# US 2004/0138155 A1 · Devices containing DNA encoding neurotrophic agents and related compositions and methods > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2004/0138155 A1 - Document ID: US20040138155A1 - Status: Published application - Kind: A1 - Application number: 10/348,051 - Filed: 2003-01-17 - Published: 2004-07-15 - Earliest claimed: 1994-03-15 - Assignees: Selective Genetics, Inc.; The University of Birmingham; King's College - Inventors: Andrew Baird; Ana Maria Gonzalez; Ann Logan; Martin Berry - Web page: https://patentgrep.com/patent/US20040138155A1 ## CPC - A61K 38/179: {for growth factors; for growth regulators} - 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)} - 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) - 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 - A61K 38/1709: {from mammals} - A61K 38/1841: {Transforming growth factor [TGF]} - 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} - 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} - 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) - 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} - 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} - A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy - 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} - A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct} - A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous} - A61P 25/00: Drugs for disorders of the nervous system - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 14/415: from plants - C07K 14/475: Growth factors; Growth regulators - C07K 14/503: {basic FGF [bFGF]} - C07K 14/52: Cytokines; Lymphokines; Interferons - C12N 15/62: DNA sequences coding for fusion proteins - C12N 15/85: for animal cells - C12N 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation - 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) - C07K 2319/00: Fusion polypeptide - C07K 2319/03: containing a transmembrane segment - C07K 2319/04: containing an ER retention signal such as a C-terminal HDEL motif - C07K 2319/09: containing a nuclear localisation signal - C07K 2319/21: containing a His-tag - C07K 2319/50: containing protease site - C07K 2319/55: containing a fusion with a toxin, e.g. diphteria toxin - C07K 2319/75: containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones - C07K 2319/80: containing a DNA binding domain, e.g. Lacl or Tet-repressor - C12N 2799/026: where the vector is derived from a baculovirus - C12N 2800/107: for mammalian - C12N 2810/851: from growth factors; from growth regulators - C12N 2830/008: cell type or tissue specific enhancer/promoter combination - Y10S 977/912: Cancer cell repair - Y10S 977/927: Diagnostic contrast agent - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS ## 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 ### Claim 1 A device for promoting neuronal regeneration, comprising: a gene activated matrix comprising a biocompatible matrix and at least one neuronal therapeutic encoding agent having an operably linked promoter. ### Claim 2 A device for promoting neuronal survival, comprising: a gene activated matrix comprising a biocompatible matrix and at least one neuronal therapeutic encoding agent having an operably linked promoter. ### Claim 3 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the promoter is an inducible promoter. ### Claim 4 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the promoter is a tissue specific promoter. ### Claim 5 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the promoter is 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. ### Claim 6 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the promoter is a neuronal cell specific promoter. ### Claim 7 (depends on 6) The device of claim 6 wherein the promoter is selected from the group consisting of GAP43 promoter, FGF receptor promoter and neuron specific enolase promoter. ### Claim 8 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the neuronal therapeutic encoding agent encodes a neurotrophic factor. ### Claim 9 (depends on 8) The device of claim 8 wherein the neurotrophic factor is a member of the neurotrophin family. ### Claim 10 (depends on 8) The device of claim 8 wherein the neurotrophic factor is a member of the FGF family. ### Claim 11 (depends on 8) The device of claim 8 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); fibroblast growth factor-1 (FGF-1), FGF-2, FGF-5, 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). ### Claim 12 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the neuronal therapeutic encoding agent encodes an inhibitor of an antagonist of axonal generation or regeneration. ### Claim 13 (depends on 12) The device of claim 12 wherein the inhibitor of an antagonist of axonal generation or regeneration is an inhibitor of TGF-beta. ### Claim 14 (depends on 13) The device of claim 13 wherein the inhibitor of TGF-beta is selected from the group consisting of decorin, a TGF-beta inhibitory chemokine, an anti-TGF-beta antibody, an antisense TGF-beta oligonucleotide, a TGF-beta gene specific ribozyme and a mutated TGF-beta. ### Claim 15 (depends on 14) The device of claim 14 wherein the TGF-beta inhibitory chemokine is an ELR containing member of the CXC chemokine family. ### Claim 16 (depends on 15) The device of claim 15 wherein the ELR containing member of the CXC chemokine family is selected from the group consisting of interleukin-8, ENA-78, GROα, GROβand GROγ. ### Claim 17 (depends on 13) The device of claim 13 wherein the inhibitor of TGF-beta is decorin. ### Claim 18 (depends on 13) The device of claim 13 wherein the inhibitor of TGF-beta is an anti-TGF-beta antibody. ### Claim 19 (depends on 13) The device of claim 13 wherein the inhibitor of TGF-beta is a mutated TGF-beta. ### Claim 20 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the neuronal therapeutic encoding agent is non-covalently associated with the gene activated matrix. ### Claim 21 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the neuronal therapeutic encoding agent is adsorbed to the gene activated matrix. ### Claim 22 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the neuronal therapeutic encoding agent is absorbed in the gene activated matrix. ### Claim 23 (depends on 1, 2) The device of either claim 1 or claim 2 wherein the neuronal therapeutic encoding agent is capable of inducing neuronal axonal generation or regeneration. ### Claim 24 A device for promoting neuronal regeneration, comprising: a gene activated matrix; at least one support cell; and at least one neuronal therapeutic encoding agent having an operably linked promoter. ### Claim 25 A device for promoting neuronal survival, comprising: a gene activated matrix; at least one support cell; and at least one neuronal therapeutic encoding agent having an operably linked promoter. ### Claim 26 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is a Schwann cell. ### Claim 27 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is an oligodendrocyte. ### Claim 28 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is an astrocyte. ### Claim 29 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is a microglial cell. ### Claim 30 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is a fibroblast. ### Claim 31 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is a macrophage. ### Claim 32 (depends on 24, 25) The device of either claim 24 or claim 25 wherein the support cell is an inflammatory cell selected from the group consisting of a macrophage, a neutrophil, a monocyte, a granulocyte and a lymphocyte. ### Claim 33 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the neuronal therapeutic encoding agent is capable of maintaining axonal generation or regeneration. ### Claim 34 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the gene activated matrix is an implant for a neuronal injury site. ### Claim 35 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the gene activated matrix is formed upon administration. ### Claim 36 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the gene activated matrix is administered to a neuronal injury site. ### Claim 37 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein 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. ### Claim 38 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the gene activated matrix is a paste. ### Claim 39 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the neuronal therapeutic encoding agent is selected from the group consisting of a nucleic acid molecule, a vector, an antisense nucleic acid molecule and a ribozyme. ### Claim 40 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a targeting agent, wherein said targeting agent is complexed with the neuronal therapeutic encoding agent and is capable of binding a neuronal cell surface receptor. ### Claim 41 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a targeting agent, wherein said targeting agent is conjugated to the neuronal therapeutic encoding agent and is capable of binding a neuronal cell surface receptor. ### Claim 42 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a targeting agent, wherein said targeting agent is complexed with the neuronal therapeutic encoding agent and is capable of binding a repair cell surface receptor. ### Claim 43 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a targeting agent, wherein said targeting agent is conjugated to the neuronal therapeutic encoding agent and is capable of binding a repair cell surface receptor. ### Claim 44 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a targeting agent, wherein said targeting agent is complexed with the neuronal therapeutic encoding agent and is capable of binding extracellular matrix. ### Claim 45 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a targeting agent, wherein said targeting agent is conjugated to the neuronal therapeutic encoding agent and is capable of binding extracellular matrix. ### Claim 46 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising a nucleic acid binding domain, wherein said nucleic acid binding domain binds to a nucleic acid sequence that forms a portion of the neuronal therapeutic encoding agent. ### Claim 47 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25, further comprising at least one linker that is selected from the group consisting of a cleavable linker, a linker that provides an intracellular protein sorting peptide sequence, a linker that reduces steric hindrance, a linker that provides a nuclear translocation signal and a linker that possesses a nucleic acid condensing ability. ### Claim 48 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the device contains sub-physiologic amounts of a neuronal therapeutic agent. ### Claim 49 (depends on 1, 2, 24, 25) The device of any one of claims 1, 2, 24 or 25 wherein the device contains physiologic amounts of a neuronal therapeutic agent. ### Claim 50 (depends on 1, 2, 24, 25) A device according to any one of claims 1, 2, 24 or 25, further comprising a conduit having a lumen. ### Claim 51 (depends on 50) The device of claim 50 wherein the conduit comprises the gene activated matrix. ### Claim 52 (depends on 50) The device of claim 50 wherein the lumen contains the gene activated matrix. ### Claim 53 (depends on 50) The device of claim 50 wherein the conduit comprises a bioabsorbable material. ### Claim 54 (depends on 53) The device of claim 53 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, glycosaminoglycans, fibronectin, epidermal growth factor, fibroblast growth factor, nerve growth factor, cytokines, and DNA encoding growth factors and cytokines. ### Claim 55 (depends on 50) The device of claim 50 wherein the conduit comprises a non-bioabsorbable material. ### Claim 56 (depends on 55) The device of claim 55 wherein the non-bioabsorbable material is selected from the group consisting of polyamide, polyimide, polyurethane, segmented polyurethane, polycarbonate, and silicone. ### Claim 57 (depends on 55) The device of claim 55 wherein the non-bioabsorbable material comprises an etched microporous synthetic polymer surface. ### Claim 58 (depends on 50) The device of claim 50 wherein the conduit is tubular. ### Claim 59 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58) A method for transferring a neuronal therapeutic encoding agent into a neuronal cell, comprising: contacting a neuronal cell with the device of any one of claims 1-58 to effectively transfer the neuronal therapeutic encoding agent into the neuronal cell. ### Claim 60 (depends on 59) The method of claim 59 wherein transfer of the neuronal therapeutic encoding agent comprises retrograde axonal transport of the neuronal therapeutic encoding agent. ### Claim 61 (depends on 59) The method of claim 59, further comprising expression of the neuronal therapeutic encoding agent at a neuronal cellular site distinct from a site of contact between the device and the neuronal cell. ### Claim 62 (depends on 59) The method of claim 59 wherein the device is contacted with a neuronal cell at a neuronal injury site. ### Claim 63 (depends on 59) The method of claim 59 wherein the device is contacted with a neuronal cell in a manner such that axonal generation or regeneration occurs. ### Claim 64 (depends on 63) The method of claim 63 wherein axonal regeneration occurs without axonal entrapment. ### Claim 65 (depends on 59) The method of claim 59 wherein the device is contacted with a neuronal cell in a manner that promotes neuronal survival. ### Claim 66 (depends on 65) The method of claim 65 wherein neuronal survival is promoted without axonal entrapment. ### Claim 67 (depends on 62, 63, 64, 65, 66) The method of any one of claims 62, 63, 64, 65 or 66 wherein a neural connection is established or reestablished. ### Claim 68 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58) A method for transferring a neuronal therapeutic encoding agent into a repair cell, comprising: contacting a repair cell with the device of any one of claims 1-58 to effectively transfer the neuronal therapeutic encoding agent into the repair cell. ### Claim 69 (depends on 68) The method of claim 68 wherein the device is contacted with a repair cell at a neuronal injury site. ### Claim 70 (depends on 68) The method of claim 68 wherein the device is contacted with a repair cell in a manner such that axonal generation or regeneration occurs. ### Claim 71 (depends on 70) The method of claim 70 wherein axonal generation or regeneration occurs without axonal entrapment. ### Claim 72 (depends on 68) The method of claim 68 wherein the device is contacted with a repair cell in a manner that promotes neuronal survival. ### Claim 73 (depends on 72) The method of claim 72 wherein neuronal survival is promoted without axonal entrapment. ### Claim 74 (depends on 69, 70, 71, 72, 73) The method of any one of claims 69, 70, 71, 72 or 73 wherein a neural connection is established or reestablished. ### Claim 75 (depends on 59, 68) The method of either claim 59 or claim 68 wherein the device contains sub-physiologic amounts of a neuronal therapeutic agent. ### Claim 76 (depends on 59, 68) The method of either claim 59 or claim 68 wherein the device contains physiologic amounts of a neuronal therapeutic agent. ### Claim 77 A method of preparing a gene activated matrix for promoting neuronal regeneration and survival, comprising contacting a neuronal therapeutic encoding agent with a biocompatible matrix such that the neuronal therapeutic encoding agent associates non-covalently with the matrix. ### Claim 78 (depends on 77) The method of claim 77 wherein the neuronal therapeutic encoding agent is adsorbed to the gene activated matrix. ### Claim 79 (depends on 77) The method of claim 77 wherein the neuronal therapeutic encoding agent is absorbed in the gene activated matrix. ### Claim 80 (depends on 77) The method of claim 77 wherein the neuronal therapeutic encoding agent is selected from the group consisting of a nucleic acid molecule, a vector, an antisense molecule and a ribozyme.