Gene therapy

Abstract

The present invention relates to a method of prolonging the expression of an exogenous gene in a cell transduced with the exogenous gene. The method comprises co-administration of the exogenous gene with a herpes virus gene, whereby such co-administration prolongs the expression of the exogenous gene in the transduced cell. The method is particularly useful as a means of effecting gene therapy.

1 . A method of prolonging the expression of an exogenous gene in a cell transduced with the exogenous gene, the method comprising co-administration of the exogenous gene with a herpes virus gene, whereby such co-administration prolongs the expression of the exogenous gene in the transduced cell.  
     
     
         2 . A method according to  claim 1  in which the exogenous gene is administered to a cell as naked DNA.  
     
     
         3 . A method according to  claim 1  in which the herpes virus gene is administered to a cell as naked DNA.  
     
     
         4 . A method according to  claim 1  in which the exogenous gene and herpes virus gene are administered to the cell on one piece of naked DNA.  
     
     
         5 . A method according to  claim 4  in which the exogenous DNA and herpes virus gene are provided on a linked piece of DNA.  
     
     
         6 . A method according to  claim 1  in which the exogenous gene is administered to a cell in a vector.  
     
     
         7 . A method according to  claim 1  in which the herpes virus gene is administered to a cell in a vector.  
     
     
         8 . A method according to  claim 6  or  claim 7  in which the exogenous gene and herpes virus gene are co-administered to a cell in one vector.  
     
     
         9 . A method according to  claim 6  or  claim 7  in which the exogenous gene and herpes virus gene are co-administered to a cell the in two separate vectors.  
     
     
         10 . A method according to any one of  claims 6  to  9  in which the vector comprises a promoter or regulator to control expression of the genes as required.  
     
     
         11 . A method according to any one of  claims 6  to  10  in which the vector further comprises targeting means which targets the vector to a particular tissue or cell type.  
     
     
         12 . A method according to any one of  claims 6  to  11  in which the vector is a viral vector.  
     
     
         13 . A method according to  claim 12  in which the vector is derived from a DNA virus, an RNA virus or a retrovirus.  
     
     
         14 . A method according to  claim 13  in which the vector is an adenovirus vector.  
     
     
         15 . A method according to any preceding claim in which the herpes virus gene is any gene from the family Herpesviridae, including Herpes Simplex Virus Type 1, Herpes Simplex Virus Type 2, Varicella Zoster Virus, Pseudorabies virus, Marek's disease virus, cercopitecine herpes virus and Epstein Barr virus.  
     
     
         16 . A method according to any preceding claim in which the herpes virus gene is any herpes virus gene is a herpes virus thymidine kinase gene or variant thereof, which converts ganciclovir to a toxic agent.  
     
     
         17 . A method according to any preceding claim in which the heterologous gene encodes a therapeutic agent or a marker protein.  
     
     
         18 . A method according to  claim 17  in which the gene is selected from one encoding glial cell derived growth factor (GDNF), neurotrophic factor (NGF), neurturin, persefin and other family members, Nurr-1, gli-1, gli-3, brain derived neurotrophic factor, ciliary derived neurotrophic factor (CNTF), amyloid precursor protein, β galactosidase, green fluorescent protein(s) (GFP), transducing growth factors β1, β2, β3, inhibitors of NF kappaB, anti-apoptotic genes such as bcl-2, bcl-x1, anti-inflammatory and immune-modulators such as interleukin 1 receptor agonist (IL-1ra), IL-receptor 2, neuropeptide neurotransmitters such as corticotrophin releasing hormone, substance P and neurokinins.  
     
     
         19 . A method of prolonging the expression of an exogenous gene in a cell transduced with the exogenous gene, the method comprising co-administration of the exogenous gene with a conditionally cytotoxic gene, whereby such co-administration prolongs the expression of the exogenous gene in the transduced cell.  
     
     
         20 . A method according to  claim 19  in which the exogenous gene is administered to a cell as naked DNA.  
     
     
         21 . A method according to  claim 19  in which the conditionally cytotoxic gene is administered to a cell as naked DNA.  
     
     
         22 . A method according to  claim 19  in which the exogenous gene and conditionally cytotoxic gene are administered to the cell on one piece of naked DNA.  
     
     
         23 . A method according to  claim 22  in which the exogenous DNA and conditionally cytotoxic gene are provided on a linked piece of DNA.  
     
     
         24 . A method according to  claim 19  in which the exogenous gene is administered to a cell in a vector.  
     
     
         25 . A method according to  claim 19  in which the conditionally cytotoxic gene is administered to a cell in a vector.  
     
     
         26 . A method according to  claim 24  or  claim 25  in which the exogenous gene and conditionally cytotoxic gene are co-administered to a cell in one vector.  
     
     
         27 . A method according to  claim 24  or  claim 25  in which the exogenous gene and conditionally cytotoxic gene are co-administered to a cell the in two separate vectors.  
     
     
         28 . A method according to any one of  claims 24  to  27  in which the vector comprises a promoter or regulator to control expression of the genes as required.  
     
     
         29 . A method according to any one of  claims 24  to  28  in which the vector further comprises targeting means which targets the vector to a particular tissue or cell type.  
     
     
         30 . A method according to any one of  claims 24  to  30  in which the vector is a viral vector.  
     
     
         31 . A method according to  claim 30  in which the vector is derived from a DNA virus, an RNA virus or a retrovirus.  
     
     
         32 . A method according to  claim 31  in which the vector is an adenovirus vector.  
     
     
         33 . A method according to any one of  claims 19  to  32  in which the conditionally cytotoxic gene encodes thymidine kinase from sources other than herpes virus, carboxypeptidase G2, alkaline phosphatase, penicillin—V amidase or cytosine deaminase gene.  
     
     
         34 . A method according to any preceding claim further comprising administration of a pro-drug to the transduced cell.  
     
     
         35 . A method according to  claim 34  in which the pro-drug is selected from GCV, aciclovir, trifluorothymidine, 1-[2-deoxy, 2-fluoro, β-D-arabino furanosyl]-5-iodouracil, ara-A, ara-T, 1-β-D-arabinofuranoxyl thymine, 5-ethyl-2′deoxyuridine, 5-iodo-5′-amino-2,5′-dideoxyuridine, idoxuridine, AZT, AIU (5-iodo-5′ amino 2′,5′-dideoxyuridine), dideoxycytidine and Ara-C.  
     
     
         36 . Use of the method of any preceding claim in for prophylaxis or treatment of a disease associated with body tissues.  
     
     
         37 . Use of the method of any one of  claims 1  to  35  in the treatment of brain diseases.  
     
     
         38 . Use according to  claim 36  for treatment of brain tumours, Alzheimer's disease, Parkinson's disease, Huntington's disease, lateral amyotrophic sclerosis, neurodegenrative and neurometabolic disorders, chronic brain infections such as HIV and measles, pituitary tumours, spinal cord degeneration, spinal cord regeneration, autoimmune diseases such as multiple sclerosis, Guillain Barre syndrome and peripheral neuropathies.  
     
     
         39 . A method for the treatment of a disorder by suicide gene therapy comprising more than one cycle of administration of a cytotoxic pro-drug.  
     
     
         40 . A method according to  claim 39  in which a cycle of administration of cytotoxic pro-drug is repeated substantially every one month, two months, three months, four months, six months, eight months, ten months or twelve months or fractions thereof.