WO1995019182A1 - Somatic gene therapy to cells associated with fluid spaces - Google Patents

Somatic gene therapy to cells associated with fluid spaces Download PDF

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WO1995019182A1
WO1995019182A1 PCT/US1995/000577 US9500577W WO9519182A1 WO 1995019182 A1 WO1995019182 A1 WO 1995019182A1 US 9500577 W US9500577 W US 9500577W WO 9519182 A1 WO9519182 A1 WO 9519182A1
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nucleic acid
acid cassette
expression vector
dna expression
cells
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English (en)
French (fr)
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Fred D. Ledley
Bert W. O'malley, Jr.
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Baylor College of Medicine
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Baylor College of Medicine
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Priority to EP95908523A priority Critical patent/EP0871723A1/en
Priority to AU16811/95A priority patent/AU1681195A/en
Publication of WO1995019182A1 publication Critical patent/WO1995019182A1/en
Anticipated expiration legal-status Critical
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12Y114/99001—Prostaglandin-endoperoxide synthase (1.14.99.1), i.e. cyclooxygenase
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2217/00—Genetically modified animals
    • A01K2217/30—Animal model comprising expression system for selective cell killing, e.g. toxins, enzyme dependent prodrug therapy using ganciclovir
    • A—HUMAN NECESSITIES
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Definitions

  • IL-1 interleukin-1
  • the IL-1 protein is an important media ⁇ tor of joint pathology. It is produced by the arthritic synovium. (Wood, D.D. et al. , Arthritis Rheum., 28:853- 862 (1985); Firestein, G.S., et al. , J. Immunol., 144: 3347-3353 (1990)) . Studies have measured IL-1 in synovial fluid. (Miossec, P., et al. , Arthritis Rheum., 29:461-470 (1986); Westacott, C.I., et al.
  • the joint capsule such as synovial membranes, synovial fluid, synovial cells (including type A cells and type B cells) ; the cartilaginous components of the joint such as chondrocytes, extracellular matrix of cartilage; the bony structures such as bone, periosteum of bone, periosteal cells, osteoblasts, osteoclasts; the immunological components such as inflammatory cells, lymphocytes, mast cells, monocytes, eosinophils; other cells like fibroblasts; and combinations of the above.
  • the joint capsule such as synovial membranes, synovial fluid, synovial cells (including type A cells and type B cells) ; the cartilaginous components of the joint such as chondrocytes, extracellular matrix of cartilage; the bony structures such as bone, periosteum of bone, periosteal cells, osteoblasts, osteoclasts; the immunological components such as inflammatory cells, lymphocytes, mast cells, monocytes, eosinophils; other cells
  • Tissues com- prising the eye include but are not limited to the cornea, lens, vitreous membrane, optic nerve, retina, supporting structure of the retinal, blood vessels of the eye, the cornea and the optic muscles.
  • the "inner ear” refers to the labyrinth which includes the vestibule, cochlea and semicircular canals.
  • the “middle ear” refers to the space in the temporal bone containing the auditory ossicles, i.e., tympanic cavity.
  • incorporation refers to uptake or transfer of the formulated DNA expression vector into a cell such that the formulated DNA expression vector can express the thera ⁇ Commissionic gene product within the cell.
  • incorporation may involve, but does not require integra ⁇ tion of the DNA expression vector or episomal replication of the DNA expression vector. Incorporation in this sense includes the short term persistence of the DNA expression vector in the cell before it is eliminated by degradation or translocation to other compartments.
  • Persistent expression refers to introduction of genes into the cell together with genetic elements which enable episomal (i.e., extrachromosomal) replication. This can lead to apparently stable trans- formation of the cell without the integration of the novel genetic material into the chromosome of the host cell.
  • the modified steroid receptor contains a DNA binding domain derived from the glucocorticoid receptor and produces a biological or therapeutic response in the target tissue similar to that produced by the administra ⁇ tion of a glucocorticoid such as cortisone, hydrocorti- sone, dexamethasone, or prednisone, in response to a novel ligand.
  • a glucocorticoid such as cortisone, hydrocorti- sone, dexamethasone, or prednisone
  • the novel ligand has a corticosteroid-like effect only on cells expressing the modified receptor, and is selected to have less systemic toxicity than natural corticosteroids.
  • a modified glucocorticoid receptor is introduced into cells which are continually on or active even in the absence of a ligand.
  • the material to be used in a formulation in the present invention can also include but is not limited to lactoferrin, histones, natural or synthetic DNA binding proteins, natural or synthetic DNA binding compounds, viral proteins, nonviral proteins or any combination of these.
  • the formulation may be comprised of synthetic compounds which bind both to DNA and function as ligands for receptors on cells comprising the thyroid, ear, eye, or structures of the joint.
  • the present invention features methods for treating diseases associated with the group selected from the joints, thyroid, ear and eye.
  • This method comprises the steps of introducing a vector into a fluid space so that cells associated with the fluid space incorporate the vector into the cell.
  • the vector is taken up by appropriate cells within the joint and expresses the protein, polypeptide or RNA.
  • the preferred embodiment of this invention involves transient or persistent expression within the joint. This is preferable to stable expression since it enables adjustment of the level of expression in response to the evolution of the disease process.
  • Gene transfer to the ear using the methods of the present invention can be utilized to treat congenital, acquired, or degenerative causes of deafness.
  • one embodiment of the present invention is use of the above vectors to treat inflammation or other dysfunctions of the vestibular system.
  • Vectors encoding for expression factors capable of inducing regeneration, reinnervation, repair, growth or revascularization of essential structures including nerves.
  • Gene therapy using the present methods can be utilized to treat congenital, acquired or degenerative causes of blindness or visual deficit.
  • Vectors can be constructed to express genes which enhance the growth, regeneration, repair, or function of the optic nerve and retinal tissues and to increase or decrease inappropriate vascularization of the retina.
  • Figure 1 is a schematic of one proposed mechanism for DNA mediated gene transfer into synovial cells.
  • Gene transfer is used to inhibit the action of prostaglandin synthase specifically in affected joints by the expression of an antisense RNA for prostaglandin synthase.
  • the complex formed between the antisense RNA and mRNA for prostaglandin synthase interferes with the proper processing and translation of this mRNA and lowers the levels of this enzyme in treated cells.
  • RNA molecules are used for forming a triple helix in regulatory regions of genes expressing enzymes required for prostaglandin synthesis.
  • RNA molecules are identified which bind the active site of enzymes required for prostaglandin synthesis and inhibit this activity.
  • CAT enzyme activity was observed in animals injected with the expression vector but not in control animals. Activity was present at 1 and 3 days but decreased thereafter and no activity was apparent after 14 days. The level of DNA estimated by southern blotting paralleled the level of enzyme activity.
  • DNA vectors with a suitable promotor and a nucleic acid cassette containing the prolactin gene sequence can be introduced into the thyroid by direct injection or by targeted delivery involving intravenous injection of vector coupled to thyrotropic proteins. Uptake of the vector by the thyroid will result in transient expression of prolactin for a period of 3-5 days. Administration of this agent at the time of parturition could facilitate the early phases of nursing, improve infant nutrition, and enhance the ability of many to breast feed. After the period of transient expression, enhanced prolactin expres ⁇ sion from the thyroid will cease and normal mechanisms regulating lactation will ensue.
  • the auditory system is comprised of a network of sensorineuroepithelium (i.e., hair cells), supporting cells, distinct afferent and efferent sensory neurons, and adjacent vascular and connective tissue elements contained mostly within the cochlea.
  • the generalized pathologic process in hearing loss is that of hair cell loss or destruction within the cochlear system.
  • Congenital infec ⁇ tions and genetic diseases, other infections (meningitis, otitis media, labyrinthitis) , systemic diseases like diabetes, trauma, ototoxicity from certain drug therapy's (i.e., antibiotics and chemotherapeutic drugs), and the senescence of aging all result in the destruction or deterioration of the hair cells and their surrounding components to variable degrees.
  • Vectors expressing platelet-derived growth factor can be utilized to stimulate the proliferation of injured or severed epi-, peri-, and endoneural connective tissue.
  • Vectors expressing growth factors such as EGF, IGF-1, IGF-2, insulin, fibroblast growth factors, TGF- alpha or TGF-beta can be utilized to increase the regener ⁇ ation, revascularization, and functional recovery of injured nerve tissue or hair cell epithelium.
  • vectors expressing antiflammatory factors such as receptor antagonist for IL-1 (PG, IL-1RA, IL-1 soluble receptor) . Expression of synthetic steroid receptors increases sensitivity to system steroids or constitutive activity expressed in the absence of pharmacological steroids.
  • gene therapy by this method applies to inflammatory disorders of the eye, cornea, retinal, conjunctiva, tear ducts, or sclera.
  • Gene transfer can be used to secrete anti-angiogenic factors such as interferon a or ⁇ or thrombospondin that would control or reverse neovascularization within the eye, a common cause of visual loss.
  • the size and strength of ocular muscles can be enhanced to correct strabismus and prevent amblyopia by using gene therapy to the eye.
  • gene transfer into muscles of the cornea can be used to treat defects associated with aging or injury.
  • protamine, polybrine, spermidine, polylysine) peptide or synthetic ligands recognizing receptors on the surface of the target cells
  • peptide or synthetic ligands capable of inducing endosomal-lysis peptide or synthetic ligands capable of targeting materials to the nucleus, gels, slow release matrices, soluble or insoluble parti ⁇ cles, as well as other formulation elements not listed.
  • coli 3-galactosidase gene (/3-gal) was titered by trans ⁇ duction of NIH3T3 cells and counting /3-gal colonies with histochemical stain. These vectors are shown schematic ⁇ ally in Figure 7. The vector was harvested from media conditioned on these cell lines for 12-18 hours. Trans- duction was performed by adding this vector containing media to cells diluted 1:1 with cell culture media with the addition of polybrene at 8 ⁇ g/ml. Transductions were performed for 12-18 hours at which time cells were fed with fresh media.

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PCT/US1995/000577 1994-01-13 1995-01-12 Somatic gene therapy to cells associated with fluid spaces Ceased WO1995019182A1 (en)

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EP95908523A EP0871723A1 (en) 1994-01-13 1995-01-12 Somatic gene therapy to cells associated with fluid spaces
AU16811/95A AU1681195A (en) 1994-01-13 1995-01-12 Somatic gene therapy to cells associated with fluid spaces

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US18170794A 1994-01-13 1994-01-13
US08/181,707 1994-01-13
US08/184,547 US5792751A (en) 1992-04-13 1994-01-21 Tranformation of cells associated with fluid spaces
US08/184,547 1994-01-21

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Cited By (6)

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AU1681195A (en) 1995-08-01
US5792751A (en) 1998-08-11

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