Tyrosine Phosphatase Protein Wedge Domain Peptide Dimer for Nervous System Repair

Description

1 / 93 Tyrosine Phosphatase Protein Wedge Domain Peptide Dimer for Nervous System Repair Related Applications

[0001] This application claims priority over U.S. Provisional Application No. 63 / 493,912, filed April 3, 2023, the full content of which is incorporated herein by reference in its entirety. Reference to a listing of sequences

[0002] This application contains a Sequence Listing that was submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy, created on March 21, 2024, is named 753221 NGT001PC.xml and is 17,882 bytes in size. Fundamentals

[0003] Spinal cord injuries and other conditions associated with damage to the central (CNS) or peripheral (PNS) nervous system can cause permanent disability or loss of motor, sensory, and / or cognitive function. Recovery after spinal cord injury The central nervous system (CNS) is limited, leading to substantial current interest in potential strategies to overcome this challenge. A key obstacle to efforts to improve neuronal function after injury is the inability of the adult CNS to regenerate.

[0004] Two well-known classes of regeneration inhibitors are myelin-associated inhibitors (e.g., MAG, Nogo, and OMGP) and inhibitors in scar tissue formed by glial cells at the site of injury (e.g., chondroitin sulfate proteoglycans (CSPGs)). CSPG deposition, which causes inhibition of axonal and synaptic repair at sites of nervous system damage, has been implicated as a key factor not only in the pathogenesis of traumatic CNS injuries but also in the progression of various neurodegenerative and neuroinflammatory diseases.

[0005] CSPGs present a barrier to regeneration of Petition 870250089855, dated 02 / 10 / 2025, page 150 / 336 2 / 93 axon through various inhibitory mechanisms. The inhibitory effects of CSPG are reflected not only in the formation of dystrophic axonal retraction bulbs that fail to regenerate through the lesion, but also in the limited collateral sprouting capacity of spared fibers. Although it has been known for almost two decades that sulfated proteoglycans are the main contributors to the repulsive nature of glial scarring, the precise inhibitory mechanism was poorly understood.

[0006] Protein tyrosine phosphatases (PTPs) play an important role during dephosphorylation, a process that can remove phosphoryl groups from phosphotyrosine-containing proteins (Jing-Fei Huang, Molecular Biology and Evolution, Volume 20, Issue 5, May 2003, Pages 815-820). Receptor-type protein tyrosine phosphatases (PTPRs) are a subgroup of PTPs that share a transmembrane domain with resulting similarities in function and target specificity (Du Y, Grandis JR. Chin J Cancer. 2015; 34 (2): 61-69).

[0007] The PTPRs subfamily of leukocyte-related common antigens (LAR) consists of three members: LAR (PTPRF), sigma protein tyrosine phosphatase receptor (PTPRS), and delta protein tyrosine phosphatase receptor (PTPD). PTPRS and PTPF have been identified as receptors for CSPGs, the main inhibitory constituents of glial scar tissue and the perineuronal network. The sugar side chains of CSPGs can bind to PTPRF and PTPRS expressed by cells, such as neural cells, and inhibit neural cell growth, plasticity, regeneration, and sprouting failure.

[0008] It has been revealed that PTPRS-deficient neurons exhibit reduced sensitivity to CSPG-mediated inhibition in several cell-based assays and have shown increased regeneration after neurological injury, such as after spinal cord injury and optic nerve crush. Results in the PTPRF knockout assay remained inconclusive, with regenerative phenotypes Petition 870250089855, dated 02 / 10 / 2025, page 151 / 336 3 / 93 increased and decreased levels were found. Since CSPGs are the main impediment to regeneration and plasticity in the injured adult nervous system, modulators of LAR family tyrosine phosphatase protein functions can be used as therapeutic agents that promote neural plasticity, regeneration, and ultimately, repair of damage in the nervous system.

[0009] In view of the foregoing, there remains an urgent need for compositions that modulate and attenuate the inhibitory function of CSPG. In addition, there is still a need for compositions that can alleviate the cellular and neurological deficits induced by CSPG associated with the function of LAR family tyrosine phosphatase proteins. Summary

[0010] This disclosure provides wedge-domain peptide dimers for nervous system repair and treatment of neurological deficits associated with the function of LAR family tyrosine phosphatase proteins. Wedge-domain peptide dimers are therefore useful in the treatment of diseases, disorders and / or conditions associated with suppression of CSPG-mediated nervous system repair.

[0011] Peptide dimers of the wedge domain are also useful for treating associated diseases and disorders in a subject who needs them.

[0012] In one aspect, the application relates to a pharmaceutical composition comprising a peptide wherein the peptide is a dimer comprising a first monomer covalently crosslinked with a second monomer, each monomer comprising a domain comprising an amino acid sequence derived from a cytoplasmic wedge domain of a receptor-type protein tyrosine phosphatase (PTPR); and wherein the mass ratio of the crosslinked dimer to the free monomer in the pharmaceutical composition is greater than 1:20.

[0013] In one aspect, the request refers to a composition Petition 870250089855, dated 02 / 10 / 2025, page 152 / 336 4 / 93 pharmaceutical comprising a peptide dimer, wherein the peptide dimer comprises an amino acid sequence comprising two monomeric subunits, each monomeric subunit comprising a peptide domain comprising an amino acid sequence independently selected from the group consisting of a PTPRF wedge domain, a PTPRD wedge domain and a PTPRS wedge domain, and variants having at least 70% identity with them; and wherein the first monomeric subunit is linked to the second monomeric subunit.

[0014] In another aspect, a method is provided here for treating a selected neurological condition, disease or disorder from the group consisting of neural injury, inflammatory or autoimmune neurological disease and neurodegenerative disease in a subject in need thereof, the method comprising administering an effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable peptide dimer or salt or solvate thereof, wherein the peptide domain comprises an independently selected amino acid sequence from the group consisting of a PTPRF wedge domain, a PTPRD wedge domain and a PTPRS wedge domain, and variants having at least 70% identity with them.

[0015] In one aspect, this application relates to the use of a pharmaceutically acceptable peptide dimer or salt or solvate thereof in the manufacture of a medicament for the treatment of a selected neurological condition, disease or disorder from the group consisting of neural injury, inflammatory or autoimmune neurological disease and neurodegenerative disease, wherein the peptide dimers comprise a peptide domain selected independently from leukocyte antigen-related family (LAR) phosphatase wedge domains or variants with at least 70% homology to them.

[0016] In one aspect, this request refers to a process Petition 870250089855, dated 02 / 10 / 2025, page 153 / 336 5 / 93 to prepare a pharmaceutically acceptable peptide dimer or salt or solvate thereof, the process comprising combining a first monomer and a second monomer in water and a) adding an oxidizing agent and / or b) oxygenating the solution, so that the peptide dimer is formed, wherein each peptide monomer comprises a peptide domain selected independently from leukocyte antigen-related family (LAR) phosphatase wedge domains or variants having at least 65% homologue to them, a transport moiety and a cysteine ​​residue or a peptide linker comprising a cysteine ​​residue connecting the peptide domain and the transport moiety, wherein a disulfide bond is formed between the two cysteine ​​residues in the first and second peptide monomers.

[0017] In another aspect, this application relates to a process for preparing the pharmaceutically acceptable peptide dimers or salt or solvate thereof provided herein, wherein the process comprises combining identical peptide monomers in a solvent with cupric sulfate to enable the formation of a non-covalent bond between two peptide monomers, wherein each peptide monomer comprises a peptide domain independently selected from leukocyte antigen-related family (LAR) phosphatase wedge domains or variants having at least 70% homology with them, a transport moiety and a cysteine ​​residue or a peptide linker comprising a cysteine ​​residue connecting the peptide domain and the transport moiety. Brief description of the figures

[0018] The accompanying drawings, which are incorporated herein and form part of this descriptive report, illustrate exemplary embodiments of the embodiment and, together with the general description provided above and the detailed description provided below, serve to explain the characteristics of the invention. Petition 870250089855, dated 02 / 10 / 2025, page 154 / 336 6 / 93

[0019] Figure 1 is a chromatogram of a purified acetate salt of Compound 8 (wedge domain dimer of TAT-CysPTPRS) obtained by an oxidative dimerization process where cupric sulfate was used as the oxidizing agent.

[0020] Figure 2 graphically represents the BBB score of rats that received Compound 8 compared to rats that received saline solution on day 7 after LME, as detailed in Example 3.

[0021] Figure 3 graphically represents the BBB score of rats that received Compound 8 compared to rats that received saline solution at week 7 after LME, as detailed in Example 3.

[0022] Figure 4 graphically represents the BBB score of rats that received Compound 8 compared to rats that received saline solution at week 12 after LME, as detailed in Example 3.

[0023] Figure 5 graphically represents the estimated weekly mean urine retention in LME rats treated with Compound 8 in saline solution and LME rats treated with a vehicle control (saline solution) during a study course.

[0024] Figure 6 graphically represents the recovery of occasional walking in rats with LME treated with Compound 8, compared to rats with LME treated with the vehicle control.

[0025] Figure 7 graphically represents the recovery of frequent walking in rats with LME treated with Compound 8, compared to rats with LME treated with the vehicle control.

[0026] Figure 8A graphically represents the effects of Compound 8, compared to Compound 4 and the vehicle control, on improving recovery of hind limb toe clearance, paw position, trunk stability, and tail position in rats with LME, as measured by Petition 870250089855, dated 02 / 10 / 2025, page 155 / 336 7 / 93 subscore BBB. Data are presented as mean ± SEM. N = 12-13 / group.

[0027] Figure 8B graphically represents the weekly BBB subscores of rats with LME treated with Compound 8 compared with animals treated with Compound 4 and saline solution. Data are presented as distributions of mean weekly BBB subscores. N = 12-13 / group.

[0028] Figure 9 graphically represents the percentage of LME rats that achieved a BBB subscore of 1 or better (higher) in the test group of LME rats treated with Compound 8, compared to the control group of LME rats treated with saline solution only and the group of LME rats treated with Compound 4.

[0029] Figure 10 graphically represents the pharmacokinetic profiles of Compound 7 in rat plasma after intravenous or subcutaneous administration of 1.75 or 10.5 mg / kg, respectively.

[0030] Figure 11 graphically represents the weekly BBB scores of rats with LME in groups treated with Compound 8 compared with animals treated with Compound 4 and saline solution, according to an example from this disclosure.

[0031] Figure 12 graphically represents the percentages of rats with LME with BBB scores of 10 or more in groups treated only with Compound 8, Compound 4 and saline solution, according to an example from this disclosure.

[0032] Figure 13 graphically represents the percentages of rats with LME with BBB scores of 11 in groups treated only with Compound 8, Compound 4 and saline solution, according to an example from this disclosure.

[0033] Figure 14 graphically represents the mean weekly bladder scores of groups of rats treated only with Compound 8, Compound 4 and saline solution, according to an example from this disclosure. Petition 870250089855, dated 02 / 10 / 2025, page 156 / 336 8 / 93

[0034] Figure 15 graphically represents the percentages of rats with LME with weekly bladder scores of 2 or less (better) in the rat groups treated with Compound 8 only, Compound 4 and saline solution, according to an example from this disclosure.

[0035] Figure 16 graphically represents the percentage of rats that achieved BBB scores of 10 or more and / or bladder scores of 2 or less at the end of a study disclosed in an example of the present application.

[0036] Figure 17 graphically represents the percentage of rats that achieved BBB scores of 11 and / or bladder scores of 2 or less at the end of a study, according to an example from this disclosure.

[0037] Figure 18 graphically represents the stability of Compound 7 in physiological buffer (HBSS), compared to Compound 3, according to an example from this disclosure.

[0038] Figures 19, 20 and 21 graphically represent the stabilities of Compound 7 in rat plasma, dog plasma and human plasma, compared to Compound 3, according to an example from this disclosure.

[0039] Figure 22 is a set of transmission electron microscopy images illustrating the distinct self-assembly patterns of Compound 7 and Compound 3 in water and isotonic saline solution, according to an example in this disclosure. Detailed description

[0040] The modalities of the present disclosure relate to peptide dimers and compositions comprising peptide dimers for repairing the nervous system of a subject.

[0041] The present disclosure also provides pharmaceutical compositions comprising the peptide dimers disclosed herein and methods of using the peptide dimers and / or pharmaceutical compositions disclosed herein to repair the system. Petition 870250089855, dated 02 / 10 / 2025, page 157 / 336 9 / 93 nervous of a subject.

[0042] In one embodiment, the pharmaceutical compositions provided herein further comprise a pharmaceutically acceptable carrier.

[0043] The modalities of this disclosure also provide methods of treatment for diseases, disorders and / or conditions associated with the activation and signaling of the LAR family of phosphatases, comprising the administration of peptide dimers and / or pharmaceutical compositions disclosed herein to a subject who needs them. Definitions

[0044] Below are listed the definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout this descriptive report and claims, unless otherwise limited in specific cases, individually or as part of a larger group.

[0045] Unless otherwise defined, all scientific and technical terms used herein shall have the meanings commonly understood by those with common knowledge in the field. Furthermore, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. Generally, the nomenclature used in conjunction with, and techniques of, cell and tissue culture, molecular biology and protein and oligo- or polynucleotide chemistry and hybridization described in this document are those known and used in the art.

[0046] As used here, “one or more of a, b, c, ab, ac, bc, or abc. The use of or here is inclusive or.

[0047] Furthermore, the use of the term including, as well as other forms such as include, includes and included, is not limiting. Petition 870250089855, dated 02 / 10 / 2025, page 158 / 336 10 / 93

[0048] As used in this document, the term "approximately" will be understood by those skilled in the art and will vary to some extent in the context in which it is used. As used herein, when referring to a measurable value, such as a quantity, a duration of time, and the like, the term "approximately" is intended to encompass variations of ± 20%, ± 10%, ± 5%, ± 1%, or ± 0.1% of the specified value, as such variations are appropriate for carrying out the disclosed methods. Chemical

[0049] As used herein, the term “alkyl” refers to a linear or branched saturated hydrocarbon. For example, an alkyl group may have from 1 to 12 carbon atoms (i.e., (C1-C12) alkyl), 1 to 6 carbon atoms (i.e., (C1-C6) alkyl), 1 to 4 carbon atoms (i.e., (C1-C4) alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3) alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CHs)2), 1-butyl (n-bu, n-butyl, CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), neopentyl (-CH2C(CH3)3), 1-hexyl (CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), heptyl ((CH2HCH3), octyl (-(CH2LCH3), 2,2,4-trimethylpentyl(CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2)10CH3) and dodecyl (-(CH2)11CH3).In one embodiment, alkyl refers to C(1-6)alkyl. In another embodiment, alkyl refers to C(1-4)alkyl. In yet another embodiment, alkyl refers to C(1-3)alkyl.

[0050] As used herein, the term “alkylene” refers to a divalent alkyl group. For example, an alkylene group may have from 1 to 12 carbon atoms (i.e., (C1-C12)alkylene), 1 to 6 carbon atoms (i.e., (C1-C6)alkylene), 1 to 2 carbon atoms (i.e., (C1-C6)alkylene), or 1 carbon atom (or Petition 870250089855, dated 02 / 10 / 2025, p. 159 / 336 11 / 93 i.e., (C1)alkylene). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), etc. Nucleic Acids

[0051] As used herein, the terms “polynucleotide sequence” and “nucleotide sequence” are also used interchangeably herein.

[0052] As used herein, the term “wild type” refers to the natural polynucleotide sequence encoding a protein, or a portion thereof, or a protein sequence, or a portion thereof, respectively, as it normally exists in vivo. As used herein, the term nucleic acid refers to polynucleotides such as deoxyribonucleic acid (DNA) and, where appropriate, ribonucleic acid (RNA). The term should also be understood as including, as equivalents, RNA or DNA analogs made of nucleotide analogs and, as applicable to the embodiment described, single-stranded (sense or antisense) and double-stranded polynucleotides.

[0053] As used herein, the term “recombinant” means that a protein is derived from either a prokaryotic or eukaryotic expression system. As used herein, the term “recombinant” refers to genetic material formed by a process of genetic recombination. A “recombinant protein” is produced through genetic engineering. A recombinant protein is encoded by an artificially created DNA sequence. A recombinant protein is a protein that is encoded by a recombinant nucleic acid sequence. A recombinant nucleic acid sequence has a sequence from two or more sources incorporated into a single molecule.

[0054] As used herein, the term “expression cassette” refers to a portion of a vector DNA used for cloning and transformation. In each successful transformation, the cassette of Petition 870250089855, dated 02 / 10 / 2025, page 160 / 336 12 / 93 Expression directs the cell's machinery to produce polypeptide. Some expression cassettes are designed for modular cloning of protein-coding sequences, so the same cassette can be easily altered to produce different proteins. Expression cassettes can also refer to a recombinantly produced nucleic acid molecule that is capable of expressing a genetic sequence in a cell. An expression cassette typically includes a regulatory region, such as a promoter (allowing transcription initiation), and a sequence that encodes one or more proteins or RNAs. Optionally, the expression cassette may include transcriptional enhancers, non-coding sequences, splicing signals, transcription termination signals, and polyadenylation signals. The sequences that control gene expression, i.e., its transcription and the translation of the transcription product, are commonly called regulatory units.Most parts of the regulatory unit are located upstream of the coding sequence of the heterologous gene and are operatively linked to it. The expression cassette may also contain a downstream 3' untranslated region comprising a polyadenylation site. The regulatory unit of the invention is either directly linked to the gene to be expressed, i.e., the transcription unit, or separated from it by intervening DNA, such as the 5' untranslated region of the heterologous gene. Preferably, the expression cassette is flanked by one or more suitable restriction sites to allow insertion of the expression cassette into a vector and / or its excision from a vector. Thus, the expression cassette according to the present invention can be used for the construction of an expression vector, in particular a mammalian expression vector.

[0055] As used herein, the term “expression vector, also known as expression construct, refers to a Petition 870250089855, dated 02 / 10 / 2025, page 161 / 336 13 / 93 A plasmid or virus designed for protein expression in cells. The vector is used to introduce a specific gene into a target cell and can command the cell's protein synthesis mechanism to produce the protein encoded by the gene. The plasmid is designed to contain regulatory sequences that act as enhancer and promoter regions and lead to efficient transcription of the gene carried in the expression vector. The goal of a well-designed expression vector is the production of a significant amount of stable messenger RNA and, therefore, proteins.

[0056] As used herein, the term “host cell” and the term “host” refer to 1) a cell that harbors foreign molecules, viruses, etc.; 2) a cell that has been introduced with DNA or RNA, such as a bacterial cell acting as a host cell for DNA isolated from a bacteriophage.

[0057] As used herein, a “fusion” or “chimeric” protein comprises a first amino acid sequence linked to a second amino acid sequence with which it is not naturally linked in nature. Amino acid sequences that normally exist in separate proteins can be joined together in the fusion polypeptide, or amino acid sequences that normally exist in the same protein can be placed in a new arrangement in the fusion polypeptide, for example, fusion of a PTPR wedge domain sequence with a transport fraction sequence. A fusion protein can be created, for example, by chemical synthesis or by the creation and translation of a polynucleotide in which the peptide regions are encoded in the desired relationship. A chimeric protein may further comprise a second amino acid sequence associated with the first amino acid sequence by a covalent, non-peptide, or non-covalent bond.

[0058] As used herein, the term “modified” and the term “mutant”, when made in reference to a gene or a product Petition 870250089855, dated 02 / 10 / 2025, page 162 / 336 14 / 93 genic, refer, respectively, to a gene or a gene product that exhibits modifications in sequence and / or functional properties (i.e., altered characteristics) when compared to the wild-type gene or gene product. Polypeptides

[0059] As used herein, the term amino acid includes alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine ​​(Cys or C); glutamine (Gln or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (Ile or I); leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); proline (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Val or V). Non-traditional amino acids are also within the scope of disclosure and include norleucine, ornithine, norvaline, homoserine, and other amino acid residue analogs, such as those described in Ellman et al. Meth. Enzym. 202: 301-336 (1991). To generate such unnatural amino acid residues, the procedures of Noren et al. Science 244: 182 (1989) and Ellman et al., supra, can be used. Briefly, these procedures involve chemically activating a tRNA suppressor with an unnaturally occurring amino acid residue, followed by in vitro transcription and translation of the RNA. The introduction of the untraditional amino acid can also be achieved using peptide chemistries known in the art. As used herein, the term polar amino acid includes amino acids that have a net zero charge but non-zero partial charges in different portions of their side chains (e.g., M, F, W, S, Y, N, Q, C). These amino acids can participate in hydrophobic and electrostatic interactions. As used in this document, the term charged amino acid includes amino acids that can have a non-zero net charge in their side chains (e.g., R, K, H, E, D). These Petition 870250089855, dated 02 / 10 / 2025, page 163 / 336 15 / 93 amino acids can participate in hydrophobic and electrostatic interactions.

[0060] As used herein, the terms peptide or polypeptide are used interchangeably herein and refer to compounds consisting of about 2 to about 90 amino acid residues inclusive, in which the amino group of one amino acid is linked to the carboxyl group of another amino acid by a peptide bond. A peptide may, for example, be derived from or removed from a native protein by enzymatic or chemical cleavage, or it may be prepared using conventional peptide synthesis techniques (e.g., solid-phase synthesis) or molecular biology techniques (see Sambrook et al., MOLECULAR CLONING: LAB. MANUAL (Cold Spring Harbor Press, Cold Spring Harbor). Harbor, NY, 1989). A peptide may comprise any suitable ε and / or δ-amino acid, for example, common α-amino acids (e.g., alanine, glycine, valine), non-α-amino acids (e.g., β-alanine, 4-aminobutyric acid, 6-aminocaproic acid, sarcosine, statin), and uncommon amino acids (e.g., citrulline, homocitrulline, homoserine, norleucine, norvaline, ornithine). The amino, carboxyl, and / or other functional groups in a peptide may be free (e.g., unmodified) or protected with a suitable protecting group. Suitable protecting groups for amino and carboxyl groups, and means for adding or removing protecting groups, are known in the art. See, for example, Green & Wuts, PROTECTING GROUPS IN ORGANIC SYNTHESIS (John Wiley & Sons, 1991). The functional groups of a peptide can also be derivatized (e.g., alkylated) using methods known in the art.

[0061] As is clear to a person skilled in the art, the peptide sequences disclosed here are shown proceeding from left to right, with the left end of the sequence being the N-terminal of the peptide and the right end of the N-terminal of the peptide being the N-terminal of the peptide. Petition 870250089855, dated 02 / 10 / 2025, page 164 / 336 16 / 93 sequence being the C-terminal of the peptide. Among the sequences disclosed herein are sequences that incorporate a “Hy” moiety at the amino terminal (N-terminal) of the sequence and a “—OH” or “—NH2” moiety at the carboxylic terminal (C-terminal) of the sequence. In these cases, and unless otherwise indicated, a “Hy-” moiety at the N-terminal of the sequence in question indicates a hydrogen atom, corresponding to the presence of a free primary or secondary amino group at the N-terminal, while a “—OH” or “—NH2” moiety at the C-terminal of the sequence indicates a hydroxyl group or an amino group, corresponding to the presence of an amide group (CONH2) at the C-terminal, respectively. In each sequence of the invention, a C-terminal “—OH” moiety can be replaced by a C-terminal “—NH2” moiety, and vice versa.

[0062] Peptides can be synthesized and assembled into libraries comprising many discrete molecular species. These libraries can be prepared using well-known combinatorial chemistry methods and can be screened as described herein or using other suitable methods to determine if the library comprises peptides of interest. Such a peptide can then be isolated by appropriate means.

[0063] As used herein, the term “peptidomimetic” refers to a protein-like molecule designed to mimic a peptide. Peptidomimetics generally arise from the modification of an existing peptide or the creation of similar systems that mimic peptides, such as peptoids and β-peptides. Regardless of the approach, the altered chemical structure is designed to advantageously adjust molecular properties, such as stability or biological activity. These modifications involve changes to the peptide that do not occur naturally (such as altered structures and the incorporation of unnatural amino acids).

[0064] As used herein, the term “monomer” or “peptide monomer” refers to a peptide molecule that can bind Petition 870250089855, dated 02 / 10 / 2025, page 165 / 336 17 / 93 chemically bonds to other molecules, such as another peptide molecule, to form a polymer.

[0065] As used herein, the term peptide dimer refers broadly to a peptide molecule comprising two monomeric subunits, which may be identical or different. Thus, the dimers of the present invention include homodimers and heterodimers.

[0066] As used herein, the term subunit refers to a separate polypeptide chain that produces a given protein, composed of two or more polypeptide chains joined together. In a protein molecule composed of more than one subunit, each subunit can form a stable folded structure on its own. The amino acid sequences of the subunits of a protein or polypeptide may be identical, similar, or completely different.

[0067] The term NH2, as used herein, may refer to a free amino group present at the amino-terminal of a polypeptide. The term OH, as used herein, may refer to a free carboxylic group present at the carboxylic-terminal of a peptide. Furthermore, the term Ac, as used herein, refers to acetyl protection via acylation of the C- or N-terminal of a polypeptide. In certain peptides shown herein, the NH2 located at the C-terminal of the peptide indicates an amino group.

[0068] As used herein, the term ligand and the term peptide ligand are interchangeable and refer to short peptide sequences that occur between functional protein domains and link the functional domains together. Linkers designed by researchers are generally classified into three categories according to their structures: flexible linkers, rigid linkers, and in vivo cleavable linkers. A flexible linker is generally composed of flexible residues, such as glycine and serine, so that adjacent protein domains are free to move relative to each other. Petition 870250089855, dated 02 / 10 / 2025, page 166 / 336 18 / 93 others. A linker can also play a role in the release of the free functional domain in vivo (as in in vivo cleavable linkers). Linkers can offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles. The composition and length of a linker can be determined according to methods well known in the art and can be tested for effectiveness. A linker may be from about 3 to about 15 amino acids in length. In some embodiments of the present invention, a linker may be from about 5 to about 10 amino acids in length; however, a longer linker may be used in embodiments of the present invention.

[0069] As used herein, the terms portion, fragment, variant, derivative, and analogue, when referring to a polypeptide of the present invention, include any polypeptide that retains at least some biological activity mentioned herein (e.g., inhibition of an interaction, such as binding). The polypeptides described herein may include portion, fragment, variant, or derivative molecules, without limitation, provided that the polypeptide still performs its function. Polypeptides or portions thereof of the present invention may include proteolytic fragments, deletion fragments, and, in particular, fragments that more readily reach the site of action when administered to an animal.

[0070] As used herein, the term protein purification refers to a series of processes designed to isolate one or more proteins or polypeptides from a complex mixture, such as cell culture media, cells, tissues, or whole organisms, etc. Typically, a protein purification protocol contains one or more chromatographic steps. The basic procedure in chromatography is to flow the solution containing the protein through a column. Petition 870250089855, dated 02 / 10 / 2025, page 167 / 336 19 / 93 filled with various materials. Different proteins interact differently with the column material and can therefore be separated by the time required to pass through the column or by the conditions required to elute the protein from the column. There are many purification strategies. For example, a protein can be attached to an antigen peptide marker by engineering and purified using an antibody against the antigen peptide marker. Typically, during purification, the protein with an antigen peptide marker can be added to a resin-loaded column coated with an antibody or by incubation with a loose resin coated with an immobilizing antibody. This specific procedure is known as immunoprecipitation. Immunoprecipitation is quite capable of generating an extremely specific interaction that usually results in the binding of only the desired protein.The purified labeled proteins can then be easily separated from other proteins in the solution and then eluted back into a clean solution.

[0071] In some embodiments, the dimers disclosed herein are substantially isolated. By “substantially isolated” it is understood that the dimer is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a dimer enriched in the compound of the invention. Substantial separation may include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% by weight of the dimer.

[0072] As used herein, the term “inhibitor” refers to a molecule, compound, or agent that reduces or inhibits at least one activity, signaling, or function of the leukocyte common antigen-related phosphatase (LAR) family induced by Petition 870250089855, dated 02 / 10 / 2025, page 168 / 336 20 / 93 proteoglycan, reduces the activity, signaling, and / or function of chondroitin sulfate proteoglycan (CSPG) and / or the interaction between chondroitin sulfate proteoglycan (CSPG) and the LAR phosphatase family. In some embodiments, inhibitor also refers to a molecule, compound, or agent that eliminates the inhibitory effects of CSPGs on CSPG-activated neural cells. In several embodiments, the inhibitors disclosed here are peptide dimers comprising an amino acid sequence derived from a cytoplasmic wedge domain of a receptor-type protein tyrosine phosphatase (PTPR). Homology

[0073] As used herein, the terms homology and identity are used synonymously and refer to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence, which can be aligned for comparison purposes. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous or identical at that position. A degree of homology or identity between sequences is a function of the number of corresponding or homologous positions shared by the sequences.

[0074] As used herein, the term analog (analogue) and the term analog (analog) refer to one of a group of chemical compounds that share structural and / or functional similarities but differ in elemental composition. A structural analog is a compound that has a structure similar to that of another, but differs from it in one or more components, such as one or more atoms, functional groups, or substructures, etc. Functional analogs are compounds that have similar physical, chemical, biochemical, or pharmacological properties. Functional analogs are not necessarily also structural analogs with a structure Petition 870250089855, dated 02 / 10 / 2025, page 169 / 336 21 / 93 similar chemistry.

[0075] As used herein, the term “sequence identity”, “percent identity”, “percent homology”, or, for example, comprising a “sequence 80% identical to”, refers to the extent to which sequences are identical on a nucleotide-by-nucleotide or amino acid-by-amino acid basis within a comparison window.Thus, a “percentage of sequence identity” can be calculated by comparing two ideally aligned sequences in the comparison window, determining the number of positions where the identical nucleic acid base (e.g., A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) occurs in both sequences to yield the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0076] Sequence similarity or sequence identity calculations between sequences (the terms are used interchangeably here) can be performed as follows. To determine the percentage of identity of two amino acid sequences, or of two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be disregarded for comparison purposes). In certain embodiments, the length of an aligned reference sequence for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. Amino acid residues or Petition 870250089855, dated 02 / 10 / 2025, p. 170 / 336 22 / 93 nucleotides that correspond to amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid or nucleotide residue as the corresponding position in the second sequence, then the molecules are identical at that position.

[0077] The percentage identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of spaces, and the length of each space, that need to be introduced for the ideal alignment of the two sequences.

[0078] Sequence comparison and determination of percent identity between the two sequences can be performed using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (1970, J. Mol. Biol. 48: 444-453), which was incorporated into the GAP program in the GCG software package, using a Blossum 62 matrix or a PAM250 matrix and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the program GAP in the GCG software package, using an NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. The percentage of identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4: 11-17) which was incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty Petition 870250089855, dated 02 / 10 / 2025, page 171 / 336 23 / 93 of 12 and a gap penalty of 4.

[0079] For example, the sequences described here can be used as a “query sequence” to perform a search in public databases to, for example, identify other family members or related sequences. These searches can be performed using the NBLAST and XBLAST (version 2.0) programs by Altschul, et al., (1990, J. Mol. Biol, 215: 403-10). Nucleotide searches BLAST searches can be performed using the NBLAST program, score=100, word length=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. Protein BLAST searches can be performed using the XBLAST program, score=50, word length=3 to obtain amino acid sequences homologous to the protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al. (Nucleic Acids Res. 25: 3389-3402, 1997). When using the BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. Compositions and Formulations

[0080] As used herein, the term “pharmaceutically acceptable” refers to a compound or drug that is approved or approveable by a federal or state government regulatory agency, listed or listable in the U.S. Pharmacopeia or another generally recognized pharmacopoeia for use in mammals, including humans.

[0081] As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds in which the original compound is modified by converting an existing acidic or basic fraction into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; salts Petition 870250089855, dated 02 / 10 / 2025, page 172 / 336 24 / 93 alkaline or organic acidic residues, such as carboxylic acids; and the like. The pharmaceutically acceptable salts of this disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. The pharmaceutically acceptable salts of this disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. The expression “pharmaceutically acceptable salt” is not limited to a mono- or 1:1 salt.For example, acceptable pharmaceutical salts also include bis-salts, such as a bis-chloride salt. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0082] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one useful compound within the disclosure with a pharmaceutically acceptable vehicle. The pharmaceutical composition facilitates the administration of the compound to a subject. There are multiple techniques in the art for administering a compound, including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0083] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a filler. Petition 870250089855, dated 02 / 10 / 2025, page 173 / 336 25 / 93 liquid or solid, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in the transport or delivery of a useful compound within the disclosure to or into the subject, so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or body part to another organ or body part. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation, including the useful compound in the disclosure, and not harmful to the subject.Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface-active agents; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other compatible non-toxic substances used in pharmaceutical formulations.

[0084] As used herein, pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, absorption retardants and the like that are compatible with the activity of the useful compound in the present disclosure and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The carrier Petition 870250089855, dated 02 / 10 / 2025, page 174 / 336 26 / 93 pharmaceutically acceptable” may also include a pharmaceutically acceptable salt of the compound disclosed herein. Other additional ingredients that may be included in pharmaceutical compositions are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0085] As used herein, the term “pharmaceutical formulation” and the term “drug formulation” refer to a mixture or structure in which different chemical substances, including the active drug, are combined to form a final medicinal product, such as a sterile product, a solution, a powder, an emulsion, a capsule, a tablet, a granule, a topical preparation, an unconventional product such as semi-solid or extended-release preparations, liquid, etc. The pharmaceutical formulation is prepared according to a specific procedure, a “formula”. The drug formed varies according to the route of administration. Medical Intervention

[0086] As used herein, the term “dose” refers to a specific amount of medication taken at one time. A “daily dose” refers to the total dosage amount administered to an individual in a single 24-hour day.

[0087] As used herein, the term “mg / kg” refers to the dose of a substance administered to an individual in milligrams per kilogram of the individual’s body weight.

[0088] As used herein, the term “dosage” refers to the administration of a specific amount, number, and frequency of doses over a specified period of time. Dosage implies duration. A “dosage regimen” is a treatment plan for administering a medication over a period of time.

[0089] As used here, the phrases “parenteral administration” and “administered parenterally” as used here Petition 870250089855, dated 02 / 10 / 2025, page 175 / 336 27 / 93 means modes of administration other than enteral and topical administration or through the digestive tract, generally by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intracisternal injection and infusion.

[0090] As used herein, the phrases “systemic administration”, “systemically administered”, “peripheral administration” and “peripherally administered”, as used herein, mean the administration of a compound, drug or other material not directly into a target tissue (e.g., the nervous system), so that it enters the animal’s system and is therefore subject to metabolism and other similar processes, e.g., subcutaneous administration.

[0091] As used herein, the term “patient”, “subject”, “animal” or “host” refers to any mammal. The subject may be a human being, but it may also be a mammal requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, poultry, pigs, horses and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).

[0092] As used herein, the term “administer” to a patient includes dispensing, delivering, or applying an active compound in a pharmaceutical formulation to a subject by any route suitable for delivering the active compound to the desired location in the subject (e.g., to thus contact a desired cell, such as a desired neuron), including administration into the cerebrospinal fluid or across the blood-brain barrier, delivery by parenteral or oral route, intramuscular injection, subcutaneous or intradermal injection, intravenous injection, administration Petition 870250089855, dated 02 / 10 / 2025, page 176 / 336 28 / 93 buccal, transdermal delivery, and administration via the rectal, colonic, vaginal, intranasal, or respiratory tract routes. The agents may, for example, be administered to a comatose, anesthetized, or paralyzed subject by intravenous injection, or may be administered intravenously to a pregnant woman to stimulate axonal growth in a fetus. Specific routes of administration may include topical application (such as by eye drops, creams, or erodible formulations to be placed under the eyelid), intraocular injection into the aqueous or vitreous humor, injection into the outer layers of the eye, such as by subconjunctival injection or subtenon injection, parenteral administration, or oral administration.

[0093] The term treat, treated, that which treats, or treatment includes the reduction or relief of at least one symptom associated with or caused by the condition, disorder, or disease being treated. The term “treatment,” as used herein, also includes: (1) inhibiting the disease or condition, that is, halting the development or progression of the disease or condition, (2) alleviating the disease or condition, that is, causing the condition to regress, (3) stopping the symptoms of the disease, and / or (4) improving the desired conditions.

[0094] As used in this document, the term prevent or prevention means no disorder or disease development if none has occurred, or no further disorder or disease development if the disorder or disease has already developed. It also refers to the ability to prevent some or all of the symptoms associated with the disorder or disease.

[0095] As used herein, an “effective amount” of a therapeutic agent or peptide dimers disclosed herein is an amount sufficient to achieve a desired therapeutic or pharmacological effect, such as an amount capable of activating neuronal growth. An effective amount of an agent, Petition 870250089855, dated 02 / 10 / 2025, page 177 / 336 29 / 93 as defined herein, may vary depending on factors such as disease status, the subject's age and weight, and the agent's ability to elicit a desired response in the subject. Dosage regimens are adjusted to provide the optimal therapeutic response. An effective amount is also one in which any toxic or harmful effects of the active compound are offset by the therapeutically beneficial effects. As used herein, the term "therapeutically effective amount" refers to an amount effective, at the dosages and for the time periods required, to achieve the desired therapeutic outcome. A therapeutic outcome may be, for example, symptom reduction, prolonged survival, improved mobility, and the like. A therapeutic outcome does not need to be a "cure".

[0096] As used herein, the terms “improve,” “enhancing,” or “improvement,” or grammatical variations thereof used in relation to behaviors, refer to the ability to achieve a measurable increase in performance in relation to tasks used to test those behaviors in a subject, including humans or non-human animals. Central nervous system

[0097] As used herein, the term “central nervous system (CNS) neurons” includes neurons in the brain, cranial nerves, and spinal cord.

[0098] As used herein, the term “neurons of the peripheral nervous system (PNS)” includes neurons that reside within or extend outside the CNS. The PNS is intended to include neurons commonly understood as being categorized within the peripheral nervous system, including sensory neurons and motor neurons.

[0099] As used herein, the term “neuron contact” or “neuron treatment” refers to any mode of delivery or “administration” of the agent, whether to cells or to whole organisms, in which the agent is able to exhibit its effect. Petition 870250089855, dated 02 / 10 / 2025, page 178 / 336 30 / 93 pharmacological in neurons. “Contact with neurons” includes in vivo and in vitro methods of bringing an agent of the invention closer to a neuron. Suitable modes of administration can be determined by experts in the field, and such modes of administration may vary between agents. For example, when axonal growth of neurons is stimulated ex vivo, agents can be administered, for example, by transfection, lipofection, electroporation, viral vector infection, or by addition to the growth medium.

[0100] As used herein, the term “neurological disorder” includes a disease, disorder, or condition that directly or indirectly affects the normal functioning or anatomy of a subject’s nervous system. The term “stroke” is recognized by science and includes sudden decrease or loss of consciousness, sensation, and voluntary movement caused by rupture or obstruction (e.g., by a blood clot) of an artery in the brain. “Traumatic brain injury” is internationally recognized and includes the condition in which a traumatic blow to the head causes damage to the brain or spinal cord, with or without penetration of the skull. Generally, the initial trauma may result in expanding hematoma, subarachnoid hemorrhage, cerebral edema, increased intracranial pressure, and cerebral hypoxia, which may, in turn, lead to serious secondary events due to low cerebral blood flow.

[0101] As used herein, the term “axonal growth” or “growth” (also referred to herein as “neuronal growth”) includes the process by which axons or dendrites extend from a neuron. Growth may result in a new neuritic projection or the extension of a previously existing cellular process. Axonal growth may include the linear extension of an axonal process by five or more cell diameters. Neuronal growth processes, including neuritogenesis, may be evidenced by the expression Petition 870250089855, dated 02 / 10 / 2025, page 179 / 336 31 / 93 of GAP-43 detected by methods such as immunostaining. "Stimulating axonal growth" means promoting axonal growth.

[0102] As used herein, the term “dieback” refers to axonal retraction that occurs as a result of trauma to the axon.

[0103] As used herein, the term “retraction” refers to the axon’s retreat away from the site of injury, such as where glial scarring forms. Here, the ends of regenerating axons stop extending and become dystrophic. These dystrophic ends may then retreat further from the glial scar and the site of injury.

[0104] As used herein, the term “neuronal migration” refers to the ability of neuronal cells to migrate or of neuronal processes to migrate, such as axonal or dendritic migration. Peptide dimers

[0105] This application relates to compositions and methods for repairing the nervous system in a subject who needs them. This application also relates to methods and compositions for treating diseases, disorders and / or conditions associated with the phosphatase function of the LAR family.

[0106] In one aspect, a pharmaceutical composition comprising a peptide is provided herein, wherein the peptide is a dimer comprising a first monomer covalently crosslinked with a second monomer, each monomer comprising a domain comprising an amino acid sequence derived from a cytoplasmic wedge domain of a receptor-type protein tyrosine phosphatase (PTPR); and wherein the mass ratio of the crosslinked dimer to the free monomer in the pharmaceutical composition is greater than 1:20.

[0107] In one embodiment, the pharmaceutical compositions provided herein further comprise a dimer comprising a transport moiety linked to the domain via a cysteine ​​residue or a peptide linker comprising a residue of Petition 870250089855, dated 02 / 10 / 2025, page 180 / 336 32 / 93 cysteine.

[0108] In one embodiment, the pharmaceutical compositions provided herein further comprise a dimer, wherein the dimer enhances the repair of neural cells.

[0109] In another embodiment, the pharmaceutical compositions provided herein further comprise the first monomer and the second monomer, each independently comprising a first domain comprising an amino acid sequence that is at least about 65% identical, at least about 70% identical, at least about 75% identical, at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical or at least about 97% identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7; a second domain comprising an amino acid sequence that is at least about 65% identical, at least about 70% identical, at least about 75% identical, at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical, or at least about 97% identical to the amino acid sequence of SEQ ID NO: 8, 9, 10, or 11; and a cysteine ​​residue;wherein the dimer comprises a chemical linker or bond between the cysteine ​​residue of the first monomer and the cysteine ​​residue of the second monomer.

[0110] In one embodiment, the pharmaceutical compositions provided herein further comprise the first monomer and the second monomer, each independently comprising an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3 or 4. In another embodiment, the pharmaceutical compositions provided herein further comprise the first monomer and the second monomer, each independently comprising an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 1, 2, 3 or 4. In yet another embodiment, the pharmaceutical compositions provided herein Petition 870250089855, dated 02 / 10 / 2025, page 181 / 336 33 / 93 also include the dimer comprising identical monomers. In another embodiment, the pharmaceutical compositions provided herein also include the dimer comprising non-identical monomers, and the proportion is calculated based on the combined total of free monomer. In another embodiment, the pharmaceutical compositions provided herein also include the first monomer and the second monomer of the dimer with different C-terminal modifications.

[0111] In another aspect, a pharmaceutical agent is provided herein for repairing a subject's nervous system, comprising a pharmaceutically acceptable peptide dimer or salt or solvate thereof, comprising two subunits, wherein each subunit comprises a peptide domain independently selected from receptor-type protein tyrosine phosphatase (PTPR) wedge domains or variants with at least 70% homology thereto. In one embodiment, a pharmaceutical agent provided herein further comprises a pharmaceutically acceptable peptide dimer or salt or solvate thereof, comprising two subunits, wherein each subunit comprises a transport moiety linked to the peptide domain via a cysteine ​​residue or a peptide linker comprising a cysteine ​​residue, wherein the two subunits are covalently crosslinked via a chemical linker between the cysteine ​​residues in each subunit.In another embodiment, a pharmaceutical agent provided herein further comprises a chemical linker selected from a disulfide bond, a thioether bond, or a thioester bond. In yet another embodiment, a pharmaceutical agent provided herein further comprises an amino acid sequence with at least 70% identity to the amino acid sequence of SEQ ID NO: 8, 9, or 11.

[0112] In another embodiment, a pharmaceutical agent provided herein further comprises a carrier fraction comprising an amino acid sequence with at least 65% identity to the Petition 870250089855, dated 02 / 10 / 2025, page 182 / 336 34 / 93 Wild-type HIV TAT. In another embodiment, a pharmaceutical agent provided herein further comprises a TAT sequence comprising an amino acid sequence that is at least 65% identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7. In another embodiment, a pharmaceutical agent provided herein further comprises an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3 or 4.

[0113] In one embodiment, a pharmaceutical agent provided herein further comprises subunits comprising different C-terminal modifications. In another embodiment, a pharmaceutical agent provided herein further comprises a peptide dimer comprising two different subunits. In another embodiment, a pharmaceutical agent provided herein further comprises the peptide dimer comprising two identical monomeric subunits. In another embodiment, a pharmaceutical agent provided herein further comprises a pharmaceutically acceptable peptide dimer or salt or solvate thereof with a purity of at least 90%.

[0114] In one embodiment, a pharmaceutical composition provided herein further comprises the pharmaceutical agent provided herein. In another embodiment, a pharmaceutical composition does not comprise DMSO. In another aspect, a use of the pharmaceutical agent provided herein is provided herein in the manufacture of a medicament for repairing the nervous system and / or treating a neurological condition, disease or disorder selected from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity and neurodegenerative disease.

[0115] In another aspect, a method is provided here for repairing the nervous system and / or treating a selected neurological condition, disease or disorder from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity, and neurodegenerative disease, in a subject in Petition 870250089855, dated 02 / 10 / 2025, page 183 / 336 35 / 93 need, the method comprising administering an effective quantity of the pharmaceutical agent provided herein to a subject in need.

[0116] In some embodiments, the dimer to free monomer ratio in the pharmaceutical composition is greater than 1:19, greater than 1:18, greater than 1:17, greater than 1:16, greater than 1:15, greater than 1:14, greater than 1:13, greater than 1:12, greater than 1:11, greater than 1:10, greater than 1:9, greater than 1:8, greater than 1:7, greater than 1:6, greater than 1:5, greater than 1:4, greater than 1:3, greater than 1:2, or greater than 1:1. In some embodiments, the dimer to free monomer ratio in the pharmaceutical composition is greater than 1:1.

[0117] In some embodiments, the dimer to free monomer ratio in the pharmaceutical composition is greater than 2:1, greater than 3:1, greater than 4:1, greater than 5:1, greater than 6:1, greater than 7:1, greater than 8:1, greater than 9:1, greater than 10:1, greater than 11:1, greater than 12:1, greater than 13:1, greater than 14:1, greater than 15:1, greater than 16:1, greater than 17:1, greater than 18:1, greater than 19:1 or greater than 20:1. In some embodiments, the dimer to free monomer ratio in the pharmaceutical composition is greater than 4:1. In some embodiments, the dimer to free monomer ratio in the pharmaceutical composition is up to 10:1, up to 15:1, up to 20:1, up to 25:1, or up to 27:1. In some embodiments, the dimer to free monomer ratio in the pharmaceutical composition is greater than 10:1 (up to 27:1).

[0118] In another embodiment, the ratio is calculated based on the combined total of free monomer.

[0119] The first and second monomers of the dimer can be connected by any method known in the art. In some embodiments, the first and second monomers are connected by a linkage. In some embodiments, the first and second monomers are connected by means of a cystine bridge. In some embodiments, the dimer comprises a ligand between the first monomer and the second monomer. In some embodiments, Petition 870250089855, dated 02 / 10 / 2025, page 184 / 336 36 / 93 The dimer comprises a disulfide bond between the first monomer and the second monomer.

[0120] In some embodiments, the dimer comprises a transport moiety that facilitates the uptake of the dimer by the cell. In some embodiments, the transport moiety may be an HIV TAT transport moiety (i.e., a TAT sequence). Transport moieties may be repeated more than once in the dimer. The repetition of a transport moiety may affect (e.g., increase) the uptake of the dimer by a desired cell. In either or both of the first and second monomers, the transport moiety may be located in the amino-terminal region or in the carboxyl-terminal region or in both regions. In one embodiment, the transport moiety is located in the N-terminal region of the monomers.

[0121] In some embodiments, the transport fraction is connected via a peptide linker. In some embodiments, the transport fraction is connected via two peptide linkers.

[0122] In some embodiments, the transport fraction may include at least one transport peptide sequence that allows the dimer to enter the cell by a receptor-independent mechanism. In some embodiments, the dimer is a synthetic peptide containing a TAT-mediated protein delivery sequence.

[0123] Other examples of known transport fractions, subdomains and the like are described, for example, in Canadian patent application No. 2,301,157 (antennapedia homeodomain-containing conjugates), international publication number PCT WO 99 / 11809, as well as in US patents Nos. 5,652,122, 5,670,617, 5,674,980, 5,747,641, 5,804,604 and Bruno P. Meloni, et al. 2020; 11 (Article 108): 1-28, all of which are incorporated herein by reference in their entirety. Thus, in some embodiments, the transport fraction is an HIV TAT peptide; a Petition 870250089855, dated 02 / 10 / 2025, pp. 185 / 336 37 / 93 VP22 peptide of the DNA-binding protein of herpes simplex-1 virus, an amino acid region of the third alpha helix of the antennapedia homeodomain, a histidine marker varying in length from 4 to 30 histidine repeats, a variant derivative or homolog thereof capable of facilitating the uptake of the active charge fraction by a receptor-independent process, or a cationic arginine-rich peptide (CARP).In some embodiments, the transport fraction can be chosen from neuroprotective CARPs that possess the following properties: (i) range in size from 4 to 40 amino acids; (ii) net positive charge > +2 to +20; (iii) one or more positively charged arginine residues comprising between 20 and 100% of the peptide; (iv) other positively charged amino acids, namely lysine and histidine; (v) amphiphilicity due to the presence of hydrophilic (e.g., arginine, lysine) and hydrophobic (e.g., tryptophan, phenylalanine, tyrosine) amino acids; and (vi) endocytic and / or non-endocytic cell membrane crossing properties, including the ability to cross the blood-brain barrier and blood-spinal cord barrier (BBB / BSCB). In certain embodiments, the transport fraction may be an arginine-rich cationic peptide fused to TAT.

[0124] In addition, the transport fraction(s) may include polypeptides with a basic amino acid-rich region. As used herein, the term “basic amino acid-rich region” refers to a region of a protein or peptide with a high content of basic amino acids, such as arginine, histidine, asparagine, glutamine, and lysine. A “basic amino acid-rich region” may, for example, have 15% or more basic amino acids. In some cases, a “basic amino acid-rich region” may have less than 15% basic amino acids and still function as a transport agent region. In other cases, a basic amino acid region will have 30% or more basic amino acids. Petition 870250089855, dated 02 / 10 / 2025, pp. 186 / 336 38 / 93

[0125] The transport fraction(s) may also include a proline-rich region. A proline-rich region refers to a region of a polypeptide that contains more prolines than is generally observed in natural proteins (e.g., proteins encoded by the human genome). As used herein, the term proline-rich region refers to a region of a polypeptide with 5% or more (up to 100%) proline in its sequence. In some cases, a proline-rich region may have between 5% and 15% prolines. Proline-rich regions of this order may function as a transport agent region.

[0126] Thus, in some embodiments, the dimer comprises a transport moiety and a cysteine ​​residue. In some embodiments, the dimer comprises a transport moiety comprising an amino acid sequence with at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% identity with the wild-type HIV TAT sequence and a cysteine ​​residue.

[0127] In some embodiments, the transport fraction comprises an amino acid sequence that is at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, or 100% identical to the amino acid sequence of SEQ ID NO: 5, 6, or 7, as shown in Table 1 below. In one embodiment, the transport fraction included in the first monomeric unit and the second monomer are identical to the amino acid sequence of SEQ ID NO: 5. Table 1. TAT Sequences Sequence SEQ ID NO GRKKRRQRRR 5 YGRKKRRQRRR 6 GRKKRRQRRRPQ 7

[0128] In some embodiments, the dimer comprises a selected domain from the group consisting of a PTPRF wedge domain, a PTPRD wedge domain and a wedge domain of PTPRS, and variants with at least 70% identity to it. In Petition 870250089855, dated 02 / 10 / 2025, page 187 / 336 39 / 93 In some embodiments, the dimer comprises a selected domain from the group consisting of a PTPRF wedge domain, a PTPRD wedge domain, and a PTPRS wedge domain, and variants that have at least about 65% identity with them, at least about 70% identity with them, at least about 75% identity with them, at least about 80% identity with them, at least about 85% identity with them, at least about 90% identity with them, at least about 95% identity with them, or at least about 97% identity with them. In some embodiments, the domain comprises an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 8, 9, 10, or 11, as listed in Table 2.In some embodiments, the domain comprises an amino acid sequence that is at least about 65% identical, at least about 70% identical, at least about 75% identical, at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical, or at least about 97% identical to the amino acid sequence of SEQ ID NO: 8, 9, 10, or 11, as listed in Table 2. Table 2: Wedge domain sequence of LAR family phosphatases PTPR Parental Domain Sequences in Wedge SEQ ID NO PTPRF DLADNIERLKANDGLKFSQEYESI 8 PTPRD ELADHIERLKANDNLKFSQEYESI 9 PTPRS (human) DMAEHTERLKANDSLKLSQEYESI 10 PTPRS (rodent) DMAEHMERLKANDSLKLSQEYESI 11

[0129] In some embodiments, the first monomer and the second monomer each independently comprise a first domain comprising an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7; a second domain comprising an amino acid sequence that is at least 70% identical to the sequence of Petition 870250089855, dated 02 / 10 / 2025, pp. 188 / 336 40 / 93 amino acids of SEQ ID NO: 8, 9, 10 or 11; and a cysteine ​​residue; wherein the dimer comprises a disulfide bond between the cysteine ​​residue of the first monomer and the cysteine ​​residue of the second monomer. In one embodiment, the first domain comprises an amino acid sequence identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7. In one embodiment, the transport moiety included in the first monomeric unit and in the second monomer are identical to the amino acid sequence of SEQ ID NO: 5. In one embodiment, the second domain comprises an amino acid sequence identical to the amino acid sequence of SEQ ID NO: 8, 9, 10 or 11.

[0130] In some embodiments, the peptide dimer disclosed here has the following structure: first domain —Cys— second domain first domain —Cy$— second domain (D .

[0131] In some embodiments, the first domain corresponds to a transport fraction described above and the second domain corresponds to a peptide domain as described above.

[0132] In some embodiments, the peptide dimer disclosed here has the following structure: first domain —Cys— second domain X first domain —Cy$— second domain (II) , where X is a chemical link or ligand between the two cysteine ​​residues.

[0133] In some embodiments, X is a linkage, for example, a disulfide bond between the thiol groups of the two cysteine ​​residues. In some embodiments, X is a chemical ligand between Petition 870250089855, dated 02 / 10 / 2025, page 189 / 336 41 / 93 the two cysteine ​​residues. The chemical linker may, for example, comprise covalent bonds with each of the thiol groups of the cysteine ​​residues (e.g., disulfide, thioether, or thioester bonds). In some embodiments, the chemical linker is between 5 Å and 50 Å in length. In some embodiments, the chemical linker is between 5 Å and 35 Å in length. In some embodiments, the chemical linker is between 10 Å and 25 Å in length. In some embodiments, the chemical ligand consists of atoms selected from C, N, S, O, and H. In some embodiments, the chemical ligand comprises atoms selected from C, N, S, O, and H. In some embodiments, the chemical ligand consists of atoms selected from C, O, and H. In some embodiments, the chemical ligand comprises atoms selected from C, O, and H. In some embodiments, the chemical ligand comprises between 1 and 8 carbon atoms.In some embodiments, the chemical linker comprises an alkylene chain (for example, a C(i-i2)alkylene, a C(i-6)alkylene or a C(i3j)alkylene). In some embodiments, the chemical linker comprises an alkylene chain in which one or more carbon atoms are replaced by oxygen (for example, a divalent polyethylene glycol chain).

[0134] In some embodiments, the first monomer and the second monomer each independently comprise an amino acid sequence that is at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4. In one embodiment, the first monomer and the second monomer each independently comprise an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.

[0135] In one embodiment, the dimer comprises identical monomers. In another embodiment, the dimer comprises monomers Petition 870250089855, dated 02 / 10 / 2025, pp. 190 / 336 42 / 93 are not identical.

[0136] In one embodiment, the first monomer and the second monomer of the dimer have different C-terminal modifications.

[0137] A potential mechanism for regulation, modulation, and / or inhibition of the LAR family of phosphatases involves dimerization of the intracellular portion of the phosphatase. In contrast to receptor tyrosine kinases, which are active as dimers and inactive as monomers, several protein tyrosine phosphatases (PTPs) have been shown to be inactive as dimers and active as monomers. PTPalfa, PTP1B, and CD45, which have been crystallized in both forms, have been shown to be active as monomers and inactive as dimers. Since PTPRF demonstrates homophilic binding under specific oxidative conditions, and PTPRS can dimerize in response to ligand binding, it is suggested that ligands of LAR family phosphatases may direct the activation state of PTPRF and PTPRS. Therefore, mimicking dimerization with intracellularly targeted therapies can directly inactivate the LAR family of phosphatases without altering the extracellular matrix or other ligands.

[0138] Peptides mimetic to the intracellular portion of the LAR phosphatase family, when administered to a neural cell, can inhibit and / or reduce CSPG-induced LAR activity or function. Suppression of LAR family activity, signaling, and / or function in response to CSPG activation has been found to promote neural cell growth, including restoration of growth cone motility, process extension, sprouting, promotion of neural cell survival and plasticity, and inhibition of neural cell regressive death.

[0139] In some embodiments, the function of a LAR family phosphatase is inhibited or reduced by a small molecule peptide or therapeutic agent that binds to and / or forms complexes with the intracellular domain of at least one LAR family phosphatase. In some embodiments, one or more activities and signaling pathways of the LAR family phosphatase are inhibited or Petition 870250089855, dated 02 / 10 / 2025, pp. 191 / 336 43 / 93 reduced by a small molecule peptide or therapeutic agent that binds to and / or forms complexes with the intracellular domain of at least one LAR family phosphatase. Consequently, therapeutic peptides or small molecules that bind to and / or form complexes with the intracellular domain of at least one LAR family phosphatase of neural cells can be used to promote cell growth, motility, survival, and plasticity of these cells.

[0140] In some embodiments, the therapeutic agent is a peptide mimetic of the wedge-shaped domain (i.e., wedge domain) of a LAR family phosphatase. Structural and sequence analysis revealed that all members of the LAR family contain a conserved 24-amino-acid wedge-shaped helix-loop-helix motif in the first intracellular catalytic domain that may potentially mediate homo / heterophilic receptor interaction.

[0141] Table 3 lists the amino acid sequences of intracellular portions of LAR family phosphatase members that contain the wedge domain. The 24 amino acid wedge domains of these intracellular portions of LAR family phosphatases are identified by underlining. Although the specific structure of the wedge domain is conserved in most LAR family wedge domains, the exact amino acids that make up the wedge domains vary between individual proteins and subfamilies.

[0142] As can be seen in Table 3, the wedge domain is highly conserved among members of the LAR family. For example, the PTPRS wedge domain sequence is highly conserved among mammals, with only a single amino acid change in mice and rats (threonine to methionine at position 6). Petition 870250089855, dated 02 / 10 / 2025, page 192 / 336 Table 3: Wedge domain of LAR family phosphatase PTPRF wedge domain alignment Mouse 1338 PIPITDLADNIERLICANDGICLFSQEYESIDPGQ 1370 SEQ ID NO: 12 Rat 1338 PIPITDLADNIERLICANDGKLFSQEYESIDPGQ 1370 SEQ ID NO: 13 Human 1347 PIPITDLADNIERLICANDGKLFSQEYESIDPGQ 1379 SEQ ID NO: 14 PTPRS wedge domain alignment Mouse 1347 PIPITDMAEHMERLKANDSLKLSOEYESIDPGQ 1379 SEQ ID NO: 15 Rat 1303 PIPITDMAEHMERLKANDSLKLSQEYESIDPGQ 1335 SEQ ID NO: 16 Human 1368 PIPIADMAEHTERLKANDSLKLSOEYESIDPGQ 1400 SEQ ID NO: 17 PTPRD wedge domain alignment Mouse 1326 PIPILELADHIERLKANDNLKFSQEYESIDPGQ 1379 SEQ ID NO: 18 Human 1335 PIPILELADHIERLKANDNLICFSOEYESIDPGQ 1367 SEQ ID NO: 19 44 / 93 Petition 870250089855, dated 02 / 10 / 2025, page 193 / 336 45 / 93

[0143] The preferred modalities are listed in Tables 4, 5 and 6. Monomeric compounds 1, 2, 3 and 4 are provided here, as well as methods of treating a subject suffering from any of the indications provided here, by administering compounds 1, 2, 3 or 4 to the subject. Petition 870250089855, dated 02 / 10 / 2025, pp. 194 / 336 Table 4: Monomers Compound Sequence 1 TAT-Cys-PTPRF GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI SEQ ID NO: 1 2 TAT-Cys-PTPRD GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI SEQ ID NO: 2 3 TAT-Cys-PTPRS GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI SEQ ID NO: 3 4 Rodent TAT-Cys-PTPRS GRKKRRQRRRCDMAEHMERLKANDSLKLSQEYESI SEQ ID NO: 4 Table 5: Homodimers Compound Product Amino acid sequence indicating disulfide bond 5 TAT-Cys-PTPRF wedge domain homodimer GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI 1 GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI SEQ ID NO: 1 SEQ ID NO: 1 6 TAT-Cys-PTPRD wedge domain homodimer GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI 1 GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI SEQ ID NO: 2 SEQ ID NO: 2 7 Human TAT-Cys-PTPRS Wedge Domain Homodimer GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI 1 GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI SEQ ID NO: 3 SEQ ID NO: 3 8 Em domain homodimer rodent TAT-Cys-PTPRS wedge GRKKRRQRRRCDMAEHMERLKANDSLKLSQEYESI 1 GRKKRRQRRRCDMAEHMERLKANDSLKLSQEYESI SEQ ID NO: 4 SEQ ID NO: 4 ” represents Cys-Cys disulfide. 46 / 93 Petition 870250089855, dated 02 / 10 / 2025, pp. 195 / 336 Table 6: Heterodimers Compound Product Heterodimer Amino acid sequence indicating disulfide bond 9 TAT-Cys-PTPRF TAT-Cys-PTPRD GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI 1 GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI SEQ ID NO: 1 SEQ ID NO: 2 10 TAT-Cys-PTPRD TAT-Cys-PTPRS GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI 1 GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI SEQ ID NO: 2 SEQ ID NO: 3 11 TAT-Cys-PTPRS TAT-Cys-PTPRF GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI 1 GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI SEQ ID NO: 3 SEQ ID NO: 1 ” represents Cys-Cys disulfide. 47 / 93 Petition 870250089855, dated 02 / 10 / 2025, pp. 196 / 336 48 / 93

[0144] In some embodiments, the amino acid residue 17T in SEQ ID NO:3 can be replaced respectively by M, resulting in the rat and mouse PTPRS variant.

[0145] In some embodiments, the peptide dimer disclosed herein may comprise a peptide domain that is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% identical to about 10 consecutive amino acids of the wedge domain of a LAR family phosphatase. In some embodiments, the peptide dimer disclosed herein may comprise a peptide domain that is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% identical to about 15 consecutive amino acids of the wedge domain of a LAR family phosphatase. In some embodiments, the peptide dimer disclosed herein may comprise a peptide domain that is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or approximately 100% identical to about 20 consecutive amino acids of the wedge domain of a LAR family phosphatase.The peptide dimer can modulate the signaling and / or function of a LAR family phosphatase in cells that express LAR family phosphatase, such as neural cells.

[0146] In some embodiments, the peptide dimer comprises a peptide domain that is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% identical to about 10 to about 20 consecutive amino acids of a PTPRS wedge domain, and the peptide dimer can promote cell viability, morphogenesis, or differentiation when subjected to inhibitory effects of CSPGs in cells, for example, neural cells.

[0147] In some embodiments, the peptide dimer disclosed herein comprises a peptide linker. In some embodiments, the peptide linker is in the middle of a monomeric subunit that Petition 870250089855, dated 02 / 10 / 2025, page 197 / 336 49 / 93 connects the transport moiety and the first or second peptide domain. In some embodiments, each peptide monomer includes a peptide linker with a cysteine ​​residue, such that the first monomeric subunit and the second monomeric subunit are cross-linked via the disulfide bond between the two cysteine ​​residues in the first and second monomeric subunits.

[0148] In some embodiments, the monomeric subunits of the peptide dimer may have one or more C-terminal modifications. The modifications may be the same or different. In one embodiment, the monomeric subunits have C-terminal amide ends, where the charge is removed from the C-terminal of the peptide by amidation, especially when the peptide monomers are chemically synthesized. The uncharged C-terminal amide end more closely mimics the native protein and therefore may increase the biological activity of the peptide.

[0149] In some embodiments, a monomeric subunit of the peptide dimer may include additional residues at the C-terminus or the N-terminus. In other embodiments, a monomeric subunit of the peptide dimer may include a peptide tag at the C-terminus or the N-terminus. In some embodiments, the tag may be an affinity tag, such as a His tag, a Flag tag, a Twin-Strep tag, etc.

[0150] The peptides described herein may also include, for example, mutants, variants, fragments, chimeras, and biologically active analogs. The term fragments encompasses amino acid sequences with truncations of one or more amino acids from the amino terminal (N-terminal), the carboxylic terminal (C-terminal), or the interior of the peptide. Analogs of the invention are peptides with an insertion or substitution of one or more amino acids. Variants, mutants, fragments, chimeras, and analogs may function as inhibitors to abolish inhibitory effects of CSPGs in neural cells activated with CSPGs (without Petition 870250089855, dated 02 / 10 / 2025, pp. 198 / 336 50 / 93 if restricted to the examples presented).

[0151] In several non-limiting embodiments, the peptide dimers disclosed herein can be used as therapeutic agents to promote cell growth, motility, survival and plasticity of these cells. Preparation of peptide dimers

[0152] The embodiments of this disclosure provide methods for preparing peptide monomers used to prepare peptide dimers and methods for preparing peptide dimers disclosed herein.

[0153] According to various embodiments, a peptide monomer used to prepare peptide dimers can be prepared by methods known to experts in the field. For example, a peptide monomer can be prepared using conventional peptide synthesis techniques (e.g., solid-phase synthesis) or molecular biology techniques.

[0154] In some embodiments, a transport moiety polypeptide, as described above, and a peptide domain described above may be synthesized and purified separately and then non-covalently linked using a non-covalently linked polypeptide transduction agent, such as that provided in the Chariot protein delivery system (see U.S. Patent No. 6,841,535; J Biol Chem 274 (35): 24941-24946; and Nature Biotec. 19: 1173-1176, all incorporated herein by reference in their entirety).

[0155] In some embodiments, a peptide monomer used to form a peptide dimer disclosed herein may be produced by genetic engineering using recombinant DNA. For example, recombinant DNA may be designed to encode a fusion peptide used to produce a peptide dimer disclosed herein. The fusion peptide may comprise a peptide domain comprising an amino acid sequence selected from phosphatase wedge domains of the related family to Petition 870250089855, dated 02 / 10 / 2025, page 199 / 336 51 / 93 leukocyte antigen (LAR) or variants that have at least 65% homology to them, and the peptide domain may be connected to a transport fraction disclosed herein by means of a cysteine ​​residue or a peptide linker comprising a cysteine ​​residue.

[0156] This recombinant DNA can be inserted into an expression cassette of an expression vector and operatively linked to a regulatory region. The regulatory region typically comprises a promoter to regulate the expression of the peptide monomer in a cell carrying the vector. In some embodiments, the promoter is a constitutive promoter, such as a CMV, so that the peptide monomer can be consistently expressed in a cell carrying the vector. In some embodiments, the promoter is an inducible promoter, and the expression of the peptide monomer can be induced as needed.

[0157] In some embodiments, the vector is a plasmid vector and can be transformed into bacteria to store or amplify, and can be transfected into mammalian cells to express the recombinant peptide.

[0158] In some embodiments, the preparation disclosed here may include the cultivation of a host cell (bacterial or eukaryotic) under conditions that provide for the expression of peptides and / or proteins within the cell.

[0159] The peptide monomer expressed in the host cell can be purified by affinity methods, ion-exchange chromatography, size-exclusion chromatography, hydrophobicity, or other purification techniques commonly used for protein purification. The purification step can be performed under non-denaturing conditions. Conversely, if a denaturation step is required, the protein can be renatured using techniques known in the art.

[0160] In some embodiments, the peptide monomers described herein may include additional residues that may be Petition 870250089855, dated 02 / 10 / 2025, pp. 200 / 336 52 / 93 added to either end of a polypeptide for the purpose of providing a linker by which polypeptides can be conveniently linked and / or attached to other polypeptides, proteins, detectable fractions, markers, solid matrices, or carriers.

[0161] Amino acid residue linkers generally have at least one residue and can have 40 or more residues, most frequently from 1 to 10 residues. Typical amino acid residues used for linking are glycine, tyrosine, cysteine, lysine, glutamic and aspartic acid, or similar. In addition, a given polypeptide may differ by the sequence being modified by terminal-NH2 acylation, for example, acetylation or amidation of thioglycolic acid, by terminal carboxylamidation, for example, with ammonia, methylamine, and similar terminal modifications. Terminal modifications are useful, as is well known, to reduce susceptibility to proteinase digestion and therefore serve to prolong the half-life of polypeptides in solutions, particularly in biological fluids where proteases may be present.In this sense, polypeptide cyclization is also a useful terminal modification and is particularly preferred due to the stable structures formed by cyclization and in view of the biological activities observed for such cyclic peptides, as described herein.

[0162] In some embodiments, the linker may be a flexible peptide linker that links the therapeutic peptide to other polypeptides, proteins, and / or molecules, such as detectable fractions, markers, solid matrices, or carriers. A flexible peptide linker may be about 20 or fewer amino acids in length. For example, a peptide linker may contain about 12 or fewer amino acid residues, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In some cases, a peptide linker comprises two or more of the following. Petition 870250089855, dated 02 / 10 / 2025, page 201 / 336 53 / 93 amino acids: glycine, serine, alanine, and threonine.

[0163] A peptide dimer disclosed herein can be prepared by dimerization of peptide monomers as prepared above, wherein the peptide monomers form the monomeric subunits in the peptide dimer. The peptide monomers used to prepare a dimer can be identical or different, resulting in a homodimer or heterodimer, respectively.

[0164] In some embodiments, peptide dimers are prepared by oxidizing a first peptide monomer and a second peptide monomer, so that the cysteine ​​residues in the first peptide monomer and in the second peptide monomer form a disulfide bond that connects the two peptide monomers.

[0165] In one embodiment, the dimerization process comprises combining a first peptide monomer and a second monomer in water, and a) adding an oxidizing agent and / or b) oxygenating the solution to allow the formation of a covalently cross-linked dimer. The first peptide monomer and the second monomer may be identical or different. In one embodiment, the combined concentration of the first and second peptide monomers in water may be at least 20 mg / mL or at least 40 mg / mL. In one embodiment, the combination of the first peptide monomer and the second monomer in water is maintained at a temperature of about 20°C to about 25°C. In one embodiment, DMSO is added to the water before, during, or after the first peptide monomer and the second monomer are added to the water.

[0166] The oxidizing agents used in the dimerization process may be chosen from any common oxidizing agents. Non-limiting examples of oxidizing agents may include bromates, chlorine oxyanions, chromates, hypoiodites, iodanes, iodates, interhalogen compounds, manganese compounds, nitrates, oxidizing acids, ozone, periodates, permanganates, Petition 870250089855, dated 02 / 10 / 2025, page 202 / 336 54 / 93 Peroxy acids, persulfates, and rocket oxidizers. In some embodiments, an oxidizing agent may be chosen from hydrogen peroxide, potassium dichromate, sodium or calcium hypochlorite, nitric acid, oxygen, ozone, potassium perchlorate, potassium chlorate, potassium permanganate, ammonium or sodium persulfate, or a combination thereof. In some embodiments, an oxidizing agent is chosen from cupric sulfate, iodide, hydrogen peroxide, trans-3,4-dihydroxy-selenolan oxide (DHS), supported methionine sulfoxide, N-chlorosuccinimide (NCS), or a combination thereof.

[0167] In one embodiment, the oxidizing agent is iodine, and the process employs microwave-assisted oxidation.

[0168] In some embodiments, a process for preparing the peptide dimers disclosed herein comprises mixing the first monomer and the second monomer in a solvent with cupric sulfate to produce the dimer. The solvent may also comprise purified water for purification (PWP). In one embodiment, the solvent may also comprise ethanol. In one embodiment, the pH of the mixture, i.e., dimerization reaction mixture, is maintained between about 8.5 and about 9.5.

[0169] An exemplary embodiment for preparing the peptide dimer disclosed herein may include the following: 1) Add PWP and ethanol to an oxidation beaker and stir for 15 minutes to make the mixture homogeneous, the amounts of PWP and ethanol required depending on the amount of peptide monomer; 2) After 15 minutes of stirring, slowly add the corresponding amount of pure Compound 3 to the beaker and mix until all the powder has been dissolved to form a clear solution, i.e., reaction mixture. Stir the reaction mixture for 15 minutes; 3) After 15 minutes of stirring, check the initial pH of the reaction mixture and adjust the pH to about 9 ± 0.5 using dilute ammonia solution, where the dilute ammonia solution is prepared by taking 100 mL of ammonia solution (25%) and Petition 870250089855, dated 02 / 10 / 2025, page 203 / 336 55 / 93 diluted to 1 l by PWP; 4) monitor the pH of the reaction mixture every hour; if the pH is less than 9 ± 0.5, adjust the reaction mixture by adding additional diluted ammonia solution; 5) After about 1 hour, add cupric sulfate to the oxidation reaction mixture periodically; 6) collect batch samples every hour and analyze the reaction progress by HPLC and allow the oxidation reaction to continue until the free peptide monomer Compound 3 is detected by HPLC as less than 4 ± 0.5%; 7) once the presence of Compound 3 is less than 4 ± 0.5%, as confirmed by HPLC, adjust the pH of the reaction mixture by adding acetic acid until the pH is about 4.5 ± 0.5; 8) After oxidation, the reaction mixture is adjusted to have a pH of approximately 4.5 ± 0.5, and then the oxidation reaction mixture is filtered through 5-micron filter paper with vacuum applied to the receiving vessel used to receive the filtered solution; 9) Collect the filtered solution and purify the filtered solution by preparative HPLC; 10) Lyophilize the peak eluate from the HPLC containing pure lyophilized peptide dimer compound. Formulations

[0170] Non-limiting examples of materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, or potassium sorbate; partial mixtures of glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; disodium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; wool fat; sugars such as lactose, glucose, and sucrose; starches such as corn starch and starch Petition 870250089855, dated 02 / 10 / 2025, pp. 204 / 336 56 / 93 potato; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol; and phosphate buffer solutions.

[0171] In addition, non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition, according to the formulator's judgment.

[0172] According to various embodiments, the disclosed pharmaceutical compositions may be formulated in any form suitable for administration to a subject in need thereof, whether with a fixed or non-fixed dose. For example, the pharmaceutical composition may be adapted for oral or parenteral administration and may be administered to the subject in the form of dosage tablets, sugar-coated tablets, capsules, delayed-release hard capsules, soft gelatin capsules, chewable tablets, gums, coated tablets, powders, granules, syrups, aerosols, inhalants, suppositories, solutions, suspensions, catheters containing the composition, syringes containing the composition, implants containing the composition, transdermal patches or the like.

[0173] In some embodiments, the pharmaceutical compositions are formulated in liquid solution, usually in physiologically compatible buffers, such as Hank's solution or solution of Petition 870250089855, dated 02 / 10 / 2025, pp. 205 / 336 57 / 93 Ringer's solution for injection. In some embodiments, a therapeutic agent comprising a peptide dimer or pharmaceutically acceptable analogue, salt or solvate thereof described herein may be formulated in solid form and immediately redissolved or suspended in a pharmaceutically acceptable solvent prior to use. For example, a peptide dimer or a pharmaceutically acceptable analogue, salt or solvate thereof may be in lyophilized form which may be dissolved to obtain a final preparation for administration to a subject at the time of use. Injectable preparations, for example, sterile injectable oil or aqueous suspensions, may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0174] In some embodiments, the pharmaceutical composition does not include DMSO.

[0175] To prolong the effect of a drug, it is often desirable to delay the absorption of the drug by subcutaneous (sc) or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The rate of drug absorption depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. The absorption of a Petition 870250089855, dated 02 / 10 / 2025, pp. 206 / 336 58 / 93 parenterally administered medication may also be delayed by dissolving or suspending the medication in an oily vehicle.

[0176] In some other embodiments, the pharmaceutical compositions disclosed herein may be formulated in a dosage form such as a tablet, a gelatin capsule, a capsule, a coated tablet, a polypill, a chewable tablet, a gum, a hard capsule, a transdermal patch, etc.

[0177] In some other embodiments, the pharmaceutical compositions disclosed herein may be formulated in liquid form for oral administration, wherein the pharmaceutical composition includes, among the therapeutic agents (or active compounds), pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the technique, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan esters of fatty acids and mixtures thereof.In addition to inert diluents, oral compositions may also include adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0178] Solid compositions of a similar type can also be used as fillers in hard and soft filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Petition 870250089855, dated 02 / 10 / 2025, pp. 207 / 336 59 / 93

[0179] Active ingredients comprising peptide dimers or analogues, salts or pharmaceutically acceptable solvates thereof may also be in microencapsulated form with one or more excipients, as noted above. Solid dosage forms of tablets, coated tablets, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation art. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances besides inert diluents, for example, tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets and pills, dosage forms may also include buffering agents.

[0180] Pharmaceutical compositions may be formulated in forms for topical or transdermal administration, where the forms may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is mixed by addition under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, eye drops, ophthalmic ointments, powders, and solutions are also contemplated as being within the scope of this disclosure.

[0181] Ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Petition 870250089855, dated 02 / 10 / 2025, pp. 208 / 336 60 / 93

[0182] Powders and sprays may contain, in addition to the compounds in this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may also contain usual propellants such as chlorofluorohydrocarbons.

[0183] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate-control membrane or by dispersing the compound in a polymer matrix or gel. Treatment Methods

[0184] Pharmaceutically acceptable peptide dimers or analogues, salts or solvates thereof, when administered to the cell (such as neural cells), are capable of promoting cell growth, motility, survival and plasticity in cells, for example, neural cells.

[0185] Thus, peptide dimers or pharmaceutically acceptable analogues, salts or solvates thereof, and / or compositions comprising peptide dimers or pharmaceutically acceptable analogues, salts or solvates thereof may be used to abolish inhibitory effects of CSPGs in neural cells activated with CSPGs and to promote cell growth, motility and survival, and to treat diseases, disorders and / or conditions associated with the accumulation of CSPGs or the activation and signaling of the LAR family of phosphatases.

[0186] Consequently, the present modalities provide methods for treating diseases, disorders and / or conditions associated with the accumulation of CSPGs or the activation and signaling of the LAR family of phosphatases using peptide dimers or Petition 870250089855, dated 02 / 10 / 2025, pp. 209 / 336 61 / 93 compositions comprising the peptide dimers disclosed herein.

[0187] In various embodiments, a method of treatment is provided for a neurological condition, disease or disorder selected from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity, neurodegenerative disease and a neurological condition, in a subject in need thereof, the method comprising administering an effective amount of a pharmaceutical composition disclosed herein to the subject.

[0188] In some modalities, neural injury is selected from the group consisting of acute neural injury, traumatic brain injury (TBI), spinal cord injury, concussion, stroke, including ischemic stroke, hemorrhagic stroke, and chronic stroke disease.

[0189] In some modalities, the neurological condition, disease or disorder is selected from the group consisting of Alzheimer's disease, Alzheimer's disease-related dementias, diffuse Lewy body disease, senile dementia, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis (MS), optic neuritis, Huntington's disease, Tourette syndrome, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, Creutzfeldt-Jakob disease, epilepsy and infectious disease.

[0190] Several embodiments further provide for the use of a peptide dimer or a pharmaceutically acceptable analogue, salt or solvate thereof in the manufacture of a medicament for the treatment of a selected neurological condition, disease or disorder from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity, neurodegenerative disease, a neurological condition or a combination thereof. Administration and Dosages Petition 870250089855, dated 02 / 10 / 2025, pp. 210 / 336 62 / 93

[0191] In general, the pharmaceutical compositions disclosed herein may be administered to a subject who requires them by any suitable route, including, for example, orally (e.g., in capsules, suspensions or tablets), systemically or by parenteral administration. Examples of non-limiting routes include subcutaneous, intramuscular, intravenous, transdermal, intranasal, rectal, ocular, topical, sublingual and buccal.

[0192] In one embodiment, the pharmaceutical compositions may be administered by lateral cerebroventricular injection into the brain of a subject, generally within 100 hours of the occurrence of an injury (resulting in a condition characterized by aberrant axonal growth of neurons in the central nervous system) (such as within 6, 12, 24, or 100 hours, inclusive, from the time of injury). The injection may be made, for example, through a hole made in the subject's skull. In another embodiment, the therapeutic agent may be administered via a shunt surgically inserted into the cerebral ventricle of a subject, generally within 100 hours of the occurrence of an injury (for example, within 6, 12, or 24 hours, inclusive, from the time of injury). For example, the injection may be made into the larger lateral ventricles, although injection into the smaller third and fourth ventricles may also be made.In another embodiment, the therapeutic agent may be administered by injection into the cisterna magna, or lumbar area of ​​a subject, within 100 hours of the occurrence of an injury (such as within 6, 12, or 24 hours, inclusive, from the time of the injury).

[0193] In another embodiment, the pharmaceutical compositions may be administered to a subject at or near the site of the injury, generally within 100 hours of the injury occurring (e.g., within 6, 12, or 24 hours, inclusive, from the time of injury). Such administration may optionally be Petition 870250089855, dated 02 / 10 / 2025, pp. 211 / 336 63 / 93 subcutaneous.

[0194] In another embodiment, pharmaceutical compositions may be administered to a subject more than 100 hours after the time of injury. In some cases, administration will occur one week after the injury, several weeks after the injury, or months or years after the injury.

[0195] In certain embodiments, a therapeutic amount or dose of the therapeutic agents or compositions disclosed herein may vary from about 0.1 mg / kg to about 500 mg / kg per kilogram of body weight. In certain embodiments, a therapeutic amount or dose of the therapeutic agent or compositions disclosed herein may vary from about 1 to about 50 mg / kg. In general, treatment regimens according to this disclosure comprise administering to a subject requiring such treatment about 10 mg to about 1000 mg of the peptide dimers or pharmaceutically acceptable analogue, salt or solvate thereof of this disclosure per day in single or multiple doses. Therapeutic amounts or doses also vary depending on the route of administration, as well as the possibility of concomitant use with other agents.

[0196] However, it should be understood that the total daily use of the compounds and compositions of this disclosure will be decided by the attending physician within the scope of good medical judgment. The specific inhibitory dose for any particular individual will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific therapeutic agents or compositions employed; the age, body weight, general health, sex, and diet of the individual; the timing of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of treatment; medications used in combination with or concurrently with the specific compound employed; and similar factors well known in the art. Petition 870250089855, dated 02 / 10 / 2025, pp. 212 / 336 64 / 93 medical. Kits

[0197] One aspect of the present disclosure relates to a kit comprising a therapeutic agent comprising a peptide dimer or a pharmaceutically acceptable salt or solvate thereof, or any composition comprising the peptide dimer or pharmaceutically acceptable analogue, salt or solvate thereof described above.

[0198] In some embodiments, the kit comprises one or more separate dosage forms, each dosage form comprising a pharmaceutical composition comprising an effective amount or dose of a pharmaceutically acceptable peptide dimer or salt, analogue or solvate thereof disclosed herein for treating diseases, disorders and / or conditions associated with inhibition of nervous system repair by chondroitin sulfate proteoglycans (CSPG) or with suppressive effects on LAR family phosphatases such as PTPRD, PTPRF and PTPRS in neurological repair.

[0199] In some embodiments, the kit may comprise a first container comprising a pharmaceutically acceptable peptide dimer or analogue, salt or solvate thereof, according to the present disclosure, which is in free form as a lyophilized powder and, optionally, a second container comprising a pharmaceutically acceptable solvent for dissolving the analogue, salt or solvate thereof. At the time of use, the pharmaceutically acceptable peptide dimer or analogue, salt or solvate thereof, according to the present disclosure, in free form, may be mixed with the solvent to produce a final preparation for administration to a subject in need.

[0200] In some embodiments, the kit may also include instructions for using the therapeutic agent or composition contained in the kit to treat diseases, disorders and / or conditions associated with inhibition of nervous system repair by chondroitin sulfate proteoglycans (CSPG) or with suppressive effects of Petition 870250089855, dated 02 / 10 / 2025, pp. 213 / 336 65 / 93 phosphatases of the LAR family, such as PTPRD, PTPRF, and PTPRS in neurological repair.

[0201] It should be understood that whenever values ​​and ranges are provided herein, all values ​​and ranges covered by these values ​​and ranges shall be covered within the scope of this disclosure. Furthermore, all values ​​that are within these ranges as well as the upper or lower limits of a range of values ​​are also covered by this disclosure.

[0202] The embodiments described herein are not limited to specific methodologies, protocols, reagents, etc., and as such may vary. The terminology used herein is intended to describe only specific embodiments and is not intended to be limiting in scope. Except in examples of operation, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used in this document shall be understood as modified in all cases by the term about.

[0203] All patents and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that may be used in connection with the present invention. These publications are provided for disclosure only prior to the filing date of this application. Nothing in this respect shall be construed as an admission that the inventors do not have the right to anticipate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the content of these documents are based on information available to the applicants and do not constitute any admission as to the accuracy of the dates or content of these documents.

[0204] The following examples further illustrate aspects of this disclosure. However, they are not in the form of Petition 870250089855, dated 02 / 10 / 2025, pp. 214 / 336 66 / 93 some limitation of the teachings of the present disclosure as presented. It should be understood that these examples are provided for illustrative purposes only. From the above discussion and these Examples, a person skilled in the art can determine the essential characteristics of embodiments of the present invention. Without departing from the spirit and scope of the invention, a person skilled in the art can make various alterations and modifications to the invention to adapt it to various uses and conditions. All publications, including patents and non-patented literature, mentioned in this specification are expressly incorporated by reference herein. Examples

[0205] Unless otherwise indicated, the practice of the present disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology that are within the skill of the art. Example 1: Synthesis and purification of the peptide dimer Compound 7

[0206] Compound 7: [Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-ArgCys-Asp-Met-Ala-15Glu-His-Thr-Glu-Arg-Leu-Lys-Ala-Asn-Asp-SerLeu-Lys-Leu-Ser-Gln-Glu-Tyr-Glu-Ser-35Ile-NH2] 2 (11Cys-11'Cys disulfide)

[0207] In this example, the peptide dimer Compound 7, comprising the wedge domain of human PTPRS, was prepared by oxidative dimerization of Compound 3 (peptide monomer of SEQ ID NO: 3 (variant of human TAT-Cys-PTPRS)) following the raw materials and procedure described below. The average molecular weight of Compound 7 is 8575.65 Da.

[0208] Raw materials: Compound 3 (peptide monomer comprising amino acid sequence SEQ ID NO:3, “TAT-Cys-PTPRS”): 11.5 g; Purified water for purification (PWP): 1800 mL; Ethanol (AR): 200 mL; Ammonia solution: 21 mL, pH 9.9 ±0.5; Petition 870250089855, dated 02 / 10 / 2025, pp. 215 / 336 67 / 93 Acetic acid (HPLC grade): 13 mL, pH 4.5 ± 0.5.

[0209] Procedure for the preparation and purification of a peptide dimer (cupric sulfate protocol): 1) Add PWP and ethanol to an oxidation beaker and stir for 15 minutes to homogenize the mixture. The amounts of PWP and ethanol needed will depend on the amount of peptide monomer. 2) After 15 minutes of stirring, slowly add the corresponding amount of pure Compound 3 to the beaker and mix until all the powder is dissolved to form a clear solution. Stir the reaction mixture for 15 minutes. 3) After 15 minutes of stirring, check the initial pH of the reaction and adjust the pH to approximately 9 ± 0.5 using a diluted ammonia solution, where the diluted ammonia solution is prepared by taking 100 mL of ammonia solution (25%) and diluting it to 1 L per PWP. 4) Monitor the pH of the reaction mixture every hour. If the pH is less than 9 ± 0.5, adjust the reaction mixture by adding additional diluted ammonia solution. 5) After about 1 hour, add cupric sulfate to the oxidation reaction mixture periodically. 6) Sample the batch every hour and analyze the reaction progress by HPLC and allow the oxidation reaction to continue until the free peptide monomer Compound 3 is detected by HPLC as less than 4 ± 0.5%. 7) When the presence of Compound 3 is less than 4 ± 0.5%, as confirmed by HPLC, adjust the pH of the reaction mixture by adding acetic acid until the pH is around 4.5 ± 0.5. 8) After the oxidation reaction mixture has been adjusted to a pH of approximately 4.5 ± 0.5, filter the oxidation reaction mixture through 5-micron filter paper by applying a vacuum to the receiving container used to receive the solution. Petition 870250089855, dated 02 / 10 / 2025, pp. 216 / 336 68 / 93 filtered. 9) Collect the filtered solution and purify the filtered solution by preparative HPLC. 10) Lyophilize the peak eluate from the HPLC containing the pure Compound to obtain lyophilized Compound 7.

[0210] The compound obtained is an acetate salt of the homodimer Compound 7, having identical monomeric subunits comprising the amino acid sequence of SEQ ID NO:3.

[0211] The peptide dimer obtained is highly purified, with a purity greater than 96.3%. Example 2: Preparation of the peptide dimer Compound 8

[0212] Compound 8: [Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-ArgCys-Asp-Met-Ala-15Glu-His-Met-Glu-Arg-Leu-Lys-Ala-Asn-Asp-SerLeu-Lys-Leu-Ser-Gln-Glu-Tyr-Glu-Ser-35Ile-NH2] 2 (11Cys-11'Cys disulfide)

[0213] In this example, the peptide dimer Compound 8, comprising the wedge domain of rat and mouse PTPRS, was prepared by oxidative dimerization of Compound 4 (peptide monomer of SEQ ID NO: 4) (rat TAT-Cys-PTPRS variant) following the procedure described above in Example 1, except that the oxidation reaction continued until the free peptide monomer Compound 4 was detected by HPLC as less than 8 ±0.5%. The average molecular weight of Compound 8 is approximately 8635.84 Da.

[0214] Raw materials: Compound 4 (peptide monomer comprising amino acid sequence of SEQ ID NO: 4, “TAT-Cys-PTPRS (rat)”): 1.1 g; Ethanol (AR): 200 mL; Diluted ammonia solution: 440 mL, pH 9.9 ± 0.5; Acetic acid (HPLC grade): 13 mL, pH 4.5 ± 0.5.

[0215] The compound obtained is a homodimer of the acetate salt of Compound 8, with identical monomeric subunits, comprising the amino acid sequence of SEQ ID NO: 4. The purity of the purified salt of Compound 8 was examined by Petition 870250089855, dated 02 / 10 / 2025, pp. 217 / 336 69 / 93 chromatography. Figure 1 is a graph illustrating the chromatogram showing the purity of the product obtained. As can be seen in Figure 1, the peptide dimer obtained is highly purified, with a single peak corresponding to the purified peptide dimer, corresponding to a purity greater than 96.3%. Example 3: Evaluation of the effectiveness of Compound 8 in the treatment of spinal cord injury. Objective

[0216] The aim of this study is to test the efficacy of a novel peptide dimer (intracellular Sigma-blocking peptide dimer (ISP)) according to the present disclosure on behavioral changes in a rat model with traumatic thoracic spinal cord injury (SCI). Materials and methods Animals

[0217] Adult female Lewis rats (~160 g on arrival) from Envigo were used as subjects receiving treatment in the study. Rats were given unique identification numbers (PGI ID and tail markings) and housed in ventilated cages. All rats were examined, handled, and weighed before the start of the study to ensure adequate health and fitness. During the study, 12 / 12 light / dark cycles were maintained. Ambient temperature was maintained between 23°C and 23°C with relative humidity maintained around 50%. Food and water were provided ad libitum throughout the study. Rats were randomly assigned to treatment groups. Body weights were measured twice weekly during the study. Formulations and Dosage

[0218] The lyophilized compound 8 was dissolved in saline solution and injected subcutaneously in a volume of 500 pL into the animal once daily, from day 1 to day 49 after spinal cord injury.

[0219] The dose concentration was 0.8 mg / mL, Petition 870250089855, dated 02 / 10 / 2025, pp. 218 / 336 70 / 93 corresponding to 400 pg / rat. After reconstitution, the solution was aliquoted and kept at -20 °C until dosage. Treatment Groups

[0220] 12-13 rats were used in each of the following two groups: 1. Control group: LME + Saline solution 2. Test group: LME + Compound 8 in saline solution. Spinal cord injury and postoperative care

[0221] Spinal cord injury (SCI) was induced in rats surgically using the Infinite Horizon (IH) Impactor (200 kDyn force) described by Scheff et al. 2003. The surgery was performed with aseptic procedures in a designated area under deep anesthesia. Rats were anesthetized with isoflurane (4% for induction, 2% for maintenance) and an O2 mixture (300 cm3 / min). Hair from the surgical site was removed with a machine, and the skin was scrubbed with an antiseptic detergent. To maintain body temperature, the animals were placed in a homeothermic blanket system. The rat's T8 vertebra was located externally, and an incision was made exposing the spinal column from T6 to T11. A laminectomy was performed using a surgical microscope to expose the dorsal spinal cord at the thoracic vertebral level (T8).The vertebral column was stabilized by pinching the nearest rostral and caudal vertebral processes, and the lesion was produced using the IH impactor device with a force of 200 kDyn. After each lesion, IH graphs and impact data were reviewed and recorded. Rats exhibiting an impact force more than 10% higher or lower than expected and / or any abnormality in the force / displacement impact graphs were excluded from the study. Additionally, animals scoring more than 1 point on the Basso, Beattie, and Bresnahan (BBB) ​​scoring scale 1 day after LME were also excluded from the study.

[0222] After the injury, the muscles were closed in layers. Petition 870250089855, dated 02 / 10 / 2025, pp. 219 / 336 71 / 93 with the use of 4-0 Ethicon Vicryl sutures, and the skin was closed with wound clips that were removed 7 to 10 days after LME.

[0223] After surgery, the animals were kept in a heated cage with readily available food and water. The rats received postoperative care that included administration of antibiotics (amoxicillin provided with the diet for 7 to 10 days); analgesics (buprenorphine 0.03 mg / kg, SC for 2 days) and fluids (6 to 8 cc of Ringer's lactate solution, SC, twice daily for 3 days). The bladders were emptied twice daily until spontaneous defecation. Bladder expression and body weights

[0224] Starting the day after the injury, the animals were observed twice daily and the bladders were manually expressed using gentle abdominal pressure. Any abnormal appearance of the urine (i.e., cloudy urine, bloody urine) was recorded, and bladder size was estimated by trained researchers to obtain a categorical score (bladder score) (empty bladders = 0; extra-small bladders = 1; small bladders = 2, medium bladders = 3, large bladders = 4). Urinary complications (blood in urine, foul-smelling urine, urine-stained fur) have been reported and treated with subcutaneous fluids twice daily and antibiotic treatment if problems persisted. Bladder expression continues until spontaneous urination is observed (empty bladder for 3 consecutive days).

[0225] Body weights were measured twice weekly during the first 7 weeks after injury and then weekly until the endpoint. The health and survival of the animals were assessed during bladder expression, body weight, and behavioral testing. Any health problems were reported and discussed with a veterinarian, if necessary. Basso, Beattie and Bresnahan (BBB) ​​Locomotor Classification Scale Petition 870250089855, dated 02 / 10 / 2025, pp. 220 / 336 72 / 93

[0226] Changes in locomotion were assessed using an open-field locomotor test (Ohio State BBB Locomotor Rating Scale developed by Basso et al. 1995). During each test, rats were observed moving in an empty shallow pool for 4 minutes. Hind limb joint movements, weight bearing, and limb coordination were scored according to the BBB scale. This scale monitors the progressive recovery of hind limb function after a thoracic spinal cord injury. The scale can be divided into three parts that reflect the stages of recovery.Scores from 0 to 7 indicate the initial recovery phase with the return of isolated movements of three joints (hip, knee, ankle); scores from 8 to 13 describe the intermediate recovery phase with the return of paw positioning, gait, and coordination between forelimbs and hindlimbs; and scores from 14 to 21 classify the late recovery phase with the return of toe play during the gait phase, predominant paw position, trunk stability, and tail position. The BHE (Body Health Scale) was assessed on days 1, 4, and 7 after the injury and then weekly until the conclusion of the study.

[0227] The BBB score obtained on day 1 after the LME was used to maintain consistency of the injury. Before the injury, all animals had normal locomotion (score 21). On day 1 after the LME, only animals that scored 0 (no observable movement of the hind limbs) or 1 (slight movement of one or two hind limb joints) on the BBB scale were included in the study and allocated to treatment groups. The treatment groups were balanced using the BBB score obtained on day 1 after the LME. Statistical Analysis

[0228] Data were analyzed by analysis of variance (ANOVA), followed by post-hoc comparisons when appropriate. An effect was considered significant if p < 0.05. The data were Petition 870250089855, dated 02 / 10 / 2025, pp. 221 / 336 73 / 93 represented as mean and standard error of the mean (SEM). Results Body Weight

[0229] The effects of Compound 8 on the body weight of rats in the control and test groups after SME were measured twice weekly during the first 7 weeks after injury and then weekly until week 13. The results showed that there was no significant difference in the body weight of the rats in the two groups during the treatment period. The results indicate that the tested compound had no adverse effects on body weight during the course of the study. Basso, Beattie and Bresnahan (BBB) ​​Locomotor Classification Scale

[0230] The effects of Compound 8 on locomotor performance in open field assessed using the BBB scale are shown in Figures 2-4, where Figure 2 depicts the BBB score of the rats in the test group compared to the control group on day 7 after LME, Figure 3 depicts the BBB score of the rats in the test group compared to the control group at week 7 after LME, and Figure 4 depicts the BBB score of the rats in the test group compared to the control group at week 12 after LME. As can be seen in Figure 2, on day 7 post-LME, all 13 rats in the test group that were treated with Compound 8 had BBB scores ranging from 2.5 to 7, with 6 rats having BBB scores of 6 to 7. In contrast, on day 7 post-LME, 5 of 12 rats in the control group that were treated with saline solution only had a BBB score of 4, and 2 of these 12 rats had a BBB score of approximately 0.5.

[0231] As shown in Figure 3, at week 7 post-LME, in the test group, 6 rats had a BBB score of 10 and 2 rats had a BBB score of 11, while in the control group, most rats had BBB scores of 8 to 9, and only 3 rats achieved a BBB score of 10, where none Petition 870250089855, dated 02 / 10 / 2025, pp. 222 / 336 74 / 93 rats in the control group achieved a BBB score of 11.

[0232] As shown in Figure 4, at week 12 post-LME, most rats (8 out of 13) in the test group that were treated with Compound 8 had BBB scores of around 10 or 11, while most rats (8 out of 12) in the control group that were treated with saline solution only had BBB scores of around 8 to 9.

[0233] The results demonstrated that Compound 8 promotes the recovery of hind limb joint movements, weight bearing, and limb coordination in rats with SLI. Bladder function data

[0234] After the injury, the animals exhibited loss of bladder function, requiring manual bladder expression. During bladder expression, the size of each bladder was estimated by trained researchers and a semi-quantitative score was obtained. Daily urine retention estimates were obtained by adding the bladder size scores from the morning and afternoon bladder expressions. Figure 5 illustrates the weekly mean urine retention in rats in the test group treated with Compound 8 in saline solution, compared to rats in the control group treated with control vehicle (saline solution).

[0235] Rats treated with Compound 8 in saline solution tended to have smaller bladders during daily examinations and therefore less urine retention compared to vehicle-treated control rats. As shown in Figure 5, this trend was noticeable from week 4 after LME. Most animals required bladder emptying once or twice a day throughout the study. Only 4 rats (1 from each experimental group) managed to recover spontaneous urination between 29 and 34 days after LME. Petition 870250089855, dated 02 / 10 / 2025, pp. 223 / 336 75 / 93

[0236] Urinary complications, including bloody urine, foul-smelling urine, and urine-stained fur, were monitored. When a new complication was observed after the resolution of a previous event, it was considered recurrent. Animals would be euthanized if complications persisted after an additional course of antibiotics, when bladders could not be emptied, or when general deterioration of health was observed.

[0237] Urinary complications, such as repeated blood in the urine, urine-stained hair, and urinary tract infections were observed, recorded, and treated as needed. Table 7 summarizes the percentage of complications observed in each experimental group. Table 7. Urinary complications identified during the study. Treatment Groups Urinary Complications Repetitive Urinary Complications Euthanasia due to urinary complications LME + Saline Solution 5 of 12 41% 3 of 12 25% none LME + Compound 8 / Saline Solution 4 of 13 31% 1 of 13 8% none

[0238] As can be seen in Table 7, urinary complications in rats that received Compound 8 / saline solution were less frequent than in rats that received the vehicle control. Summary

[0239] Acute administration of Compound 8 had no adverse effect on the body weight of rats during the study. Bladder complications were less frequent in animals that received Compound 8 compared to animals that received the vehicle control. Animals that received Compound 8 showed a decrease in the estimated size of their bladders, which was evident from week 8 to 13. Example 4 - Effect of Compound 8 on Gait Recovery in Petition 870250089855, dated 02 / 10 / 2025, pp. 224 / 336 76 / 93 Animals with LME

[0240] In this experimental example, the effect of Compound 8 on gait recovery was evaluated in an animal model of spinal cord injury. Animal Materials and Methods

[0241] Adult female Lewis rats (~160 g on arrival) from Envigo were used as subjects receiving treatment in the study. Rats were given unique identification numbers (PGI ID and tail markings) and housed in ventilated cages. All rats were examined, handled, and weighed before the start of the study to ensure adequate health and fitness. During the study, 12 / 12 light / dark cycles were maintained. Ambient temperature was maintained between 23°C and 23°C with relative humidity maintained around 50%. Food and water were provided ad libitum throughout the study. Rats were randomly assigned to treatment groups. Body weights were measured twice weekly during the study.

[0242] Spinal cord injury (SCI) was introduced into the animals and postoperative care was followed after the injury according to the methods described in Example 3. Formulations and Dosage

[0243] The lyophilized compound 8 was dissolved in saline solution and injected subcutaneously in a volume of 500 pL into the animal once daily, from day 1 to day 49 after spinal cord injury.

[0244] The target dose concentration was 0.8 mg / mL. After reconstitution, the solution was aliquoted and kept at -20°C until dosing. Treatment Groups

[0245] 12-13 rats were used in each of the following two groups: 1) Control group: LME + Saline solution Petition 870250089855, dated 02 / 10 / 2025, pp. 225 / 336 77 / 93 2) Test group: LME + Compound 8 in saline solution. Assessment of occasional and frequent walks

[0246] The inverse Kaplan-Meier plots were generated based on the open-field locomotor assessment of Basso, Beattie, and Bresnaham (BBB) ​​described above in Example 3. A Kaplan-Meier plot is a statistical method for estimating the gain of a behavior (threshold) as a percentage of the population over a given period of time. An animal reaching a threshold, as defined below, is indicated as an upward step, with the Y-axis denoting the cumulative percentage of a group reaching the threshold, and the X-axis indicating the time since the LME.

[0247] The BBB is an ordinal scale ranging from 0 to 21, with 0 indicating complete motor loss of the hind limbs and 21 indicating normal motor function. The BBB assesses recovery in performing various locomotor movements, including weight-bearing ability, standing, walking, proper foot placement, and coordination. A step is defined as when the hind limb foot is in plantar contact with the weight-bearing surface, then the hind limb is advanced forward and re-establishes plantar contact with the weight-bearing surface.

[0248] Recover occasional walking: Occasional walking is defined as less than or equal to half of the attempted steps being successful, corresponding to a BBB score of 10. The post-LME week in which an animal achieved 10 or more was recorded and plotted on the Kaplan-Meier chart, as defined above.

[0249] Recovering frequent walking: Frequent walking is defined as more than half of attempted steps being successful and corresponds to a BBB score of 11. The week post-LME in which an animal achieved 11 or more was recorded and plotted on the Kaplan-Meier chart, as defined above.

[0250] Statistical methods: Kaplan-Meier curves were analyzed using the log-rank test. The effects of Composite 4 and Petition 870250089855, dated 02 / 10 / 2025, pp. 226 / 336 78 / 93 The statistical significance of Compound 8 in locomotor function and bladder function was assessed using repeated measures ANOVA (RM-ANOVA) with Geisser-Greenhouse correction for data non-sphericity and Tukey correction for multiple comparisons, or by the non-parametric Friedman test with Dunn's correction for multiple comparisons. The choice of RM-ANOVA or Friedman test for the analysis of each data type (BBB scores, BBB subscores, and bladder scores) was determined by the normality distribution tests performed for each of the functional scores in all treatment cohorts. RM-ANOVA was selected when the normality distribution test passed for all three treatment cohorts of rats with LME (saline only, Compound 4, and Compound 8). The Friedman test was used when at least one of the treatment cohorts failed the normality distribution test.A further quantitative assessment of the effects of treatment with Compound and Compound 8 was performed by calculating and comparing the percentages of animals that reached pre-specified thresholds of functional improvement in BBB scores, BBB subscores, and bladder score. Results Compound 8 improves recovery from occasional walking in animals with LME.

[0251] Figure 6 is a graph depicting the recovery of occasional walking in rats with spinal cord injury (SCI) treated with Compound 8, compared to rats with SCI treated with the vehicle control. As can be seen in Figure 6, rats with SCI, in both the test and control groups, were unable to walk even occasionally during the first two weeks after spinal cord injury. Rats with SCI in both groups began to show some degree of recovery of occasional walking (less than 10%). From the fourth week after injury, Petition 870250089855, dated 02 / 10 / 2025, pp. 227 / 336 79 / 93 consistent recovery of occasional walking was detected in LME rats treated with Compound 8, where recovery reached 50% in less than 6 weeks and almost 80% at week 12. In contrast, recovery of occasional walking in LME rats treated with the vehicle control was significantly slower compared to the recovery observed in LME rats treated with Compound 8 and did not reach 50% even at week 12.

[0252] The result demonstrates that Compound 8 provides effective treatment for spinal cord injuries, significantly improving recovery of occasional walking in animals with spinal cord injury. Compound 8 improves recovery from frequent walking in animals with LME.

[0253] Figure 7 is a graph depicting the recovery of frequent walking in rats with spinal cord injury (SCI) treated with Compound 8, compared to rats with SCI treated with the vehicle control. As can be seen in Figure 7, frequent walking in rats with SCI was not detected during the first three weeks after spinal cord injury. Recovery of frequent walking in rats with SCI treated with Compound 8 was detected three weeks after injury, where recovery was consistent and reached almost 50% by week 12. In contrast, frequent walking was not detected in vehicle-treated rats with SCI until week 9 after injury, with minimal improvement (10%) even after 12 weeks.

[0254] The result demonstrates that Compound 8 effectively improves recovery from frequent walking in animals with spinal cord injury. Example 5 - Comparison of BBB subscores of animals treated with Compound 8 and Compound 4

[0255] In this example, the effect of Compound 8 on improving recovery of toe slack, paw position, trunk stability and tail use, independently of coordination of Petition 870250089855, dated 02 / 10 / 2025, pp. 228 / 336 80 / 93 forelimbs and hindlimbs, was evaluated in comparison with Compound 4 (monomer of the TAT-Cys-PTPRS rat variant) and saline solution.

[0256] Compound 4: Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-ArgCys-Asp-Met-Ala-15Glu-His-Met — Glu-Arg-Leu-Lys-Ala-Asn-Asp-SerLeu-Lys-Leu-Ser-Gln-Glu-Tyr-Glu-Ser-35Ile-NH2 Materials and methods

[0257] Compound 4 was synthesized and purified by HPLC with a purity greater than 95%.

[0258] The animals were prepared according to the methods described above in Example 3.

[0259] Lyophilized compound 8 and compound 4 were dissolved separately in saline solution and injected subcutaneously in a volume of 500 pL into the animal once daily, from day 1 to day 49 after spinal cord injury.

[0260] The target dose concentration was 0.8 mg / mL. After reconstitution, the solutions were aliquoted and kept at -20 °C until dosing.

[0261] 12-13 rats were used in each of the following three groups: 1) Control group: LME + Saline solution alone 2) Test group: LME + Compound 4 in saline solution 3) Test group: LME + Compound 8 in saline solution.

[0262] Spinal cord injury (SCI) was introduced into the animals and postoperative care was provided to the animals according to the methods described in Example 3. BBB sub-score measurement

[0263] The BBB subscores quantify recovery of toe slack, paw position, trunk stability, and tail use, independently of forelimb and hindlimb coordination. The BBB subscores were calculated using observations recorded on the BBB record sheets. During the BBB test, the predominant paw position Petition 870250089855, dated 02 / 10 / 2025, pp. 229 / 336 81 / 93 hind legs (parallel vs. rotated), toe clearance, trunk stability, and tail position (up, down, in the middle) were assessed for animals that achieved a BBB score of 10 or more. Animals with a score below 10 on the BBB scale were considered to have a BBB subscore of 0. Each rat could achieve a maximum subscore of 13 using the following scale shown in Table 8. Table 8: Locomotor characteristics considered for calculating the BBB subscore. Sub-scoring BBB Left Right Parallel paw position (up to 4 points) On initial contact 1 1 On suspension 1 1 Toe play (up to 6 points) Occasional 1 1 Frequent 2 2 Consistent 3 3 Trunk stability (1 point) 1 Tail position (up to 2 points) Middle 1 Above 2 Total (Up to 13 points) Results

[0264] As described above in Example 3, the upper points on the BBB scale (14-21) quantify fine motor movements associated with hind limb locomotion, including toe spread, dominant paw position, trunk stability, and tail position. These fine motor movements are only considered if the animals demonstrate consistent coordination. A BBB subscore was applied to quantify these improvements independently of coordination.

[0265] Figures 8A and 8B represent the effects of Compound 8, compared to Compound 4 and the saline control, on improving the recovery of fine motor movements associated with hind limb toe slack, paw position, trunk stability, and tail position in rats with LME, as measured by the BBB subscore. The data in Figure 8A are presented Petition 870250089855, dated 02 / 10 / 2025, pages 230 / 336 82 / 93 as mean ± SEM. N = 12-13 / group. As can be seen in Figure 8A, after LME, all rats presented a BBB subscore of 0 during the first 14 days of behavioral assessment, indicating that there was no recovery during the first 14 days. Treatment with Compound 8 resulted in accelerated onset of functional improvement when compared to the corresponding effects of the vehicle control (saline only) and Compound 4. The onset of functional improvement was observed on day 21 in the Compound 8 cohort of rats with LME, on day 42 in the Compound 4 cohort, and on day 35 in the control cohort (saline only). A sustained trend of continuous functional improvement was apparent in the Compound 8 treated rat cohort and was not apparent in the control (saline only) or Compound 4 cohorts.

[0266] Figure 8B represents violin plots showing distributions of mean weekly BBB subscores in the saline-alone, Compound, and Compound 8 treatment cohorts of rats with LME. Each data point represents a mean weekly BBB subscore in the saline-alone (control), Compound 4, and Compound 8 treatment cohorts, as noted on the geometric X-axis. The numbers adjacent to the data points indicate the number of days post-LME at which the mean weekly BBB subscores for the individual and treatment cohort were calculated. Statistical comparison of treatment effects was performed using the Friedman test (repeated measures ANOVA for non-parametric values) with Dunn's correction for multiple comparisons and a p-value less than 0.05 defined as the criterion for statistical significance.As can be seen in Figure 8B, treatment of LME rats with Compound 8 produced a statistically significant effect on the BBB subscore when compared to the effect of the control vehicle (saline solution only) (p=0.0008) or the effect of Compound 4 (p=0.0201). No difference was observed. Petition 870250089855, dated 02 / 10 / 2025, pp. 231 / 336 83 / 93 statistically significant (p>0.9999) difference between the cohort treated with Compound 4 and the cohort treated with saline solution only (control).

[0267] Figure 9 further illustrates the percentages of rats with LME that achieved a BBB subscore of 1 or higher when treated with Compound 8 compared to rats with LME treated with Compound 4 alone or saline solution. Solid bars represent data corresponding to the administration period of saline, Compound 4, or Compound 8 treatment. Striped bars represent data collected after treatment discontinuation. As can be seen in Figure 9, at each post-LME time point, for example, days 28, 42, 63, 70, 77 and 84, the percentage of rats that achieved the sub-score. A BBB score of 1 or better (percentage achieved) was higher in the group treated with Compound 8 compared to the groups treated with Compound 4 or saline solution alone. Treatment with Compound 8 resulted in continued functional improvement after discontinuation of Compound 8 administration. In contrast, no similar effect was observed in the LME rat cohorts treated with Compound 4 or saline solution alone. Example 6 - Pharmacokinetic profiles of Compound 7

[0268] The pharmacokinetic profiles of the Tat-Cys-PTPRS wedge domain dimer in rat plasma after intravenous or subcutaneous administration were studied using Compound 7 as an example. In this study, Compound 7 in saline solution, as prepared according to Example 3, was administered intravenously to three rats at a dose of 1.75 mg / kg (rat body weight) and subcutaneously to three other rats at a dose of 10.5 mg / kg (rat body weight). Concentrations of Compound 7 in rat plasma after administration were measured. The results are illustrated in Figure 10, which shows the pharmacokinetic profiles of the Tat-Cys-PTPRS wedge domain dimer (Compound 7) in Petition 870250089855, dated 02 / 10 / 2025, pp. 232 / 336 84 / 93 rat plasma after intravenous or subcutaneous administration of 1.75 or 10.5 mg / kg, respectively. Example 7 - Comparison of BBB scores and bladder function of animals treated with Compound 8 and Compound 4

[0269] In this study, the effects of Compound 8 on improving recovery of open field locomotor performance and bladder function in rats with LME were evaluated in comparison with Compound 4, assessing BBB scores and bladder scores according to the methods described in Example 3.

[0270] In this evaluation, 12-13 rats were included in each of the following groups: (1) Control group 1: LME + saline solution alone; (2) Control group 2: LME + Compound 4 in saline solution; (3) Test group: LME + Compound 8. Treatment was initiated on day 1 post-injury and continued until (last dose administered on) day 49 post-injury. The post-treatment observation period began on day 50 post-injury and continued until the end of the study on day 84 post-injury.

[0271] The results of the BBB score assessment are shown in Figures 11, 12, and 13. Figure 11 depicts violin plots presenting distributions of the mean weekly BBB scores in each of the three treatment cohorts, as noted on the geometric X-axis. Each data point represents a mean weekly BBB score in the treatment cohorts with saline alone (control), Compound 4, and Compound 8, as noted on the geometric X-axis. The numbers adjacent to the data points indicate the number of days post-LME at which the individual and treatment cohort mean weekly BBB scores were calculated. Statistical comparison of treatment effects was performed using repeated measures ANOVA with Tukey correction for multiple comparisons and a p-value less than 0.05 defined as the criterion for statistical significance.

[0272] The results of the BBB score assessment are Petition 870250089855, dated 02 / 10 / 2025, pp. 233 / 336 85 / 93 shown in Figures 11, 12, and 13. Figure 11 depicts violin plots presenting distributions of mean weekly BBB scores in each of the three treatment cohorts, as noted on the geometric X-axis. Each data point represents a mean weekly BBB score in the treatment cohorts with saline alone (control), Compound 4, and Compound 8, as noted on the geometric X-axis. The numbers adjacent to the data points indicate the number of days post-LME at which the individual and treatment cohort mean weekly BBB scores were calculated. Statistical comparison of treatment effects was performed using repeated measures ANOVA with Tukey's correction for multiple comparisons and a p-value less than 0.05 defined as the criterion for statistical significance.

[0273] As can be seen in Figure 11, rats treated with Compounds 4 and 8 showed higher BBB scores compared to rats treated with saline solution alone. Compound 4 and Compound 8 each produced a significant improvement in locomotor performance as measured by BBB scores. The corresponding p-values ​​were as follows: p < 0.0001 for the comparison of rat cohorts with LME of Compound 4 vs. saline solution alone; p < 0.0001 for the comparison of rat cohorts with LME of Compound 8 versus saline solution alone. Furthermore, Compound 8 was significantly (p=0.0017) more effective than Compound 4 in improving BBB scores. Figure 12 depicts the percentages of rats in each group that exhibited BBB scores of 10 or higher after LME. Solid bars represent data corresponding to the administration period of the test article (saline solution, Compound 4, or Compound 8). Striped bars represent data collected during the observation period after discontinuation of active treatment with saline solution alone, Compound 4, or Compound 8. The results show that, during day 28 to day 84 of treatment... Petition 870250089855, dated 02 / 10 / 2025, pp. 234 / 336 86 / 93 post-LME, less than 20% of LME rats treated with saline solution alone had BBB scores of 10 or higher, while approximately 30% to approximately 60% of LME rats treated with Compound 4 and Compound 8 achieved BBB scores of 10 or higher. The overall percentages of rats achieving BBB scores of 10 or higher during treatment were higher in group (3) compared to rats in group (2). More than half of the rats in group (3) achieved BBB scores of 10 or higher after 70 days post-LME.

[0274] Figure 13 depicts the percentages of rats in each group that achieved BBB scores of 11 after LME. Solid bars represent data corresponding to the period of administration of the test article (saline solution, Compound 4, or Compound 8). Striped bars represent data collected during the observation period after discontinuation of active treatment with saline solution alone, Compound 4, or Compound 8. As can be seen in Figure 13, more than 20% and approximately 50% of rats treated with Compound 8 achieved a BBB score of 11 on day 77 and day 84, respectively. These results were not observed in rats treated with saline solution alone or with Compound 4 and demonstrate that Compound 8 was more effective than Compound 4 in promoting recovery of locomotor function as assessed using the BBB score metric.

[0275] The results of the bladder score assessment are illustrated in Figures 14 and 15. Figure 14 depicts violin plots showing distributions of mean weekly bladder scores in each of the three LME rat treatment cohorts, as indicated on the X-axis. Each data point represents a mean weekly bladder score in the saline-only (control), Compound 4, and Compound 8 treatment groups, as indicated on the X-axis. The numbers adjacent to the data points indicate the number of days after LME at which the mean weekly bladder scores Petition 870250089855, dated 02 / 10 / 2025, pages 235 / 336 87 / 93 individual and treatment cohort scores were calculated. Statistical comparison of the treatment effects of Compound 4 and Compound 8 was performed using repeated measures ANOVA with Tukey's correction for multiple comparisons and a p-value less than 0.05 defined as the criterion for statistical significance. As can be seen in Figure 14, the mean weekly bladder scores of rats treated with Compound 8 were significantly lower than the scores of rats treated with Compound 4 or saline solution alone. (In Figure 14: p=0.0001 between the groups treated with saline solution and Compound 8, ep=0.0085 between the groups treated with Compound 8 and Compound 4). This result indicates that rats treated with Compound 8 tended to have smaller bladders during daily examinations and therefore less urine retention compared to rats treated with Compound 4 alone or saline solution.

[0276] The percentages of rats that achieved a bladder score of 2 or less (best) during post-LME treatment are illustrated in Figure 15. Solid bars represent data corresponding to the administration period of the test article (saline only, Compound 4, or Compound 8). Striped bars represent data collected during the observation period after discontinuation of active treatment with saline alone, Compound 4, or Compound 8. The results show that, overall, more rats in the Compound-treated group had better bladder scores than rats treated with saline alone or Compound 4. Approximately 25% of rats treated with Compound 8 showed bladder scores of 2 or better starting at week 6 after LME. Bladder scores of rats treated with Compound 8 continued to improve from week 8 to week 13, with over 40% of rats achieving a score of 2 or better during weeks 10 to 13. These results were not observed in rats Petition 870250089855, dated 02 / 10 / 2025, pages 236 / 336 88 / 93 treated only with saline solution or with Compound 4.

[0277] At the end of the study, the performance of Compound 8 was evaluated in comparison with Compound 4 and saline solution alone, calculating the percentages of animals that reached predefined thresholds of functional improvement in the following categories: (i) Simultaneous improvement in BBB and bladder scores, (ii) Improvement in locomotor function (BBB score) alone, but not in bladder score, (iii) Improvement in bladder score alone, but not in BBB score. Figure 16 represents the percentage of rats in each of these three categories, as noted on the geometric X-axis. An additional group (noted as Combined) represents the combined percentage of rats that achieved improvement in any of the first three categories for each treatment cohort (saline solution only, Compound 4, and Compound 8).The predefined thresholds for functional improvement were defined as a BBB score of at least 10 and a bladder score of 2 or less at the end of the study (day 84 of the study).

[0278] As shown in Figure 16, nearly 50% of LME rats treated with Compound 8 achieved BBB scores of at least 10 and bladder scores of 2 or less simultaneously, while only about 17% of rats treated with saline or Compound 4 alone achieved this combined improvement at the end of the study. Improvement in BBB score alone (without improvement in bladder score) was observed in approximately 40% of the rats treated with Compound 4, compared to about 17% of the rats treated with saline solution alone, and about 15% of the rats treated with Compound 8 showed improvement. Additionally, approximately 8% of the rats treated with Compound 8 showed improvement only in bladder scores (reduction in bladder scores). In contrast, rats treated with Compound 4 showed no improvement in bladder scores alone, compared to rats treated with Compound 8. The rates Petition 870250089855, dated 02 / 10 / 2025, pages 237 / 336 89 / 93 combined functional improvement (simultaneous BBB score and bladder score improvement, BBB score only and bladder score percentages combined) were approximately 33%, approximately 60%, and approximately 70% in LME rats treated with saline only, Compound 4, or Compound 8, respectively.

[0279] Figure 17 shows the percentage of rats that achieved BBB scores of 11 and / or bladder scores of 2 or less at the end of the study. These results further demonstrate that Compound 8, but not Compound 4, predominantly caused simultaneous improvement in BBB and bladder scores, in isolation. At the end of the study, approximately 40% of LME rats treated with Compound 8 achieved simultaneous improvement in BBB score levels of 11 and BL scores of 2 or less, while only about 8% of rats achieved this simultaneous improvement in each of the saline-only and Compound 4 cohorts. No LME rats achieved a BBB score of 11 alone in the saline-only and Compound 4 cohorts of LME rats, compared to approximately 8% in the Compound 8 cohort.The combined rate of functional improvement (the combined percentages of LME rats that achieved a BBB score of only 11, a bladder score of 2 or less only, and a BBB score of 11 and a bladder score of 2 or less simultaneously) was approximately 60%. This rate of functional improvement was not observed in rats treated with saline solution alone or Compound 4 alone.

[0280] Taken together, the results presented in Figures 16 and 17 show that Compound 8 was more effective than Compound 4 in promoting simultaneous improvement in both locomotor function (BBB score) and bladder function (bladder score), while the effect of Compound 4 was predominantly limited to improvement in locomotor function only and of lesser magnitude (maximum BBB score of 10 in the Compound 4 cohort vs. 11 in the Compound 8 cohort). Petition 870250089855, dated 02 / 10 / 2025, pp. 238 / 336 90 / 93 Example 8 - In vitro stability of Compound 3 and Compound 7 in simulated biological matrices (buffered saline solution and plasma)

[0281] The stability of Compound 7 (human variant) in physiological buffer (Hanks Balanced Saline Solution, HBSS) and in plasma was evaluated in comparison with Compound 3.

[0282] The stability of the compound was defined as % recovery of the compound after 5 min, 15 min and 30 min of incubation in the presence of the corresponding plasma. Materials and methods

[0283] 200 μL of 1.6 μM solutions of Compound 3 and Compound 7 were incubated in the matrix (Hank's balanced saline solution or plasma) at 37°C for 0, 5, 15, or 30 minutes. Incubation was followed by the addition of 200 μL of acetonitrile, vortexing, and subsequent acidification with 45 μL of pure acetic acid. After further agitation, the resulting mixture was centrifuged for 5 minutes at 14,000 rpm and the supernatant was collected for analysis.

[0284] The determination of the levels of Compound 3 or Compound 7 in the supernatant samples prepared as described above was performed using an LC-MS / MS method as follows: 40 μL of 5 μM Compound 7 in 10% aqueous acetic acid solution were added to 160 μL of the supernatant. 20 μL of 5 μM Compound 3 in 10% aqueous acetic acid solution were added to 180 μL of the supernatant. The processed sample (20 μL) was injected onto an ACE Excel 2 C18 column (3.0 mm x 75 mm, 2.0 μL).

[0285] The recovery percentages of Compound 3 and Compound 7 after 0 minutes (at the start of the experiment), 5 minutes, 15 minutes, and 30 minutes of incubation were calculated by dividing the corresponding peak areas by the peak area obtained from the samples prepared without incubation (0 minutes of incubation time). The recovery percentage at time 0 was defined Petition 870250089855, dated 02 / 10 / 2025, pages 239 / 336 91 / 93 as 100% recovery.

[0286] The specific presence of Compound 3 or Compound 7 in the chromatographic peak fractions was verified using the Agilent 1200 high-performance liquid chromatography (HPLC) system coupled to a Sciex API 3200 triple quadrupole mass spectrometer.

[0287] Figure 18 illustrates the stability of Compound 7 in physiological buffer (HBSS) compared to Compound 3. It can be observed that Compound 7 was highly stable in HBSS, with a 90% recovery after at least 30 minutes of incubation with HBSS. In contrast, Compound 3 was less stable in HBSS, with approximately 42% recovery after 30 minutes. Results

[0288] Figures 19, 20, and 21 illustrate the stabilities of Compound 7 in rat plasma, dog plasma, and human plasma, respectively, compared to Compound 3. The results show that Compound 7 was highly stable in plasma, with a recovery rate of 92% in rat plasma, 100% in dog plasma, and 99% in human plasma after 30 minutes of incubation. In contrast, Compound 3 showed low stability in plasma. Example 9 - Distinct colloidal behavior of Compound 7 and Compound 3

[0289] The self-assembly patterns of Compound 7 and Compound 3 were analyzed by negative staining transmission electron microscopy. Materials and methods

[0290] Compound 3 and Compound 7 were dissolved in sterile water or in 0.9% (w / v) sodium chloride in sterile water to obtain a 20 mg / mL solution. Formvar / carbon-coated grids were exposed to 15 mL droplets of the Compound 3 or Compound 7 solutions for approximately 1 minute, dried, and then exposed to 15 mL droplets of sterile water for 10 seconds. Petition 870250089855, dated 02 / 10 / 2025, pp. 240 / 336 Samples 92 / 93 were dried again and then stained with 2% (w / v) aqueous uranyl acetate for 30 seconds. The stained samples were exposed to 15 mL drops of sterile water for 10 seconds and dried before examination by transmission electron microscopy. Results

[0291] Figure 22 presents a set of transmission electron microscopy (TEM) images showing colloidal structures resulting from the self-assembly of Compound 3 (aec panels) and Compound 7 (bed panels) in water (aeb panels) and in isotonic saline solution (ced panels). The images presented in the aeb panels demonstrate the formation of rod-like nanostructures by both Compound 3 and Compound 7. The images presented in the ced panels demonstrate the formation of an amyloid-like fibrillar mesh by Compound 3, while Compound 7 formed distinct, larger helical colloidal particles, not observed with Compound 3. These data illustrate the different physicochemical behavior of Compound 3 compared to Compound 7 in the simulated biological matrix (isotonic saline solution).

[0292] The disclosed subject matter should not be limited in scope by the specific embodiments and examples described herein. In fact, several modifications of the disclosure, in addition to those shown and described herein, will be evident to those skilled in the art from the preceding description and the accompanying Figures. Such modifications are intended to be within the scope of the appended claims.

[0293] All references (e.g., publications, patents, or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes, to the same extent as if each individual reference (e.g., publication, patent, or patent application) were specifically and individually indicated for incorporation by reference in Petition 870250089855, dated 02 / 10 / 2025, pp. 241 / 336 93 / 93 in its entirety for all purposes. Other modalities are within the scope of the following claims. Petition 870250089855, dated 02 / 10 / 2025, pp. 242 / 336

Claims

1 / 10 CLAIMS 1. Pharmaceutical composition, characterized in that it comprises a peptide that is a dimer comprising a first monomer covalently crosslinked with a second monomer, each monomer comprising a domain comprising an amino acid sequence derived from a cytoplasmic wedge domain of a receptor-type protein tyrosine phosphatase (PTPR); and wherein the mass ratio of the crosslinked dimer to the free monomer in the pharmaceutical composition is greater than 1:

20.

2. Pharmaceutical composition according to claim 1, characterized in that the ratio is greater than 1:

1.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the ratio is greater than 4:

1.

4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that the ratio is greater than 10:

1.

5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the dimer comprises a transport moiety linked to the domain via a cysteine ​​residue or a peptide linker comprising a cysteine ​​residue.

6. Pharmaceutical composition according to claim 5, characterized in that the transport fraction comprises a TAT sequence.

7. Pharmaceutical composition according to claim 6, characterized in that the TAT sequence comprises an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7.

8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the dimer enhances the repair of neural cells.

9. Pharmaceutical composition according to any of the claims 1 to 7, characterized in that the domain is selected from the group consisting of a PTPRF wedge domain, a PTPRD wedge domain and a PTPRS wedge domain, and variants that have at least 70% identity with them.

10. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that the domain comprises an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 8, 9, 10 or 11.

11. Pharmaceutical composition according to any one of claims 1 to 10, characterized in that the first monomer and the second monomer each independently comprise: a first domain comprising an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7; a second domain comprising an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 8, 9, 10 or 11; and a cysteine ​​residue; wherein the dimer comprises a chemical linker or bond between the cysteine ​​residue of the first monomer and the cysteine ​​residue of the second monomer.

12. Pharmaceutical composition according to claim 11, characterized in that the first domain comprises an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7.

13. Pharmaceutical composition according to claim 11 or 12, characterized in that the first domain comprises an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO:

5.

14. Pharmaceutical composition according to any of the claims 11 to 13, characterized in that the second domain comprises an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 8, 9, 10 or 11.

15. Pharmaceutical composition according to any one of claims 11 to 14, characterized in that the dimer has the following structure: first domain —Cys— second domain X first domain —Gy$— second domain (II) , wherein X is a chemical link or ligand between the two cysteine ​​residues.

16. Pharmaceutical composition according to claim 15, characterized in that X is a chemical ligand selected from a disulfide bond, a thioether bond or a thioester bond.

17. Pharmaceutical composition according to claim 15 or 16, characterized in that X is a chemical ligand consisting of atoms selected from C, N, S, O and / or H.

18. Pharmaceutical composition according to any one of claims 15 to 17, characterized in that X is a chemical ligand comprising between 1 and 8 carbon atoms.

19. Pharmaceutical composition according to any one of claims 15 to 18, characterized in that X is a chemical ligand comprising an alkylene chain, wherein, optionally, one or more carbon atoms of the alkylene chain are replaced by oxygen.

20. Pharmaceutical composition according to any one of claims 11 to 19, characterized in that the dimer has the following structure: Petition 870250089855, dated 02 / 10 / 2025, page 117 / 336 4 / 10 first domain —Cys— second domain first domain —Cy$— second domain (D .

21. Pharmaceutical composition according to any one of claims 1 to 20, characterized in that the first monomer and the second monomer each independently comprise an amino acid sequence that is at least 70% identical to the amino acid sequence of SEQ ID NO: 1, 2, 3 or 4.

22. Pharmaceutical composition according to any one of claims 1 to 21, characterized in that the first monomer and the second monomer each independently comprise an amino acid sequence that is identical to the amino acid sequence of SEQ ID NO: 1, 2, 3 or 4.

23. Pharmaceutical composition according to any one of claims 1 to 22, characterized in that the dimer comprises identical monomers.

24. Pharmaceutical composition according to any one of claims 1 to 23, characterized in that the dimer comprises non-identical monomers and the ratio is calculated based on the combined total of free monomers.

25. Pharmaceutical composition according to claim 24, characterized in that the first monomer and the second monomer of the dimer have different C-terminal modifications.

26. Pharmaceutical composition according to any one of claims 1 to 25, characterized in that the dimer has a structure selected from the group consisting of: GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI I SEQ ID NO: 1 1 GRKKRRQRRRCDLADNIERLKANDGLKFSQEYESI SEQ ID NO: 1 Petition 870250089855, dated 02 / 10 / 2025, page. 118 / 336 5 / 10 GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI 1 GRKKRRQRRRCELADHIERLKANDNLKFSQEYESI SEQ ID NO: 2 SEQ ID NO: 2 GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI 1 GRKKRRQRRRCDMAEHTERLKANDSLKLSQEYESI SEQ ID NO: 3 SEQ ID NO: 3 GRKKRRQRRRCDMAEHMERLKANDSLKLSQEYESI 1 GRKKRRQRRRCDMAEHMERLKANDSLKLSQEYESI SEQ ID NO: 4 SEQ ID NO: 4 27. A method for repairing the nervous system and / or treating a selected neurological condition, disease or disorder from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity and neurodegenerative disease, in a subject in need thereof, the method being characterized in that it comprises administering an effective amount of the pharmaceutical composition, as defined in any one of claims 1 to 26, to a subject in need thereof.

28. Method according to claim 27, characterized in that the neural lesion is selected from the group consisting of acute neural injury, traumatic brain injury (TBI), spinal cord injury, concussion, stroke, including ischemic stroke, hemorrhagic stroke and chronic stroke disease, aneurysm, cerebral hemorrhage, thrombus and embolism.

29. Method according to claim 27, characterized in that the neurological condition, disease or disorder is selected from the group consisting of Alzheimer's disease, Alzheimer's disease-related dementias, diffuse Lewy body disease, senile dementia, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis (MS), optic neuritis, Huntington's disease, Tourette syndrome, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, Jakob-Creutzfeldt disease, epilepsy and infectious disease.

30. Use of the pharmaceutical composition, as defined in any one of claims 1 to 26, characterized by being for the manufacture of a medicament for the treatment of a neurological condition, disease or disorder selected from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity and neurodegenerative disease.

31. Process for preparing the pharmaceutical composition, as defined in any one of claims 1 to 26, the process being characterized in that it comprises combining the first monomer and the second monomer in water and a) adding an oxidizing agent and / or b) oxygenating the solution, so that the dimer is formed.

32. Process according to claim 31, characterized in that the combined concentration of the first and second monomers in water is at least 20 mg / mL.

33. Process according to claim 31 or 32, characterized in that the combined concentration of the first and second monomer in water is at least 40 mg / mL.

34. Process according to any one of claims 31 to 33, characterized in that the combination of the first and second monomer in water is maintained at a temperature of about 20 °C to about 25 °C.

35. Process according to any one of claims 31 to 34, characterized in that it further comprises the addition of DMSO to the first and second monomers and to water.

36. Process according to any one of claims 31 to 35, characterized in that the oxidizing agent is selected from cupric sulfate, iodide, hydrogen peroxide, trans-3,4-dihydroxy-selenolan oxide (DHS), supported methionine sulfoxide and N-chlorosuccinimide (NCS).

37. Process according to any one of claims 31 to 36, characterized in that the oxidizing agent is iodine Petition 870250089855, dated 02 / 10 / 2025, page 120 / 336 7 / 10 (I2), and the process employs microwave-assisted oxidation.

38. Process for preparing the pharmaceutical composition, as defined in any one of claims 1 to 23 and 26, the process being characterized in that it comprises combining the first monomer and the second monomer in a solvent with cupric sulfate to form a mixture to produce the dimer; wherein the first monomer is identical to the second monomer.

39. Process according to claim 38, characterized in that the solvent comprises purified water for purification (PWP).

40. Process according to claim 39, characterized in that the solvent further comprises ethanol.

41. Process according to any one of claims 38 to 40, characterized in that the pH of the mixture is maintained between about 8.5 and about 9.

5.

42. Pharmaceutical agent for repairing the nervous system of a subject, characterized in that it comprises a pharmaceutically acceptable peptide dimer or salt or solvate thereof, comprising two subunits, wherein each subunit comprises a peptide domain independently selected from receptor-type protein tyrosine phosphatase (PTPR) wedge domains or variants with at least 70% homology thereto.

43. Pharmaceutical agent according to claim 42, characterized in that each subunit comprises a transport moiety linked to the peptide domain via a cysteine ​​residue or a peptide linker comprising a cysteine ​​residue, wherein the two subunits are covalently crosslinked via a chemical linker between the cysteine ​​residues in each subunit.

44. Pharmaceutical agent according to claim 43, characterized in that the chemical linker is chosen from among a disulfide bond, a thioether bond or a thioester bond.

45. Pharmaceutical agent according to claim 43, characterized in that the chemical ligand comprises between 1 and 8 carbon atoms.

46. ​​Pharmaceutical agent according to any one of claims 42 to 45, characterized in that the peptide domain of each subunit independently comprises an amino acid sequence with at least 70% identity to the amino acid sequence of SEQ ID NO: 8, 9, 10 or 11.

47. Pharmaceutical agent according to any one of claims 43 to 46, characterized in that the transport fraction is selected from a group consisting of an HIV TAT peptide, a VP22 peptide of the DNA-binding protein of herpes simplex-1 virus, an amino acid region of the third alpha helix of the antennapedia homeodomain, a histidine marker varying in length from 4 to 30 histidine repeats, a derivative variation or homolog thereof capable of facilitating the uptake of the active cargo fraction by a receptor-independent process, an arginine-rich cationic peptide, and combinations thereof.

48. Pharmaceutical agent according to any one of claims 43 to 47, characterized in that the transport fraction comprises an amino acid sequence with at least 65% identity to wild-type HIV TAT.

49. Pharmaceutical agent according to claim 48, characterized in that the TAT sequence comprises an amino acid sequence that is at least 65% identical to the amino acid sequence of SEQ ID NO: 5, 6 or 7.

50. Pharmaceutical agent according to any one of claims 42 to 49, characterized in that each subunit independently comprises an amino acid sequence that is at least 70% identical to the amino acid sequence of Petition 870250089855, dated 10 / 02 / 2025, page 122 / 336 9 / 10 of SEQ ID NO: 1, 2, 3 or 4.

51. Pharmaceutical agent according to any one of claims 42 to 50, characterized in that the subunits have different C-terminal modifications.

52. Pharmaceutical agent according to any one of claims 42 to 51, characterized in that the peptide dimer comprises two different subunits.

53. Pharmaceutical agent according to any one of claims 42 to 51, characterized in that the peptide dimer comprises two identical monomeric subunits.

54. Pharmaceutical agent according to any one of claims 42 to 53, characterized in that the pharmaceutically acceptable peptide dimer or salt or solvate thereof has a purity of at least 90%.

55. Pharmaceutical composition, characterized in that it comprises the pharmaceutical agent as defined in any one of claims 42 to 54.

56. Pharmaceutical composition according to claim 55, characterized in that it does not comprise DMSO.

57. Pharmaceutical composition according to any one of claims 1 to 26, characterized in that it does not comprise DMSO.

58. Use of the pharmaceutical agent, as defined in any of claims 42 to 54, characterized by being for the manufacture of a medicament for repairing the nervous system and / or treating a neurological condition, disease or disorder selected from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity and neurodegenerative disease.

59. A method for repairing the nervous system and / or treating a selected neurological condition, disease or disorder from the group consisting of neural injury, neurological disease caused by inflammation or autoimmunity, and neurodegenerative disease, in a subject in need thereof, the method being characterized in that it comprises administering an effective amount of the pharmaceutical agent as defined in any one of claims 42 to 54, to a subject in need thereof.

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