, Alphabody, Anticalin, Armadillo repeat proteins, Atrimer / tetranectin, Avimer / Maxibody, Centyrin, DARPin1;artificial protein ligands of less than 50 kDa, preferably less than 30 kDa and, more preferably, less than 5 kDa, grafted onto a nanoparticle or polymer of more than 5 nm hydrodynamic diameter, preferably more than 100 kDa, or mixtures thereof.

[0032] According to a preferred embodiment, the device is used in the treatment of: systemic and / or localized amyloidosis; including amyloidosis selected from: AL type amyloidosis (immunoglobulin light chains), AH type amyloidosis (immunoglobulin heavy chains), AA amyloidosis (serum amyloid protein), ATTR amyloidosis (transthyretin), amyloid cardiomyopathies, renal amyloidosis, type II diabetes, prion diseases or diseases related to an amyloid protein, tauopathies including: tauopathies selected from: Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia; pathologies presenting a deposit based on at least one protein; diseases presenting a metallic dyshomeostasis including Wilson's disease or neurological disorders without amyloid characteristics such as autism or schizophrenia, ...), or neurological disorders with amyloid characteristics such as amyloidosis affecting or not the central and / or peripheral nervous system. Brief description of the drawings

[0033] Other features, details, and advantages of the invention will become apparent upon reading the detailed description below and analyzing the accompanying drawings, in which: Fig. 1 [ Fig. 1 [ ] shows a dialysis system according to an embodiment of the invention; said system comprising a dialysis probe 1, 17 placed in the brain. In such an embodiment, the biological fluid is cerebrospinal fluid. Fig. 2 [ Fig. 2 [ ] shows a dialysis system according to another embodiment of the invention; said system comprising a dialysis or microdialysis probe 1, 17 placed at the spinal level in cerebrospinal fluid. In such an embodiment, the biological fluid is advantageously spinal fluid. Fig. 3 [ Fig. 3] shows a microdialysis system according to an embodiment of the invention; said system comprising i) a microdialysis probe 1 with a first lumen 4, a second lumen 5 and a microdialysis membrane 2 between the second lumen 4 and the outside of the microdialysis probe 1 in contact with the biological fluid; ii) a perfusion reservoir 7 comprising the perfusion fluid 11 and a collection reservoir 8 comprising the perfusion fluid comprising the extracted compounds 12; iii) a bidirectional catheter 3 connecting the microdialysis probe 1 to the perfusion reservoir 7 and collection reservoir 8 contained in a microdialysis housing 6. Fig. 4 [ Fig. 4] shows a system according to a second embodiment of the invention; said system comprising a microdialysis probe 1; a bidirectional catheter 3 and a mixed reservoir 22. Said mixed reservoir 22 has the function of containing a given volume of perfusion fluid whose composition in extracted compounds (metallic cations and target molecules) increases as the fluid passes through the system through cycles. Fig. 5 [ Fig. 5] shows a dialysis system according to a third embodiment; said system comprising at least: a split lumen probe 17, comprising a second catheter 5bis allowing the entry of the biological fluid into the system and a first catheter 4bis allowing the exit of the biological fluid from the system; an extraction fluid reservoir 23 comprising i) a perfusion fluid 11; ii) a dialysis compartment comprising a dialysis membrane 18 separating the perfusion fluid 11 from the biological fluid, the biological fluid entering said dialysis compartment via the second catheter 5bis and exiting via the first catheter 4bis. Detailed description

[0034] The drawings and description below contain, for the most part, elements of a definite nature. They can therefore not only serve to better explain the present invention, but also contribute to its definition, if necessary.

[0035] The inventors have developed a medical device enabling the joint extraction of at least one metallic cation and at least one target molecule, preferably at least two target molecules, from a fluid, biological aggregate, organ or tissue for diagnostic or therapeutic purposes.

[0036] The term "joint extraction of at least one metal cation and at least one target molecule" means the simultaneous extraction of said metal cation and said target molecule or the successive extraction of said metal cation and said target molecule in any order, the extraction of these two compounds being carried out with a short period of time between the two extractions, that is to say preferably less than 24h, more preferably less than 12h, more preferably still less than 1 hour.

[0037] The term "a metallic cation" refers to at least one metallic cation. If it refers to several metallic cations, they may be of the same type or of different types.

[0038] The term "a target molecule" refers to at least one target molecule. If there are multiple target molecules, they may be of the same type or of different types.

[0039] A "ligand" is defined as a molecule that binds, preferentially reversibly, to a target molecule in a specific manner. Advantageously, the specific ligand-target molecule bond is formed through forces between molecules, such as ionic bonds, hydrogen bonds, hydrophobic interactions, and van der Waals forces. Thus, the ligand-target molecule interaction is reversible and its strength varies depending on the number and nature of the bonds formed. The strength of this interaction is defined by the affinity for the target molecule, which is related to the dissociation constant.

[0040] The extraction of these biological compounds—that is, the metallic cation and the target molecule—aims to maintain homeostasis in these compounds for therapeutic or diagnostic purposes. Maintaining homeostasis means regulating the concentration of these compounds within an organism, particularly to extract excess compounds that may be responsible for pathologies. These compounds may be present in excess within a biological fluid or a biological aggregate. The extraction of one of the components may also aim to reduce the concentration of at least one of the biological compounds below the solubility threshold of the biological aggregates associated with the pathology, thereby decreasing their formation and / or causing their dissolution.

[0041] The term "biological fluid" refers to any fluid produced by the organism to which it relates. This may be a circulating or non-circulating fluid. More specifically, it may include blood, lymph, bone marrow, chyle, any interstitial fluid, cerebrospinal fluid (CSF), or more specifically cerebrospinal fluid or spinal fluid, synovial fluid, and peritoneal fluid.

[0042] The term "biological aggregate" refers to any accumulation of target molecules and / or metals in the form of fibrils, matrix compounds, or plaques. Examples include amyloid components in the form of fibrils or plaques, accumulations of Tau proteins, fatty plaques such as atherosclerotic plaques, and so on.

[0043] According to the invention, the term "organ" means any organ with which the device of the invention can be brought into contact or into which said device can be implanted or inserted. Preferably, the organ(s) are chosen from among the brain, liver, pancreas, intestines, and lungs.

[0044] According to the invention, the term "tissue" refers to all tissues with which the device of the invention can be brought into contact or into which said device can be implanted or inserted. Preferably, the tissue(s) are chosen from the peritoneum and tumor tissue (where applicable, from a tumor). For example, said device can be brought into contact, inserted, or implanted endoscopically, particularly within a tumor.

[0045] By "at least one", we mean one or more of the compounds in question, of the same nature or of different natures.

[0046] The term "dialysis" also refers to specific types of dialysis such as, for example, microdialysis.

[0047] The extraction device includes a ligand with a specific affinity for the target molecule. This compound is thus capable of binding specifically to the target molecule. It may be an antibody, a nanobody, a peptide, a protein, or any other ligand capable of binding specifically to the target molecule.

[0048] The term “antibody” means an immunoglobulin made up of 4 polypeptide chains, two heavy H and two light L, capable of specifically binding an antigen, also called the target molecule in the context of the present invention.

[0049] The term "nanobody" refers to an antibody element capable of specifically binding to a target antigen or molecule within the framework of the present invention.

[0050] An "artificial protein ligand" (also known as a "scaffold protein" or "engineered protein") is defined as a compound or protein fragments selected for their affinity for specific target molecules. They are generally lighter than antibodies, often easier to produce, and chemically stable. Advantageously, artificial protein ligands are less than 50 kDa, preferably less than 30 kDa, and even more preferably less than 3 kDa. Such ligands exhibit a good specific surface area. These artificial protein ligands can be selected from among: ABD, Adhiron, Adnectin, Affibody, Affilin, Affimer, Affitin, Alphabody, Anticalin, Armadillo repeat proteins, Atrimer / tetranectin, Avimer / Maxibody, Centyrin, and DARPin1.

[0051] The extraction device further includes a means for extracting at least one metallic cation, said means being a perfusion fluid comprising at least one chelating agent, said perfusion fluid being contained in a dialysis system.

[0052] According to the invention, the term "chelating agent" refers to an organic group capable of complexing at least one metal cation. The complexation reaction may be a transmetallation, that is, an exchange of two metal cations. In such a case, the chelating agent may be pre-complexed with a first metal cation, which will subsequently be exchanged with the target metal cation.

[0053] In an advantageous embodiment, at least 10% of the chelating agents of said device are pre-complexed with an alkaline earth cation, preferably 20%, more preferably 30% and more preferably still more than 50% of the chelating agents of said device are pre-complexed with an alkaline earth cation.

[0054] According to a preferred embodiment, the complexation constant log(KC1) of said chelating agent for at least one of said metal cations is greater than 10, in particular 11, 12, 13, 14, 15 and is preferably greater than or equal to 15. When the chelating agent is pre-complexed with a first metal cation, the complexation constant log(KC1') for the first metal cation is less than the complexation constant log(KC1) of the target metal cation.

[0055] Advantageously, the complex chelating agent with a constant at least greater than or equal to 10 and preferably greater than or equal to 15, is at least one of the following metal cations: Copper (Cu), Iron (Fe), Zinc (Zn), Mercury (Hg), Cadmium (Cd), Lead (Pb), Aluminum (Al), Manganese (Mn), Arsenic (As), Mercury (Hg), Cobalt (Co), Nickel (Ni), Vanadium (V), Tungsten (W), Zirconium (Zr), Titanium (Ti), Chromium (Cr), Silver (Ag), Bismuth (Bi), Tin (Sn), Scandium (Sc), Yttrium (Y), Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Samarium (Sm), Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), Lutetium (Lu), Actinium (Ac), Uranium (U), Plutonium (Pu), Americium (Am) taken alone or in combination. Even more advantageously, the chelating agent complexing at least one of the metal cations Copper, Iron, Zinc, Mercury, Cadmium, Lead, Aluminum, Manganese, and Gadolinium, particularly Manganese and Gadolinium.Even more advantageously, the complex chelating agent binds at least one of the metal cations Copper, Iron and Zinc, taken alone or in combination.

[0056] Advantageously the specificity of the chelating agent for said metallic cation to be extracted is high compared to other cationic trace elements, in particular the difference between the complexation constants is preferably greater than 3 and; more particularly, the difference between the complexation constants with calcium and magnesium is preferably greater than 3 and even greater than 5.

[0057] According to a preferred embodiment, the device, or more specifically the means for extracting at least one metal cation, also contains trace elements, selected from calcium, magnesium, iron, copper, zinc, and manganese, either within the perfusion fluid or directly on the chelating agent. In the latter case, this is a transmetallization reaction, and the cations are specifically chosen to enable such a reaction. This embodiment allows, for example, the regulation of essential metal homeostasis. The chelating agent contains at least one alkaline earth cation, preferably a cation of metals selected from calcium and magnesium.

[0058] According to one embodiment of the invention, the metallic cation extraction means makes it possible to extract said metallic cation from a biological fluid, a biological aggregate, an organ or a tissue when its content is less than 1 ppm, in particular 0.1 ppm, 0.01 ppm and is preferably less than 1 ppb.

[0059] According to an advantageous embodiment, said means of extracting the metal cation makes it possible to extract a quantity of metal cations representing at least 1% of its mass and, preferably, more than 10% of its mass.

[0060] Furthermore, the extraction device includes at least one ligand with a specific affinity for a target molecule. This target molecule is preferentially chosen from proteins, peptides, and glycoproteins, and even more preferably from components of amyloid structures. In an advantageous embodiment, the target molecule comprises a specific peptide sequence recognized by the ligand.

[0061] According to one embodiment of the invention, the target molecule is chosen from proteins, peptides, glycoproteins.

[0062] Advantageously, the target molecule is chosen from among amyloidogenic proteins and components of amyloid structures, particularly in native monomeric form or as oligomers, fibrils, or biological aggregates. The target molecule may also be one or more molecules responsible for the formation or accumulation of said oligomers, fibrils, or biological aggregates.

[0063] According to a preferred embodiment, the target molecule is chosen from among the molecules involved in amyloidosis, tauopathies or any pathology presenting a deposit based on one or more proteins.

[0064] According to an embodiment compatible with the preceding embodiments, the target molecule is chosen from proteins and / or their precursors such as light and heavy immunoglobulin chains, serum amyloid protein, transthyretin, apolipoprotein AI, All, AVI, CII or CIII, beta 2 microglobulin, gelsolin, lysozyme, fibrinogen, cystatin C, atrial natriuretic factor, calcitonin, amylin, insulin, prolactin, lactoferrin, cadherin, A-Bri, A-Dan, beta amyloid peptide, prion protein, alpha-synuclein, Tau protein, superoxydismutase, huntingtin, neuroserpin, actin, ferritin or mixtures thereof.

[0065] Preferably, the ligand is an antibody or an artificial protein ligand of the target molecule. Advantageously, the ligand is chosen from: antibodies targeting beta-amyloid protein, preferably Aducanumab, Crenezumab, Ponezumab, GSK933776, Gantenerumab, AAB-003, AAB-001, BAN2401, LY2599666, LY3002813, LY3372993, MEDI1814, SAR228810; antibodies targeting alpha-synuclein, preferably BII054 or PRX002; antibodies targeting tau protein, preferably BII076, BII092, ABBV-8E12, JNJ-63733657, LY3303560, RG7345, RO7105705, UCB0107; antibodies targeting serum amyloid protein, preferably: Dezamizumab or GSK2398852, Miridesap or GSK2315698, GSK3039294; antibodies targeting transthyretin, preferably PRX004; aptamers; antibodies targeting molecules, including proteins, peptides and / or their precursors, involved in amyloidosis, tauopathies or pathologies with protein-based deposition; or all proteins and their precursors;Artificial protein ligands, advantageously less than 50 kDa, preferably less than 30 kDa, and more preferably less than 3 kDa, are grafted onto a nanoparticle, preferably a polysiloxane nanoparticle, or a polymer with a hydrodynamic diameter greater than 5 nm, preferably greater than 100 kDa, and advantageously less than 1 µm in hydrodynamic diameter or less than 1 MDa. Such ligands exhibit a good specific surface area. In this embodiment, there may be one or more proteins per nanoparticle or polymer. Furthermore, it is possible to graft one or more chelating agents onto the nanoparticle or polymer. These artificial protein ligands can be chosen from: ABD, Adhiron, Adnectin, Affibody, Affilin, Affimer, Affitin, Alphabody, Anticalin, Armadillo repeat proteins, Atrimer / tetranectin, Avimer / Maxibody, Centyrin, DARPin1, or mixtures thereof.

[0066] According to one embodiment, the extraction device includes a perfusion fluid comprising at least one chelating agent, said perfusion fluid being contained in a dialysis or microdialysis system or any miniaturized dialysis device, in particular with a fixed exchange reservoir.

[0067] Advantageously, and according to a preferred embodiment, the dialysis or microdialysis system comprises: a. a semi-permeable dialysis membrane 18 or microdialysis membrane 2, b. one or more reservoirs 7 / 8 or 22 or 23 containing the perfusion fluid.

[0068] According to one embodiment, said means of extracting the metal cation is a perfusion fluid used in a dialysis or microdialysis system which further comprises the ligand having a specific affinity for the target molecule.

[0069] According to the invention, the term "dialysis system" means any system allowing the passage of metallic cations and / or at least one target molecule of interest from the extraction device through a dialysis membrane 18 or microdialysis membrane 2 semi-permeable to water and to the aforementioned cations and / or molecules.

[0070] A "microdialysis system" is defined as a dialysis system performed on a very small scale. For example, a microdialysis technique requires the insertion of a small microdialysis catheter, also called a microdialysis probe, into the tissue. The microdialysis probe is designed to mimic a blood capillary and consists of a tube with a semipermeable membrane at its tip, such as a hollow fiber membrane, which is connected to the inlet and outlet tubing. Microdialysis allows for the extraction or delivery of only those compounds capable of passing through a semipermeable membrane whose cutoff threshold is chosen according to the intended application. In the case of dialysis, this is often a dynamic diffusion phenomenon, driven by the difference in concentration of diffusing species between each side of the dialysis membrane.

[0071] When using dialysis systems to extract compounds at low concentrations (metal cations and / or target molecules), the driving force is often quickly limited or saturated, and the trapping of the compound(s) in question is limited by the equilibrium concentration. Advantageously, a microdialysis system makes it possible to bypass the problems of conventional chelating agents or ligands and to extract, locally or more generally, a very high proportion of the targeted metal cations (or of metal cations and target molecules), thanks to the retention within the dialysis membrane of the complexing chemical species (chelating agent(s) and / or ligand(s)) of at least one target metal cation and / or target molecule.Chelating agents are advantageously grafted onto macromolecules or nanoparticles that have a mass greater than the membrane cutoff threshold so that the complexing species remain within the perfusion fluid on one side of the dialysis membrane. Similarly, ligands are advantageously present within or grafted onto macromolecules or nanoparticles that have, or are inherently endowed with, a mass greater than the membrane cutoff threshold. The dialysis system containing the complexing species is placed at the site of interest, for example, in the brain ( ). Figure 1 ) in the case of the treatment of neurodegenerative diseases or in the vicinity of the spinal cord ( Figure 2Since metal cations and / or target molecules are smaller than the cutoff threshold of the dialysis membrane, they can diffuse through the membrane into the perfusion fluid containing the chelating agents and / or ligands. The strong complexing properties of the chelating agents and / or ligands used allow for the chelation of the target metals and / or molecules even if they are present in very small quantities in the biological fluid. For example, the target compounds (metal cations and / or molecules) may be present in small quantities in the biological fluid because they are in the form of biological aggregates.Chelation of metal cations and / or binding to target molecules will therefore decrease the concentration of the compounds to be extracted in the solution within the reservoir containing the perfusion fluid. This maintains a strong concentration gradient of the compounds to be extracted across the dialysis membrane 18 or microdialysis membrane 2, thus prolonging the extraction and maintaining a flow of target compounds. To avoid disrupting the homeostasis of other compounds, such as other metal cations and other molecules present in the biological fluid, these elements may be included in the perfusion fluid at a concentration equivalent to that of the biological fluid.

[0072] Dialysis or microdialysis devices known to those skilled in the art may be used, provided they contain a semi-permeable dialysis membrane and a reservoir containing a perfusion fluid with at least one chelating agent and / or ligand as mentioned above. For example, devices that may be used include medical devices developed by M Dialysis AB, Sweden; Integra Life Sciences; and, in particular, microdialysis catheters (references 8010509, P000049, 8010337, this list being non-exhaustive).

[0073] Dialysis systems, advantageously compact dialysis systems, or microdialysis systems can be used with a fixed-volume exchange reservoir 22 or 23. The specific capture of the cations to be extracted by the chelating agent and that of the target molecule by the ligand maintain a purification gradient between the biological fluids to be purified and the perfusion fluid, even for small volumes of non-circulating fluids. In this embodiment, the components of the biological fluids to be purified are preserved.

[0074] In one embodiment, the dialysis system comprises a dialysis membrane 18 and a fixed-volume reservoir 23, preferably without fluid circulation. Advantageously, the reservoir has a volume of less than 100 ml, preferably less than 20 ml, and even more preferably less than 10 ml. Such a dialysis system is particularly suitable for a biological fluid such as cerebrospinal fluid.

[0075] Advantageously, and according to a preferred embodiment, the dialysis or microdialysis system comprises a microdialysis probe 1 continuously perfused with an infusion fluid in the form of an aqueous solution (perfusate) that resembles the (ionic and / or molecular) composition of the surrounding biological fluid at a low flow rate of less than 1 mL / min and preferably less than 0.1 mL / min. According to another embodiment, the means for extraction comprises a dialysis probe 1 continuously perfused with an infusion fluid at a flow rate of less than 10 mL / min and preferably between 1 and 5 mL / min.

[0076] In an embodiment illustrated in the figure 3 The system includes at least: a perfusion reservoir 7 comprising the perfusion fluid 11 and a collection reservoir 8 comprising the perfusion fluid comprising the extracted compounds (metallic cations and target molecules) 12; a bidirectional catheter 3 connecting the microdialysis probe 1 to the perfusion reservoir 7 and to the collection reservoir 8; a microdialysis probe 1 comprising i) a first lumen 4 allowing the passage of the perfusion fluid 11 to a second lumen 5, said second lumen 5 allowing the evacuation of the perfusion fluid comprising the extracted compounds 1e to the collection reservoir 8 and ii) a microdialysis membrane 2 between the second lumen 5 and the outside of the microdialysis probe 1 in contact with the biological fluid.

[0077] The microdialysis probe is preferably a linear or concentric probe. According to an embodiment illustrated in the figure 3The microdialysis probe is a concentric probe, the first lumen 4 being advantageously contained within the second lumen 5. Such a dialysis or microdialysis system allows not only the extraction of metallic cations and target molecules but also the performance of quantitative and / or qualitative analyses of the biological fluid.

[0078] In another embodiment illustrated in the figure 4The system includes a microdialysis probe 1 and a bidirectional catheter 3, as in the previous model. The system further includes, instead of a perfusion reservoir and a collection reservoir, a single reservoir, referred to as the mixed reservoir 22. The mixed reservoir 22 is designed to contain a given volume of perfusion fluid, the concentration of which (metallic cations and target molecules, free and / or bound and / or chelated) increases with each fluid flow cycle through the device. Advantageously, the dialysis or microdialysis system is equipped with a system for replacing the perfusion fluid in the mixed reservoir 22. After several fluid cycles, the fluid saturated with extracted compounds can be replaced with perfusion fluid free of compounds to be extracted.

[0079] In another embodiment illustrated in the figure 5 The dialysis system includes: a separate lumen probe 17, comprising a second catheter 5bis allowing the entry of biological fluid into the system (indicated "unpurified biological fluid 19 - figure 5 ) and a first catheter 4bis allowing the biological fluid to exit the system (indicated "purified biological fluid 20" - figure 5A reservoir 23 comprising i) an perfusion fluid 11; ii) a dialysis compartment comprising a dialysis membrane 18 separating the perfusion fluid 11 from the biological fluid 19, 20, the biological fluid entering said dialysis compartment via the second catheter 5bis and exiting via the first catheter 4bis. The bidirectional catheter 3 allows connection between the split-lumen probe 17 and the reservoir 23 contained in the compact dialysis unit 6. Advantageously, the perfusion fluid 11 is not circulating. A device advantageously allows for the intermittent replacement of said perfusion fluid 11, i.e., at given time intervals, when the free concentration of metal cations and / or target molecules is at or near equilibrium with that of the biological fluid. In one embodiment, the dialysis compartment is located within the perfusion fluid.

[0080] According to an advantageous embodiment compatible with any of the preceding embodiments, the tanks 7 / 8, 22 or 23 are included in a housing 6 further comprising at least one of the following elements: a miniaturized pump 9; a lockable connection system 10 suitable for enabling or stopping the circulation of fluid in the catheter(s) 3, optionally said lockable connection system is suitable for disconnecting the housing 6 and the probe 1 or 17 in order, for example, to be able to replace one of the two independently; at least one sensor 16 suitable for measuring the velocity of the fluid within the dialysis or microdialysis system, the pressure within said system or any other parameter relating to the fluid, for example its temperature, and / or its composition;an electronic control / recording system 15 capable of calibrating the flow rate or infusion duration parameters, allowing, for example, action on the pump(s) 9, comprising, for example, an electronic board 14, a control screen 13 capable of displaying the parameters measured within the dialysis or microdialysis system, a syringe pump 21, preferably included in the infusion reservoir 7 in order to circulate the infusion fluid 11 within the system; optionally a regulation and communication device with the outside.

[0081] According to a preferred mode, the perfusion fluid comprises i) a nanoparticle solution including at least one chelating agent as an active ingredient and ii) a solution of at least one ligand having a specific affinity for the target molecule, the average diameter of said nanoparticles and that of the ligand being greater than the pores of the dialysis membrane 18 or microdialysis membrane 2. In one aspect, the cutoff threshold of the porous dialysis membrane 18 or microdialysis membrane 2 is less than the mass of the chelating agent, i.e. the mass of the nanoparticle including at least one chelating agent.

[0082] Alternatively, the perfusion fluid comprises a polymer solution, said polymers being grafted to at least one active ingredient, which is a chelating agent, and a solution of at least one ligand exhibiting a specific affinity for the target molecule, the average diameter of which is greater than the pores of said dialysis or microdialysis membrane. In this aspect, the cutoff threshold of the dialysis membrane 18 or microdialysis membrane 2 is less than the mass of the chelating agent, i.e., the mass of the polymer to which at least one chelating agent is grafted.

[0083] According to the invention, the term "solution" refers to a mixture of liquid and solid particles, which remain regularly dispersed, the particles often being small enough (microscopic or nanoscopic) for the mixture to remain stable and homogeneous.

[0084] In an advantageous embodiment, the perfusion fluid is an "artificial cerebrospinal fluid" type liquid comprising chelating agents based on polysiloxane and / or chitosan. Advantageously, it contains approximately 1 to 10 millimoles per liter of chelating agents of the EDTA, DTPA, and DOTA type. In a preferred embodiment, it may be one of the MetAEx® or proMetAEx® solutions marketed by Mexbrain.

[0085] According to one embodiment, said average diameter is greater than the pores of said dialysis or microdialysis membrane by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0086] According to the invention, the term "mean diameter" refers to the harmonic mean of the diameters of the compounds, particularly nanoparticles or polymers, and the ligands. The compound size distribution is measured, for example, using a commercial particle size analyzer, such as a Malvern Zeta Sizer Nano-S based on PCS (Photon Correlation Spectroscopy), which is characterized by a mean hydrodynamic diameter. A method for measuring this parameter is also described in ISO 13321:1996.

[0087] In one embodiment, the solution contains more than 1% by mass of nanoparticles or polymers, in particular more than 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and preferably more than 10% by mass.

[0088] In one embodiment, the chelating agent can be grafted onto the specific ligand of the target molecule. Thus, chelating agents can be directly attached, for example by covalent and covalent bonds and, more particularly, by peptic bonds, to the ligands.

[0089] The nanoparticles usable in the extraction device advantageously include two characteristics: They are based on polysiloxane or carbon, they have an average hydrodynamic diameter greater than 3 nm and preferably less than 50 nm.

[0090] In one embodiment, the nanoparticle comprises, as an active principle, at least one chelating agent capable of complexing metal cations, said chelating agent having a complexation constant log(KC1) for at least one of said metal cations greater than 10 and, preferably, greater than or equal to 15.

[0091] According to the invention, the term "silica-based nanoparticles" means nanoparticles characterized by a silicon mass percentage of at least 8%.

[0092] According to the invention, the term "polysiloxane-based nanoparticles" means nanoparticles characterized by a silicon mass percentage of at least 8%.

[0093] According to the invention, the term "polysiloxane" refers to an inorganic crosslinked polymer consisting of a chain of siloxanes.

[0094] The structural units of polysiloxane, whether identical or different, have the following formula: Si(OSi)nR4-n in which: R is an organic molecule linked to silicon by a covalent bond SiC n is an integer between 1 and 4.

[0095] As a preferred example, the term "polysiloxane" notably includes polymers resulting from the sol-gel condensation process of tetraethylorthosilicate (TEOS) and aminopropyltriethoxysilane (APTES).

[0096] Advantageously, the said nanoparticle comprises the following: a. polysiloxanes, with a silicon mass ratio of at least 8% of the total nanoparticle mass, preferably between 8% and 50% of the total nanoparticle mass, b. chelating agents, preferably in a proportion of between 5 and 1000, and preferably between 50 and 500 per nanoparticle, c. where appropriate, metallic elements, for example in a proportion of between 50 and 500, and preferably between 100 and 200 per nanoparticle, said metallic elements being complexed with the chelating agents.

[0097] In one embodiment, the nanoparticles usable according to the present invention do not comprise any metallic elements. In other words, in the above definition, said nanoparticle comprises only elements a. (polysiloxanes or silicon) and b. (chelating agents).

[0098] In one embodiment, the chelating agents complex the metal cations Cu, Fe, Zn, Hg, Cd, Pb, Mn, Al, Ca, Mg, Gd.

[0099] In one embodiment, the chelating agents are obtained by grafting (covalent bonding) onto the nanoparticle one of the following complexing molecules or its derivatives, such as polyamine polycarboxylic acids and their derivatives, in particular selected from: DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), DO3A-pyridine of formula (I) below: EDTA (2,2',2",2"'-(ethane-1,2-diyldinitrilo)tetraacetic acid), EGTA (ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTAGA (2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid), DFO (deferoxamine), amide derivatives such as DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10 tetraazacyclododecane) or NOTAM (1,4,7-tetrakis(carbamoylmethyl)-1,4,7-triazacyclononane), as well as mixed carboxilic acid / amide derivatives, phosphonic derivatives such as DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate)) or NOTP (1,4,7-tetrakis(methylene phosphonate)-1,4,7-triazacyclononane), cyclamium derivatives such as TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'- tetraacetic acid), TETAM (1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'- tetrakis(carbamoylmethyl)), TETP (1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'- tetrakis(methylene phosphonate)) or mixtures thereof.

[0100] Preferably, the above-mentioned chelating agents are linked directly or indirectly by covalent bonding to the silicon atoms of the polysiloxanes in the nanoparticle. The term "indirect" linking refers to the presence of a molecular linker or spacer between the nanoparticle and the chelating agent, said linker or spacer being covalently bonded to one of the constituents of the nanoparticle.

[0101] According to a preferred embodiment, said nanoparticle is a polysiloxane-based nanoparticle with an average hydrodynamic diameter between 3 and 100 nm, comprising the chelating agent obtained by grafting DOTA, DOTAGA, EDTA or DTPA onto the nanoparticle.

[0102] According to a preferred embodiment, said nanoparticle is a nanoparticle with an average diameter greater than 20 kDa and less than 1 MDa, comprising the chelating agent obtained by grafting DOTA, DOTAGA, EDTA or DTPA onto the nanoparticle.

[0103] According to a preferred embodiment, said solution comprising said nanoparticles also contains trace elements, selected from Calcium, Magnesium, Iron, Copper, Zinc or Manganese.

[0104] In another embodiment of the invention, polymers may be used instead of the aforementioned nanoparticles. In such a case, said polymers are grafted onto at least one chelating agent.

[0105] The term "polymer" refers to any macromolecule formed by the covalent linking of a very large number of repeating units derived from one or more monomers. Preferred polymers include, for example, chitosan, polyacrylamide, polyamine, polycarboxylic acid, polyethylene glycol, and polyvinyl alcohol (PVA) families. For instance, these may be polymers containing amine groups, such as chitosan. In a preferred embodiment, the polymer is biocompatible.

[0106] In one embodiment, the chelating agents or their derivatives grafted onto said polymers are polyamine polycarboxylic acids and their derivatives, in particular selected from: DOTA, DTPA, DO3A-pyridine of formula (I) above, EDTA, EGTA, BAPTA, NOTA, DOTAGA, DFO, DOTAM, NOTAM, DOTP, NOTP, TETA, TETAM and TETP or mixtures thereof.

[0107] Preferably, the above-mentioned chelating agents are linked directly or indirectly by covalent bond to the polymer or to a polymer chain of more than 10 kDa and preferably more than 100 kDa. The term "indirect" linkage means the presence of a molecular "linker" or "spacer" between the polymer and the chelating agent, said linker or spacer being covalently bonded to one of the constituents of said polymer.

[0108] In one embodiment, the chelating agents or their derivatives grafted onto said polymers will comprise dithiocarbamate functions.

[0109] According to a preferred embodiment, said polymer grafted to a chelating agent is selected from: chitosan grafted to DPTA-BA or chitosan grafted to DFO or chitosan grafted to EDTA-BA or chitosan grafted to DOTAGA-A.

[0110] According to a preferred embodiment, said solution comprising said polymers also contains trace elements, selected from Calcium, Magnesium, Iron, Copper, Zinc, or Manganese.

[0111] Alternatively, the perfusion fluid is a solution of chelating agents. These chelating agents may have an average diameter greater than the pores of the dialysis or microdialysis membrane, i.e., greater than the membrane's cutoff threshold, in order to be retained within the dialysis membrane fluid. In another embodiment, they may have an average diameter smaller than the pores of the dialysis or microdialysis membrane, and in this case, they may pass through the membrane pores before entering the body and being naturally eliminated by the kidneys or liver. Industrial application

[0112] The invention may be applicable in particular in the maintenance of homeostasis, especially the maintenance of homeostasis of two target compounds such as a metal cation and a target molecule.

[0113] According to a preferred embodiment, the device for the joint extraction of at least one metal cation and at least one target molecule from a biological fluid or biological aggregate mentioned above is used in the treatment of a disease selected from: Systemic and / or localized amyloidosis; in particular, amyloidosis selected from: AL amyloidosis (immunoglobulin light chains), AH amyloidosis (immunoglobulin heavy chains), AA amyloidosis (serum amyloid protein), ATTR amyloidosis (transthyretin), amyloid cardiomyopathies, renal amyloidosis, type II diabetes, prion diseases or diseases related to an amyloid protein. Amyloidosis is also implicated in neurodegenerative diseases, including Alzheimer's disease (beta-amyloid), Parkinson's disease (alpha-synuclein), amyotrophic lateral sclerosis (superoxide dismutase), Huntington's disease (Huntingtin).tauopathies, in particular: selected tauopathies from: Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia; pathologies presenting a deposit based on at least one protein; diseases presenting a metallic dyshomeostasis, in particular Wilson's disease or neurological disorders without amyloid features, such as autism or schizophrenia, or neurological disorders with amyloid features such as the amyloidoses mentioned above, affecting or not the central and / or peripheral nervous system.

[0114] According to a preferred embodiment, the device for the joint extraction of at least one metal cation and at least one target molecule from the aforementioned biological aggregate is used to slow down the formation, dissociate or dissolve a biological aggregate, preferably in the form of oligomers, fibrils or plaques comprising at least the target molecule, and is used in diagnosis, prevention and / or therapy.

[0115] A present aspect of the application, but not part of the invention, also relates to a method for extracting metal cations and target molecules from a subject comprising the administration of an implant onto which at least one chelating agent is grafted, or the use of a perfusion fluid containing at least one chelating agent within a device such as those mentioned above.

[0116] According to the invention, the said "subject" is understood to be a man or an animal to be prevented or treated.

[0117] The invention is not limited to the preceding description but encompasses all the variants that a person skilled in the art may consider within the framework of the protection sought; the extent of the protection sought by the present invention is limited by the play of the claims. List of reference signs

[0118] 1. Microdialysis probe 2. Microdialysis membrane 3. Bidirectional catheter 4. First lumen 4bis. First catheter 5. Second lumen 5bis. Second catheter 6. Compact housing 7. Infusion reservoir 8. Collection reservoir 9. Pump 10. Lockable connection system 11. Infusion fluid 12. Infusion fluid containing extracted compounds (metal cations and target molecules) 13. Control screen (parameter display) 14. Electronic board 15. Parameter control 16. Sensors 17. Dual lumen probe 18. Dialysis membrane 19. Unpurified biological fluid 20. Purified biological fluid 21. Syringe pump 22. Combination reservoir 23. Reservoir List of documents cited Patent documents

[0119] For the record, the following patent document(s) is / are cited: US2013 / 0045216 A1 (Appl. No.: US13 / 655,234) Non-patent literature

[0120] For the record, the following non-patent element(s) is / are cited: G. Crisponi, V. M. Nurchi, V. Bertolasi, M. Remelli, G. Faa, « Chelating agents for human diseases related to aluminium overload », Coordination Chemistry Reviews, Volume 256, Issues 1-2, January 2012, pp. 89-104 E. J. McAllum et D.Finkelstein, « Metals in Alzheimer's and Parkinson's Disease: Relevance to Dementia with Lewy Bodies", Journal of Molecular Neuroscience, Volume 60(3), Août 2016, pp. 279-288] S. Wiethoff et H. Houlden "Neurodegeneration with brain iron accumulation", Handb. Clin. Neurol., Volume 145, 2017, pp. 57-166 J Acosta-Cabronero, Matthew J. Betts, Arturo Cardenas-Blanco, Shan Yang et Peter J. Nestor, "In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan", Journal of Neuroscience, Janvier 2016, 36 (2) pp. 364-374; A. A. Belaidi et A. I. Bush, "Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics", Journal of Neurochemistry, Vol. 139, Issue S1, 2016, pp. 179-197 Simon J.A. van den Bogaard, Eve M.Dumas, Raymund A.C. Roos "Metal Related Neurodegenerative Disease - International Review of Neurobiology, Volume 110, 2013, pp. 241-250 https: / / www.sciencedirect.com / science / article / pii / B9780124105027000119, G. Bartzokis, J. Cummings, S. Perlman, D. B. Hance, J. Mintz, Increased basal ganglia iron levels in Huntington disease, Arch. Neurol., 1999, 5, 569-574. https: / / jamanetwork.com / journals / jamaneurology / fullarticle / 775016 M. Meendez-Gonzalez, H. S. Padilla-Zambrano, G. Alvarez, E. Capetillo-Zarate, C. Tomas-Zapico, A. Costa, "Targeting beta-amyloid at the CSF: a new therapeutic strategy in Alzheimer's didease", Hypothesis and Theory, Vol. 10 (100), Avril 2018; DOI: 10.3389 / fnagi.2018.00100 Menéndez González Mechanical, "Dilution of Beta-amyloid Peptide and Phosphorylated Tau Protein in Alzheimer's Disease: Too Simple to be True?", Cureus. 2017 Feb 28;9(2):e1062. doi: 10.7759 / cureus.1062. Tõugu V., Tiiman A, Palumaa P, "Interactions of Zn(II) and Cu(II) ions with Alzheimer's amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity.", Metallomics. 2011 Mar;3(3):250-61. doi: 10.1039 / c0mt00073f. Cremades N, Dobson CM, "The contribution of biophysical and structural studies of protein self-assembly to the design of therapeutic strategies for amyloid diseases", Neurobiol Dis. 2018 Jan;109 (Pt B):178-190. doi: 10.1016 / j.nbd.2017.07.009. A Czlonkowska, T. Litwin, P. Dusek, P. Ferenci, S. Lutsenko, V. Medici, J. K. Rybakowski, K. H. Weiss, M. L. Schilsky, Wilson disease, Nature Rev. Dis. Primers, 2018, 4:21. https: / / www.nature.com / articles / s41572-018-0018-3. Pfaender S, Grabrucker AM. Characterization of biometal profiles in neurological disorders. Metallomics. 2014 May;6(5):960-77.Boland B, Yu WH, Corti O, Mollereau B, Henriques A, Bezard E, Pastores GM, Rubinsztein DC, Nixon RA, Duchen MR, Mallucci GR, Kroemer G, Levine B, Eskelinen EL, Mochel F, Spedding M, Louis C, Martin OR, Millan MJ. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2018 Sep;17(9):660-688. ladanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE.A new era for understanding amyloid structures and disease. Nat Rev Mol Cell Biol. 2018 Dec;19(12):755-773.

Claims

1. A device for the simultaneous extraction of at least one metal cation and at least one target molecule from a patient's biological fluid for therapeutic purposes, characterised in that it includes a dialysis or microdialysis system comprising a dialysis membrane and a reservoir comprising a perfusion fluid, said perfusion fluid being selected from: - a solution of nanoparticles, with said nanoparticles being grafted to at least one active ingredient that is a chelating agent for the metal cation, and a solution of at least one ligand having a specific affinity for the target molecule, the mean diameter of said nanoparticles and that of the ligand being greater than the pores of the dialysis membrane, - a solution of polymers, with said polymers being grafted to at least one active ingredient that is a chelating agent for the metal cation, and a solution of at least one ligand having a specific affinity for the target molecule, the mean diameter of said polymers and said ligand being greater than the pores of the dialysis membrane.

2. The device according to claim 1, characterised in that: - the complexation constant log(KC1) of the chelating agent for at least one metal cation is greater than 10, preferably greater than or equal to 15 and - said at least one cation is selected from cations of the metals Cu, Fe, Zn, Hg, Cd, Pb, Mn, Co, Gd, and Al, either alone or in combination, and more particularly Cu, Fe, and Zn, either alone or in combination.

3. The device according to any one of the preceding claims, characterised in that the chelating agents are obtained by grafting, onto the nanoparticles or onto the polymer, one of the following complexing molecules: DOTA, DTPA, EDTA, EGTA, BAPTA, NOTE, DOTAGA, DFO, DOTAM, NOTAM, DOTP, NOTP, TETA, TETAM, TETP and DTPABA, or mixtures thereof.

4. The device according to any one of the preceding claims, characterised in that said nanoparticles are polysiloxane-based nanoparticles with a mean diameter between 3 and 50 nm, comprising the chelating agent obtained by grafting DOTA, DOTAGA, EDTA or DTPA onto the nanoparticles.

5. The device according to any one of the preceding claims, characterised in that the chelating agent contains at least one alkaline earth cation, preferably a cation of metals selected from Ca and Mg.

6. The device according to any one of the preceding claims, characterised in that the nanoparticles are based on polysiloxane, or said polymers are based on chitosan, polyethylene glycol, or polyvinyl alcohols.

7. The device according to any one of the preceding claims, characterised in that the target molecule is selected from proteins, peptides, and glycoproteins, in particular, the target molecule is selected from amyloidogenic proteins and components of amyloid structures, in particular the target molecule is selected from proteins and / or precursors thereof such as light and heavy immunoglobulin chains, serum amyloid protein, transthyretin, apolipoprotein AI, AII, AVI, CII or CIII, beta-2-microglobulin, gelsoline, lysosyme, fibrinogen, cystatin C, natriuretic atrial factor, calcitonin, amyline, insulin, prolactin, lactoferrin, cadherin, A-Bri, A-Dan, amyloid beta peptide, prion protein, alpha-synuclein, Tau protein, superoxydismutase, huntingtin, neuroserpine, actin, ferritin, or mixtures thereof.

8. The device according to any one of the preceding claims, characterised in that the target molecule is selected from molecules involved in amyloidoses, tauopathies, or any pathology having a deposition based on one or more proteins.

9. The device according to any one of the preceding claims, characterised in that the ligand is either an antibody or an artificial protein ligand of the target molecule.

10. The device according to any one of the preceding claims, characterised in that the ligand is selected from: - antibodies targeting the beta-amyloid protein, preferably Solanezumab, Aducanumab, Crenezumab, Ponezumab, GSK933776, Gantenerumab, AAB-003, AAB-001, BAN2401, LY2599666, LY3002813, LY3372993, MEDI1814, SAR228810; - antibodies targeting alpha-synuclein, preferably BII054 or PRX002; - antibodies targeting the tau protein, preferably BII076, BII092, ABBV-8E12, JNJ-63733657, LY3303560, RG7345, RO7105705, UCB0107; - antibodies targeting the serum amyloid protein, preferably: Dezamizumab or GSK2398852, Miridesap or GSK2315698, GSK3039294; - antibodies targeting transthyretin, preferably PRX004; - aptamers; - artificial protein ligands with a specific affinity for at least one of the molecules, optionally selected from: ABD, Adhiron, Adnectin, Affibody, Affilin, Affimer, Affitin, Alphabody, Anticalin, Armadillo repeat proteins, Atrimer / tetranectin, Avimer / Maxibody, Centyrin, DARPin1; - artificial protein ligands of less than 50 kDa, preferably less than 30 kDa, and more preferably less than 5 kDa, grafted onto a nanoparticle or polymer with a hydrodynamic diameter of more than 5 nm, preferably of more than 100 kDa, or - mixtures thereof.

11. The device according to any one of the preceding claims, for use in a patient with a pathology from: - systemic and / or localised amyloidoses; preferably amyloidoses selected from: AL-type amyloidosis (light immunoglobulin chains), AH-type amyloidosis (heavy immunoglobulin chains), AA- amyloidosis (serum amyloid protein), ATTR- amyloidosis (transthyretin), amyloid heart diseases, renal amyloidoses, type II diabetes, Prion diseases, or diseases related to amyloid proteins; - tauopathies preferably selected from: Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia; - pathologies having a deposition based on at least one protein; - diseases having a metal dyshomeostasis, preferentially Wilson's disease, or neurological disorders without amyloid characteristics, such as autism or schizophrenia, etc.), or neurological disorders with amyloid characteristics, such as amyloidoses, which may or may not affect the central and / or peripheral nervous system.

12. A microdialysis system comprising an extraction device according to any one of the preceding claims, and such that it comprises at least: - an infusion reservoir (7) containing the infusion fluid (11) and a collection reservoir (8) comprising the infusion fluid comprising the extracted compounds (12); or a mixed reservoir (22) comprising the infusion fluid (11, 12); - a bidirectional catheter (3) connecting the microdialysis catheter (1) to the infusion reservoir (7) and to the collection reservoir (8) or the mixed reservoir (22) ; - a microdialysis probe (1) comprising a first lumen (4) allowing the infusion fluid (11) to pass therethrough to a second lumen (5), with the second lumen (5) allowing discharge of the infusion fluid comprising the extracted compounds (12), and a microdialysis membrane (2) situated between the second lumen (5) and the exterior of the microdialysis probe (1), in contact with the biological fluid.

13. A dialysis system comprising an extraction device according to any one of the preceding claims, and such that it comprises at least: - a probe with separate lumens (17), comprising a second catheter (5bis) allowing entry of biological fluid into the dialysis system and a first catheter (4bis) allowing exit of the biological fluid from the dialysis system; - a reservoir (23) comprising i) the infusion fluid (11); ii) a dialysis compartment comprising a dialysis membrane (18) separating the infusion fluid (11) from the biological fluid, with the biological fluid entering the dialysis compartment via the second catheter (5bis) and exiting through the first catheter (4bis) therefrom.