WO2022200260A1 - Utilisation de ligands peptidiques à énantiomères l de la superoxyde dismutase 1 (sod1) humaine plissée nativement pour le traitement de la sclérose latérale amyotrophique (sla) - Google Patents

Utilisation de ligands peptidiques à énantiomères l de la superoxyde dismutase 1 (sod1) humaine plissée nativement pour le traitement de la sclérose latérale amyotrophique (sla) Download PDF

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WO2022200260A1
WO2022200260A1 PCT/EP2022/057329 EP2022057329W WO2022200260A1 WO 2022200260 A1 WO2022200260 A1 WO 2022200260A1 EP 2022057329 W EP2022057329 W EP 2022057329W WO 2022200260 A1 WO2022200260 A1 WO 2022200260A1
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peptide
seq
sodi
peptide according
linked
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English (en)
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Dieter Willbold
Jeannine Mohrlüder
Karoline Bianka Santur
Tim Altendorf
Marc Sevenich
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Forschungszentrum Juelich GmbH
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Forschungszentrum Juelich GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to a peptide comprising the amino acid sequence according to SEQ ID NO: 1 and homologues, fragments and parts thereof, and such a peptide for use in the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Amyotrophic lateral sclerosis is a neurodegenerative disease of the motor nervous system characterized by progressive, irreversible motor neuron loss in middle age. With an incidence of 2 per 100,000, ALS is a rare disease.
  • the clinical picture of ALS is characterized by peripheral and central paresis caused by damage or degeneration of the first and second motor neurons. In the course of the disease, after initial asymmetrical paralysis of the extremities, speech and swallowing muscles, generalization of the paresis usually occurs relatively quickly. The survival time of the patients is usually 3 to 5 years after the onset of the first symptoms. Recent findings suggest that non-neuronal cells also play a role in ALS symptoms, for example by activating inflammatory processes and/or influencing signal transduction processes.
  • SODI ubiquitously expressed SODI gene
  • the goal of causal treatment should be to stabilize the native structure of SOD1 and thus minimize the formation of toxic SODI oligomers.
  • NINDS National Institute of Neurological Disorders and Stroke
  • the existing forms of therapy are purely palliative and primarily serve to treat symptoms and maintain existing abilities.
  • Riluzole is an already approved drug that affects glutamate metabolism and extends the survival time of those affected by a few months.
  • the symptoms of the disease can be improved by the therapeutic drug edaravone. It is therefore of the utmost urgency to unveil the pathomechanism underlying the clinical picture in order to develop a drug that enables causal ALS therapy and can stop or at least significantly slow down the progression of the disease.
  • a causal and significantly life-prolonging therapy for ALS is not yet available and is urgently needed.
  • the object of the present invention was therefore the development of new chemical units which can inhibit SODI aggregation by stabilizing the native conformation and which can be used therapeutically in the treatment of ALS.
  • the chemical unit to be used in therapy or its variants should bind as affinely and specifically as possible to the native, endogenous SODI protein and thus stabilize it. The balance of misfolded and natively folded SODI conformation is thus shifted in favor of the latter. Ideally, already existing SODI oligomers and fibrils can be converted into natively folded SOD1 and thus eliminated.
  • a peptide according to claim 1 in particular by a peptide comprising the amino acid sequence according to SEQ ID NO: 1, and homologues, fragments and parts thereof.
  • the peptide of SEQ ID NO: 1 was found using an optimized phage display selection.
  • the method for phage display can of course also be used to find specific oligomer binders or even to find ligands for other species that occur in protein misfolding diseases.
  • phage display z. B a recombinant library of randomized peptide sequences presented on the gp3 protein of the M13 phage and encoded in its genome, selected against the target molecule (e.g. SOD1).
  • the gp3 molecule also known as gene product 3, is a protein that is located in the phage coat and is required for contact with the host cell.
  • the peptide sequence is advantageously presented at the N-terminus of the gp3 protein of M13 phage and is encoded in its genome.
  • the DNA sequence of the p3 gene of a selected phage is linked to the DNA sequence containing the genetic information about the corresponding peptide sequence on the gp3 molecule, allowing it to be sequenced. After sequencing, the gene sequence can be transcribed into an amino acid sequence and synthesized.
  • the entirety of the phages which present different peptides as a fusion protein with gp3 on their surface is referred to below as a phage library.
  • the corresponding peptides represent the biomolecules to be selected in the experiment.
  • So-called panning rounds can be carried out, e.g. B. three rounds.
  • the phage library is brought into contact with a fixed target molecule, also known as a bait, and binding phages are isolated from the billions of background other, non-binding phages.
  • the amount of phages that preferentially bind to oligomeric or fibrillar species of SOD1 is reduced by not offering these species as bait.
  • Phage that show an increased affinity for SODI oligomers and fibrils can be removed in this way from the phage pool, so that z.
  • the procedure can, of course, be carried out in an analogous manner be adjusted to identify SODI oligomer-binding ligands and peptides.
  • different substrate surfaces are preferably used in all panning rounds.
  • a combination of the substrate used plastic plate, in this case polystyrene with a 3D NFIS matrix which has NFIS ester as a functional group
  • the blocking or quenching agents used is defined as the substrate surface.
  • the selection pressure is successively increased.
  • the concentration of the target molecule e.g. native SOD1
  • the number of washing steps after the phage incubation is continuously increased from the 2nd round of selection in order to remove phages that do not have an affinity for SODI.
  • a different substrate surface is chosen by using different agents to block the surface (e.g., BSA, milk powder, no blocking) after the target molecule has been immobilized on the substrate.
  • BSA surface-specific antigen
  • the change between different substrate surfaces increases the specificity for the target molecule or the bait compared to the surface.
  • control selections can be carried out, which are identical to the basic selection with regard to the implementation - with the important difference that no bait is used here.
  • a data analysis of the sequences resulting from the control selections enables the identification of peptides that accumulate during the selection even without decoy and are therefore irrelevant for all subsequent steps.
  • the method is characterized by the following steps: a) Providing an immobilized bait on a substrate surface. b) contacting the baited immobilized molecule with a solution containing a library of biomolecules to be selected. c) Bringing the immobilized bait occupied with the biomolecules into contact with a washing solution. d) Separation and multiplication of the biomolecules still bound to the bait after the immobilized bait occupied with the biomolecules has been brought into contact with washing solution. e) repeating said steps using a different substrate in each repetition. f) Identification of the sequence of the biomolecules remaining on the decoys after repetition.
  • a different substrate is z. B. by changing the type of substrate and / or its blocking or non-blocking by means of possibly different reagents.
  • a molecule from the group consisting of proteins, peptides, RNA, DNA, mRNA and chemical compounds is often used as a decoy.
  • natively folded SOD1 is used as the bait.
  • z. B used a component from the group consisting of microtiter plates, magnetic particles, agarose or sepharose beads.
  • the bait according to point a) is therefore a compound to which the biomolecule to be selected is to be bound. It is fixed to a first surface (the substrate) according to methods known in the art. Proteins, peptides, RNA or DNA molecules, in particular native SOD1, can be mentioned as baits by way of example but not limitation. Microtiter plates, magnetic particles, agarose or sepharose beads can be used as possible substrates, for example. The surface with the immobilized bait can then be quenched, thereby inactivating the functional groups of the substrate. In addition, the hydrophobic free areas remaining on the substrate can be blocked with suitable agents. In the second step b), the immobilized bait is brought into contact with a randomized library of molecules, specifically biomolecules.
  • the randomized library is a mixture of very many, for example 10 12 , but also 10 4 or only 100 different biomolecules in a mixture.
  • a library can consist, for example, of peptides, proteins, DNA, RNA or mRNA, which are bound to specific vehicles and which can bind to baits. Examples of suitable vehicles are phages, polysomes or bacterial surfaces.
  • the library can consist of artificial components or components isolated from nature, or a mixture of both. For the purposes of the invention, artificially means, for example, compounds produced from oligonucleotide synthesis.
  • the immobilized bait covered with biomolecules can be brought into contact with a washing substance in step c).
  • a washing step is carried out in step c), in which a buffer solution is brought into contact with or rinsed with the immobilized baits.
  • the solution with the library of biomolecules is preferably repeatedly exchanged for a possibly similar or identical solution.
  • those library molecules are removed which dissociate less quickly from the immobilized decoys than other library molecules.
  • the speed of the detachment reaction of the binding library molecules is mainly determined by the different dissociation constants (in particular the k 0ff values) of the individual molecules.
  • the liquid containing the wash buffer is preferably aqueous and may contain a pH buffer.
  • Optional components of the solution for the washing step can be salts, detergents or reducing agents.
  • the bound biomolecules are separated from the bait.
  • the separation or elution can take place, for example, by changing the pH, heating or other changes, in particular increasing the salt concentration.
  • the separated or eluted biomolecules are then multiplied using known methods. For this purpose, for example, phage particles obtained and eluted according to steps a) to c), which carry the biomolecules on their surface, can be introduced into cells and multiplied.
  • step e the concentration of the selected biomolecules in the solution that is fed to the bait after step a) is increased.
  • 3 to 6 rounds of selection containing steps a) to e) are carried out.
  • 1 to 10 or 1 to 20 repetitions can also be carried out.
  • An increase in the washing steps in step c), which is preferably carried out, with an increasing number of cycles leads to improved selection.
  • a particularly relevant phage display provides natively folded, L-enantiomeric SOD1 in step a), a recombinant phage library carrying peptides on its surface in step b) and a buffer solution in step c) in addition to native SOD1 as bait.
  • An elution as a separation step takes place z.
  • S1VL-21 e.g. sequence variation
  • the present invention may also relate to other peptides that can be identified using the method disclosed above.
  • the peptide according to SEQ ID NO: 1 can be used as a possible drug against ALS by specific binding to the natively folded SOD1.
  • the object according to the invention is also achieved by a peptide containing homologues, fragments and parts of the amino acid sequence according to SEQ ID NO:
  • SODI peptide or SODI protein is understood here as meaning preferably the SODI peptide or SODI protein, where SOD1 stands for superoxide dismutase or superoxide dismutase 1, preferably the human one.
  • homologous sequences or “homologs” means that an amino acid sequence has an identity with one of the abovementioned amino acid sequences of the monomers of at least 50, 55, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% 80% and 90% are preferred.
  • identity the terms “homologous” or “homology” are used interchangeably in the present description.
  • the identity between two nucleic acid sequences or polypeptide sequences is based on comparison using the BESTFIT program calculated on the algorithm of Smith, T.F. and Waterman, M.S (Adv. Appl. Math. 2: 482-489 (1981)) setting the following parameters for amino acids: gap creation penalty: 8 and gap extension penalty: 2; the following parameters for nucleic acids: gap creation penalty: 50 and gap extension penalty: 3.
  • the identity between sc Where two nucleic acid sequences or polypeptide sequences are defined by the identity of the nucleic acid sequence/polypeptide sequence over the entire sequence length in each case, as determined by comparison using the program GAP based on the algorithm of Needleman, S.B. and Wunsch, CD. (J. Mol. Biol. 48: 443-453) by setting the following parameters for amino acids: gap creation penalty: 8 and gap extension penalty: 2; and the following parameters for nucleic acids gap creation penalty: 50 and gap extension penalty: 3.
  • Two amino acid sequences are identical for the purposes of the present invention if they have the same amino acid sequence.
  • homologues are to be understood as meaning sequences which differ from the specified sequences by up to two or three amino acids.
  • sequences which contain the above-mentioned sequences can also be used as peptides.
  • the peptide according to the invention is preferably characterized in that an acid amide group (CONH 2 - Group) or a COH group, COCI group, COBr group, CONH-alkyl residue or a CONH-alkyl-amine residue or the peptide is present in cyclized form.
  • an acid amide group CONH 2 - Group
  • COH group COCI group
  • COBr group CONH-alkyl residue
  • CONH-alkyl-amine residue or the peptide is present in cyclized form.
  • This also particularly advantageously solves the problem of providing a peptide without a negative charge at the C-terminus.
  • This has the advantageous effect that it can bind to the target molecule with higher affinity than a peptide which has a carboxyl group at the free C-terminus.
  • peptides with a free, unmodified carboxyl group have a negative charge at this end.
  • the peptides according to the invention are in the physiological state, in particular at pH 6-8, in particular 6.5-7.5, in particular at pH 6.0, pH 6.1, pH 6.2, pH 6.3 , pH 6.4, pH 6.5 pH 6.6, pH 6.7, pH 6.8, pH 6.9, pH 7.0, pH 7.1, pH 7.2, pH 7.3, pH 7.4, pH 7.5, pH 7.6, pH 7.7, pH 7.8, pH 7.9 or pH 8.0 modified in such a way that the C-terminus does not carry a negative charge, but instead is neutral or has one or more positive charges.
  • the peptide is characterized in that an acid amide group is present at the free C-terminus instead of the carboxyl group.
  • an acid amide group (-CONH 2 group) is arranged at the C-terminus.
  • the peptide is particularly advantageously amidated at the free C-terminus and not modified at the free N-terminus.
  • the following additional groups are present instead of the carboxyl group: COH, COCl, COBr, CONH-alkyl radical, CONH-alkyl-amine radical (positive net charge), etc., without being limited to this, if the technical teaching of the main claim is followed.
  • the affinity of the binding of the peptides modified according to the invention without a negative net charge at the C-terminus is therefore by 1%, 2, 3, 4, 5, 6, 7, 8, 9, especially 10%, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
  • the Ku value as a measure of the binding affinity of a modified peptide to the natively folded SOD1 is 1%, 2, 3, 4, 5, 6 compared to a linear binding peptide with a negative charge at the free C-terminus , 7, 8, 9, especially 10%, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
  • the peptide according to the invention is further preferably characterized in that it contains 2, 3, 4, 5, 6, 7, 8, 9, 10 or more copies of the sequence with SEQ ID NO:1.
  • variants are also conceivable in which the peptide contains 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more peptides with SEQ ID NO:1.
  • Dimers of the sequences with SEQ ID NO: 1 are particularly preferred.
  • the peptide according to the invention is further preferably characterized in that the peptide consists essentially of L-amino acids.
  • the term "essentially composed of L-enantiomeric amino acids" means that the peptide used according to the invention contains at least 50%, 55%, 60%, 65%, 70%, preferably 75%, 80%, particularly preferably 85%, 90%, 95%, in particular 96%, 97%, 98%, 99%, 100% is composed of L-enantiomeric amino acids.
  • the peptide according to the invention is also preferably characterized in that it consists of the amino acid sequence according to SEQ ID NO:1.
  • the peptide according to the invention is also preferably characterized in that the peptide is linked to another substance.
  • the linkage is a chemical bond such as that described in Römpp Chemie Lexikon, 9th edition, volume 1, page 650 et seq.
  • the substances are drugs or active ingredients, defined according to the Drugs Act ⁇ 2 or ⁇ 4 (19), as of September 2012.
  • active ingredients are therapeutically active substances that are used as medicinally active substances.
  • Anti-inflammatory drugs are preferred.
  • the substances are compounds that enhance the effect of the peptides.
  • Another alternative involves compounds that improve the solubility of the peptides and/or the passage of the blood-brain barrier.
  • the peptides according to the invention have any combination of at least two or more features of the variants, embodiments and/or alternatives described above.
  • the peptide according to the invention is also preferably characterized in that several peptides of SEQ ID NO: 1 are linked to one another covalently or non-covalently.
  • a covalent connection or linkage of the peptide units is present within the meaning of the invention if the peptides are linearly linked head to head, tail to tail or head to tail, with or without linkers or linker groups inserted in between.
  • the peptide according to the invention is also preferably characterized in that several peptides of SEQ ID NO: 1 are linked to one another without a linker, ie directly linked, or are linked to one another with a linker group.
  • a non-covalent linkage within the meaning of the invention is present if the peptides are linked to one another, for example via biotin and streptavidin, in particular streptavidin tetramer.
  • the peptide according to the invention is also preferably characterized in that several peptides of SEQ ID NO: 1 are linked to one another in a linear or branched manner.
  • the peptides can be linked to one another in a linear manner, in particular as described above.
  • the peptides are linked to one another in a branched manner to form the peptide according to the invention.
  • a branched peptide can be a dendrimer in which the peptide monomers are linked to one another covalently or non-covalently.
  • the peptides can also be linked to a platform molecule (such as PEG or sugar) to form a branched peptide.
  • a platform molecule such as PEG or sugar
  • the affinity of the binding of the peptides is defined via the dissociation constant (Ku value).
  • the dissociation constant (BRA value) of a peptide according to the invention is advantageously reduced in an advantageous embodiment of the invention. Associated with this are improved properties of the peptides according to the invention, such as higher binding affinity and higher effectiveness of the degradation and/or prevention of the formation of toxic SODI oligomers or aggregates.
  • peptides are used which bind to native SOD1 with a dissociation constant (ku value) of at most 500 pM, preferably 250, 100, 50 pM, particularly preferably 25, 10, 1 pM, particularly preferably with a dissociation constant ( Ku value) of at most 500 nM, 250, 100, 50, particularly preferably 25, 10, 1 nM, 500 pM, 100, 50, 25, 20, 15, 10, 9,
  • a dissociation constant es are used which bind to native SOD1 with a dissociation constant (kra value) of at most 500 pM, preferably 250, 100, 50 pM, particularly preferably 25, 10, 1 pM, 500 pM, 100, 50, 25, 20, 15, 10, 9,
  • the peptides according to the invention are also preferably characterized in that they bind to the native SOD1 with a K D of less than 20 pM.
  • the peptides can be produced, for example, via chemical synthesis or peptide synthesis.
  • Peptide according to any one of the preceding claims for preventing the formation of SODI peptide oligomers and/or SODI peptide aggregates.
  • Another variant is a peptide according to the invention for inhibiting or preventing the formation of SODI peptide oligomers and/or SODI peptide aggregates.
  • Another variant is a peptide according to the invention for the detoxification of SODI peptide oligomers and/or SODI peptide aggregates.
  • the peptides according to the invention detoxify the SODI peptide oligomers and/or SODI peptide aggregates or polymers formed therefrom, as well as fibrils, preferably by binding to natively folded SOD1 rather than to them and by shifting the equilibrium to the reduction of the SODI oligomers and thus lead to them converted into non-toxic compounds. Accordingly, the subject of the present invention is also a method for detoxifying the SODI oligomers, aggregates or fibrils formed therefrom.
  • SODI peptide oligomers and/or SODI peptide aggregates can take place in vitro or in vivo.
  • the present invention also relates to a peptide according to any one of the preceding claims for use in the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the S1VL-21 peptide was examined in more detail.
  • S1VL-21 exhibits micromolar binding affinity to hSODI.
  • MST measurement of CF633-hSODI (250 nM) and the peptide S1VL-21 with increasing concentration (13 nM - 210 pM) in 50 mM sodium acetate buffer pH 6 including 150 mM NaCl and 0.05% Tween-20 were performed at 25 °C with an LED and MST output of 40% on the Monolith NT.115 (Nanotemper technologies, Kunststoff, Germany).
  • a ThT assay was performed to analyze the influence of S1VL-21 on amyloid-like hSODI aggregation.
  • 5 pM native hSODI corresponds to 10 pM monomeric hSODI
  • 5 mM EDTA corresponds to 10 pM monomeric hSODI
  • 150 mM NaCl and 5 pM ThT for 15 min at 37° C incubated before the measurement of the fluorescence intensity development was started in a microtiter plate with one stainless steel ball (3.2 mm) per well.
  • Figure 3 Atomic force microscopy images of the resulting hSODI species after aggregation indicate less formation of large hSODI aggregates when incubated with S1VL-21.
  • the flea images were performed with a Nanowizard3 system (JPK Instruments AG, Berlin, Germany) with 10 pL of the samples from the ThT assay as described in Figure 2 after 65 h of aggregation. Samples were incubated on a freshly cleaved mica for 10 min at RT and then washed 4x with 100 pL ddl-hO before they were carefully dried with l ⁇ . The measurements were made with a resolution of 512 pixels at a line rate of 0.5 to 2 Hz in intermittent contact mode with a silicon cantilever with a nominal spring constant of 26 N/m and a nominal tip radius of 7 nm. The data was processed with Using the manufacturer's data processing software (JPK Data Processing Software 5.0.69). A.
  • Figure 4 Additional atomic force microscopy images of the samples from Figure 3 for an overview of the distribution of hSODI aggregates and to assess the influence of S1VL-21 on hSODI aggregation.
  • the height images were performed with a Nanowizard3 system (JPK Instruments AG, Berlin, Germany) with 10 pL of the samples from the ThT assay as described in Figure 2 after 65 h of aggregation.
  • the samples were incubated on a freshly split mica for 10 min at RT and then washed 4 ⁇ with 100 ⁇ L ddH2O before they were carefully dried with l ⁇ .
  • the measurements were made with a resolution of 256 pixels at a line rate of 2 Hz in intermittent contact mode with a silicon cantilever with a nominal spring constant of 26 N/m and a nominal tip radius of 7 nm.
  • the data was processed for comparison of the samples using the manufacturer's data processing software (JPK Data Processing Software 5.0.69) with the same parameters.
  • JPK Data Processing Software 5.0.69 JPK Data Processing Software 5.0.69
  • a cell viability assay was performed with Neuro2a cells (2500 cells/well) cultured in a microtiter plate in DMEM containing 10% FBS and 1% streptomycin and penicillin. After 6 h, the cells were treated with the pellet of the hSODI samples, which were incubated with and without increasing concentrations of S1VL-21 for 65 h under hSODI-aggregating conditions as described in FIG. For this, the samples were centrifuged at 10,000 x g for 1 h at 4 °C and the pellet was dissolved in medium and diluted 1:1. After 3 days, the cell viability was measured in a 5-fold determination using the cell proliferation kit I according to the manufacturer's instructions (Roche, Basel, Switzerland).
  • Proliferation was normalized to the mean of medium treated cells. 10% DMSO diluted in medium served as a control for the toxicity. A simple analysis of variance (one-way ANOVA) with Fisher's post-hoc test was used for the statistical evaluation (** p ⁇ 0.01; *** p ⁇ 0.001).
  • the treatment of the cells with the hSODI samples in which hSODI was incubated with an increasing concentration of S1VL-21 under hSODI-aggregating conditions led to a concentration-dependent increase in cell viability compared to the non-peptide-treated hSODI sample.

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Abstract

L'invention concerne un peptide comprenant la séquence d'acides aminés selon SEQ ID NO : 1 ainsi que des homologues, des fragments et des parties de celui-ci, ainsi qu'un tel peptide destiné à être utilisé dans le traitement de la sclérose latérale amyotrophique (SLA).
PCT/EP2022/057329 2021-03-22 2022-03-21 Utilisation de ligands peptidiques à énantiomères l de la superoxyde dismutase 1 (sod1) humaine plissée nativement pour le traitement de la sclérose latérale amyotrophique (sla) Ceased WO2022200260A1 (fr)

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DE102021107051.1 2021-03-22
DE102021107051.1A DE102021107051A1 (de) 2021-03-22 2021-03-22 Verwendung von l-enantiomeren peptidliganden von nativ gefalteter humaner superoxiddismutase 1 (sod1) für die therapie von amyotropher lateralsklerose (als)

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Citations (1)

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WO2017115367A1 (fr) * 2015-12-28 2017-07-06 The National Institute for Biotechnology in the Negev Ltd. Composition et méthode pour le traitement de la sclérose latérale amyotrophique

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Publication number Priority date Publication date Assignee Title
WO2017115367A1 (fr) * 2015-12-28 2017-07-06 The National Institute for Biotechnology in the Negev Ltd. Composition et méthode pour le traitement de la sclérose latérale amyotrophique

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