TREATMENT OF NERVOUS SYSTEM INJURY AND NEURODEGENERATIVE DISORDERS AND RELATED CONDITIONS

• US 20200131237A1
• Filed: 06/26/2018
• Published: 04/30/2020
• Est. Priority Date: 06/28/2017
• Status: Active Grant

• Current Assignee: Cleveland Clinic Foundation
• Original Assignee: Cleveland Clinic Foundation
• Inventors: Lee, Yu-Shang, Lin, Ching-Yi
• Granted Patent: US 10,906,949 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/6031 Proteins
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 49/14 Peptides, e.g. proteins
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2430/32 : for nerve reconstruction
• CPC Class Codes: A61L 27/22 : Polypeptides or derivatives thereof , e.g. degradation products
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 14/4703 : Inhibitors; Suppressors
• CPC Class Codes: C07K 19/00 : Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment
• CPC Class Codes: C07K 2319/06 : containing a lysosomal/endosomal localisation signal
• CPC Class Codes: C07K 2319/10 : containing a tag for extracellular membrane crossing, e.g. TAT or VP22
• CPC Class Codes: C07K 2319/70 : containing domain for protein-protein interaction
• CPC Class Codes: C07K 2319/95 : containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence)
• CPC Class Codes: C12N 9/16 : acting on ester bonds (3.1)
• CPC Class Codes: C12Y 301/03048 : Protein-tyrosine-phosphatase (3.1.3.48)
• CPC Class Codes: G01N 33/5058 : Neurological cells
• CPC Class Codes: G01N 33/68 : involving proteins, peptides or amino acids involving lipoproteins G01N33/92

Abstract

Provided herein are compositions, systems, kits, and methods for treating nervous system injuries caused by trauma or neurodegeneration or aging in a subject by administering a CSPG or SOCS3 reduction peptide (CRP and SRP respectively), or a nucleic acid sequence encoding the CRP or SRP, wherein both the CRP and SRP comprise a cell membrane penetrating domain, and a lysosome targeting domain, and the CRP further comprises a chondroitin sulfate proteoglycan (CSPG) binding domain, and the SRP further comprises a suppressor of cytokine signaling-3 (SOCS3) binding domain.

Claims

1. A method of treating nervous system injury or trauma or degeneration or aging in a subject comprising:

administering a CSPG reduction peptide (CRP), or a nucleic acid sequence encoding said CRP, to a subject with a nervous system injury or trauma or degeneration or aging,

wherein said CRP comprises;

i) a first amino acid sequence encoding a cell membrane penetrating domain,

ii) a second amino acid sequence encoding a chondroitin sulfate proteoglycan (CSPG) binding domain, and

iii) a third amino acid sequence encoding a lysosome targeting domain.

2. The method of claim 1, wherein said nervous system injury or trauma or degeneration or aging is localized to at least one nervous system site on said subject.

3. The method of claim 2, wherein said administering is under conditions such that said CRP reduces the level of CSPG present at said at least one nervous system site.

4. The method of claim 2, wherein said nervous system site is in the spinal cord and/or brain of said subject.

5. The method of claim 1, wherein said nervous system injury or trauma or degeneration or aging is to said subject'"'"'s central nervous system.

6. The method of claim 1, wherein said nervous system injury or trauma or degeneration or aging is to said subject'"'"'s peripheral nervous system.

7. The method of claim 1, wherein administering is conducted within about 24 hours of said nervous system injury or trauma or degeneration or aging.

8. The method of claim 1, wherein said administering is conducted after at least two days of said nervous system injury or trauma or degeneration.

9. The method of claim 1, wherein said administering is conducted at least one week after said nervous system injury or trauma or degeneration.

10. The method of claim 1, wherein said administering is conducted at least two weeks after said nervous system injury or trauma or degeneration.

11. The method of claim 1, wherein said administering is conducted at least one month after said nervous system injury or trauma or degeneration.

12. The method of claim 1, wherein said administering is conducted at least two months after nervous system injury or trauma or degeneration.

13. The method of claim 1, wherein said first amino acid sequence is located at the N-terminal or C-terminal of said CRP.

14. The method of claim 1, wherein said third amino acid sequence is located at the N-terminal or C-terminal of said CRP.

15. The method of claim 1, wherein said second amino acid sequence is located between said first and third amino acid sequences.

16. The method of claim 1, wherein said first amino acid sequence comprises or consists of an amino acid sequence shown in SEQ ID NOS:

1 and 5-27, or a sequence with one amino acid addition, subtraction or substitution.

17. The method of claim 1, wherein said third amino acid sequence comprises or consists of an amino acid sequence shown in SEQ ID NOS:

2 or 28-36, or a sequence with one amino acid addition, subtraction or substitution.

18. The method of claim 1, wherein said second amino acid sequence comprises or consists of an amino acid sequence shown in SEQ ID NO:

3 or 37-53, or a sequence with one amino acid addition, subtraction or substitution.

35. The method of claim 1, wherein said second amino acid sequence is located between said first and third amino acid sequences.

19. A composition, system, or kit comprising:

a CSPG reduction peptide (CRP), or a nucleic acid sequence encoding said CRP, wherein said CRP comprises;

a) a first amino acid sequence encoding a cell membrane penetrating domain,

b) a second amino acid sequence encoding a chondroitin sulfate proteoglycan (CSPG) binding domain, and

c) a third amino acid sequence encoding a lysosome targeting domain.

20. The composition, system, or kit of claim 19, further comprising a device for injecting a composition comprising said CRP into a subject'"'"'s nervous system.

21. A method of treating nervous system injury or trauma or degeneration or aging in a subject comprising:

administering a SOCS3 reduction peptide (SRP), or a nucleic acid sequence encoding said SRP, to a subject with a nervous system injury or trauma or degeneration or aging,

wherein said SRP comprises;

i) a first amino acid sequence encoding a cell membrane penetrating domain,

ii) a second amino acid sequence encoding a suppressor of cytokine signaling 3 (SOCS3) binding domain, and

iii) a third amino acid sequence encoding a lysosome targeting domain.

22. The method of claim 21, wherein said nervous system injury or trauma or degeneration or aging is localized to at least one nervous system site on said subject.

23. The method of claim 22, wherein said administering is under conditions such that said SRP reduces the level of SOCS3 present at said at least one nervous system site.

24. The method of claim 22, wherein said nervous system site is in the spinal cord and/or brain of said subject.

25. The method of claim 21, wherein said nervous system injury or trauma or degeneration or aging is to said subject'"'"'s central nervous system.

26. The method of claim 21, wherein said nervous system injury or trauma or degeneration or aging is to said subject'"'"'s peripheral nervous system.

27. The method of claim 21, wherein administering is conducted within about 24 hours of said nervous system injury or trauma or degeneration.

28. The method of claim 21, wherein said administering is conducted after at least two days of said nervous system injury or trauma or degeneration.

29. The method of claim 21, wherein said administering is conducted at least one week after said nervous system injury or trauma or degeneration.

30. The method of claim 21, wherein said administering is conducted at least two weeks after said nervous system injury or trauma or degeneration.

31. The method of claim 21, wherein said administering is conducted at least one month after said nervous system injury or trauma or degeneration.

32. The method of claim 21, wherein said administering is conducted at least two months after nervous system injury or trauma or degeneration.

33. The method of claim 21, wherein said first amino acid sequence is located at the N-terminal or C-terminal of said SRP.

34. The method of claim 21, wherein said third amino acid sequence is located at the N-terminal or C-terminal of said SRP.

36. The method of claim 21, wherein said first amino acid sequence comprises or consists of an amino acid sequence shown in SEQ ID NOS:

1 and 5-27, or a sequence with one amino acid addition, subtraction or substitution.

37. The method of claim 21, wherein said third amino acid sequence comprises or consists of an amino acid sequence shown in SEQ ID NOS:

2 or 28-36, or a sequence with one amino acid addition, subtraction or substitution.

38. The method of claim 21, wherein said second amino acid sequence comprises or consists of an amino acid sequence shown in SEQ ID NO:

54-89, or a sequence with one amino acid addition, subtraction or substitution.

39. A composition, system, or kit comprising:

a SOCS3 reduction peptide (SRP), or a nucleic acid sequence encoding said SRP, wherein said SRP comprises;

a) a first amino acid sequence encoding a cell membrane penetrating domain,

b) a second amino acid sequence encoding a suppressor of cytokine signaling 3 (SOCS3) binding domain, and

c) a third amino acid sequence encoding a lysosome targeting domain.

40. The composition, system, or kit of claim 39, further comprising a device for injecting a composition comprising said SRP into a subject'"'"'s nervous system.