Compositions and methods for delivery of agents for neuronal regeneration and survival

• US 6,551,618 B2
• Filed: 10/23/1998
• Issued: 04/22/2003
• Est. Priority Date: 03/15/1994
• Status: Expired due to Fees

• Current Assignee: Cardium Biologics, Inc., King'S College, University of Birmingham
• Original Assignee: King'S College, Selective Genetics, Inc., University of Birmingham
• Inventors: Gonzalez, Ana Maria, Berry, Martin, Logan, Ann, Baird, Andrew
• Primary Examiner(s): NGUYEN, DAVE TRONG
• Application Number:
  US09/178,286
• Publication Number:
  US 20020168338A1
• Time in Patent Office: 1,642 Days
• Field of Search: 514/44, 424/93.2, 424/423, 424/424, 424/425, 424/468, 424/469, 424/484, 424/486, 424/143.1, 435/320.1, 435/91.4, 435/455, 536/24.5, 536/24.1, 536/24.2
• US Class Current: 424/484
• CPC Class Codes: A61K 35/15 Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00
• CPC Class Codes: A61K 35/30 Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
• 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 38/1709 from mammals
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 41/0042 Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
• 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 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/0008 characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
• CPC Class Codes: A61K 48/0058 Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/415 from plants
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 14/503 : basic FGF [bFGF]
• CPC Class Codes: C07K 14/52 : Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment
• CPC Class Codes: C07K 2319/04 : containing an ER retention signal such as a C-terminal HDEL motif
• CPC Class Codes: C07K 2319/09 : containing a nuclear localisation signal
• CPC Class Codes: C07K 2319/21 : containing a His-tag
• CPC Class Codes: C07K 2319/50 : containing protease site
• CPC Class Codes: C07K 2319/55 : containing a fusion with a toxin, e.g. diphteria toxin
• CPC Class Codes: C07K 2319/75 : containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
• CPC Class Codes: C07K 2319/80 : containing a DNA binding domain, e.g. Lacl or Tet-repressor
• CPC Class Codes: C12N 15/62 : DNA sequences coding for fusion proteins
• CPC Class Codes: C12N 15/85 : for animal cells
• CPC Class Codes: C12N 15/87 : Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: C12N 2799/026 : where the vector is derived from a baculovirus
• CPC Class Codes: C12N 2800/107 : for mammalian
• CPC Class Codes: C12N 2810/851 : from growth factors; from growth regulators
• CPC Class Codes: C12N 2830/008 : cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: Y10S 977/912 : Cancer cell repair
• CPC Class Codes: Y10S 977/927 : Diagnostic contrast agent

Abstract

Devices useful in the delivery of DNA encoding neurotrophic agents, anti-fibrotic agents, and related compositions are disclosed herein for use in the treatment of central and/or peripheral nervous system injury. Methods of making and using the disclosed devices and DNA are also described. In various embodiments, the invention also discloses compositions and devices that may further include a targeting agent, such as a polypeptide that is reactive with an FGF receptor (e.g., bFGF), or another ligand that binds to cell surface receptors on neuronal cells, or a support cell. The invention also discloses methods of promoting neuronal survival and regeneration via transfection of an axon as it grows through a device or composition of the present invention, or via transfection of a repair cell.

Claims

1. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises an inducible promoter.

2. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a tissue specific promoter.

3. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter selected from the group consisting of GAP43 promoter, GFAP promoter, neuron specific enolase promoter, FGF-receptor promoter, elastase I gene control region, immunoglobulin gene control region, alpha-1-antitrypsin gene control region, beta-globin gene control region, myelin basic protein gene control region, myosin light chain 2 gene control region, RSV promoter, vaccinia virus 7.5K promoter, SV40 promoter, HSV promoter, MLP adenovirus promoter, MMTV LTR promoter, CMV promoter, metallothionein promoter, a promoter having at least one cAMP response element, tie promoter, VCAM-1 promoter, alpha V-beta 3 integrin promoters, ICAM-3 promoter, CD44 promoter, CD40 promoter, notch 4 promoter, and an event type-specific promoter.

4. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a neuronal cell specific promoter.

5. The device of claim 4 wherein the promoter is selected from the group consisting of GAP43 promoter, FGF receptor promoter and neuron specific enolase promoter.

6. A device for promoting neuronal regeneration or survival, comprising a gene activated matrix comprising a biocompatible matrix and a complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter; and

wherein the neurotrophic factor is selected from the group consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), cardiotrophin-1 (CT-1), choline acetyltransferase development factor (CDF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM);

glial cell-line-derived neurotrophic factor (GDNF), insulin, insulin-like growth factor-1 (IGF-1), IGF-2, interleukin-6 (IL-6), leukemia inhibitor factor (LIF), neurite promoting factor (NPF), neurotrophin-3 (NT-3), NT-4, platelet-derived growth factor (PDGF), protease nexin-1 (PN-1), S-100, transforming growth factor-β

(TGF-β

) and vasoactive intestinal peptide (VIP).

7. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is non-covalently associated with the gene activated matrix.

8. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is adsorbed to the gene activated matrix.

9. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is absorbed to the gene activated matrix.

10. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is capable of inducing neuronal axonal generation or regeneration.

11. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the neurotrophic factor is capable of maintaining axonal generation or regeneration.

12. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is an implant for a neuronal injury site.

13. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is formed upon administration.

14. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is a composition selected from the group consisting of a solution, a paste, a suspension, a powder, a semisolid, an emulsion and a gel.

15. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is a paste.

16. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the receptor targeting ligand is capable of binding a neuronal cell surface receptor.

17. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the receptor targeting ligand is conjugated to the vector construct and is capable of binding a neuronal cell surface receptor.

18. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and said nucleic acid binding domain binds to a nucleic acid sequence that forms a portion of the vector construct.

19. A device for promoting neuronal regeneration, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and a conduit having a lumen.

20. The device of claim 19 wherein the conduit comprises the gene activated matrix.

21. The device of claim 19 wherein the lumen contains the gene activated matrix.

22. The device of claim 19 wherein the conduit comprises a bioabsorbable material.

23. The device of claim 22 wherein the bioabsorbable material comprises material selected from the group consisting of gene activated matrix, type I collagen, laminin, polyglycolic acid, glycolide trimethylene carbonate (GTMC), poly (L-lactide-co-6-caprolactone), glycoproteins, proteoglycans, heparan sulfate proteoglycan, nidogen, glycosarninoglycans, fibronectin, epidermal growth factor, fibroblast growth factor, nerve growth factor, cytokines, and DNA encoding growth factors and cytokines.

24. The device of claim 19 wherein the conduit comprises a non-bioabsorbable material.

25. The device of claim 24 wherein the non-bioabsorbable material is selected from the group consisting of polyamide, polyimide, polyurethane, segmented polyurethane, polycarbonate, and silicone.

26. The device of claim 24 wherein the non-bioabsorbable material comprises an etched microporous synthetic polymer surface.

27. The device of claim 19 wherein the conduit is tubular.

28. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises an inducible promoter.

29. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a tissue specific promoter.

30. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter selected from the group consisting of GAP43 promoter, GFAP promoter, neuron specific enolase promoter, FGF-receptor promoter, elastase I gene control region, immunoglobulin gene control region, alpha-1-antitrypsin gene control region, beta-globin gene control region, myelin basic protein gene control region, myosin light chain 2 gene control region, RSV promoter, vaccinia virus 7.5K promoter, SV40 promoter, HSV promoter, MLP adenovirus promoter, MMTV LTR promoter, CMV promoter, metallothionein promoter, a promoter having at least one cAMP response element, tie promoter, VCAM-1 promoter, alpha V-beta 3 integrin promoters, ICAM-3 promoter, CD44 promoter, CD40 promoter, notch 4 promoter, and an event type-specific promoter.

31. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a neuronal cell specific promoter.

32. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is non-covalently associated with the gene activated matrix.

33. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is adsorbed to the gene activated matrix.

34. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is absorbed in the gene activated matrix.

35. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter and is capable of inducing neuronal axonai generution or regeneration.

36. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the neurotrophic factor is capable of maintaining axonal generation or regeneration.

37. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is an implant for a neuronal injury site.

38. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is formed upon administration.

39. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is a composition selected from the group consisting of a solution, a paste, a suspension, a powder, a semisolid, an emulsion and a gel.

40. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the gene activated matrix is a paste.

41. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the receptor targeting ligand is capable of binding a neuronal cell surface receptor.

42. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and the receptor targeting ligand is conjugated to the vector construct and is capable of binding a neuronal cell surface receptor.

43. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and said nucleic acid binding domain binds to a nucleic acid sequence that forms a portion of the vector construct.

44. A device for promoting neuronal survival, comprising:

a gene activated matrix comprising a biocompatible matrix and complex comprising a receptor targeting ligand, a nucleic acid binding domain and a non-viral vector construct encoding a neurotrophic factor;

wherein the vector construct comprises a promoter, and a conduit having a lumen.