ADENOVIRAL-BASED BIOLOGICAL DELIVERY AND EXPRESSION SYSTEM FOR USE IN THE TREATMENT OF OSTEOARTHRITIS

1 . An adenoviral-based biological delivery and expression system for use in the treatment or prevention of osteoathritis in human or mammalian joints by long-term inducible gene expression of human or mammalian interleukin-1 receptor antagonist (Il-1 Ra) in synovial cells, comprising a helper-dependent adenoviral vector containing a nucleic acid sequence encoding for human or mammalian interleukin-1 receptor antagonist (Il-1 Ra), left and right inverted terminal repeats (L ITR and R ITR), the adenoviral packaging signal and non-viral, non-coding stuffer nucleic acid sequences, wherein the expression of the human or mammalian interleukin-1 receptor antagonist (Il-1 Ra) gene within synovial cells is regulated by an inflammation-inducible promoter, which is located upstream of the reading frame of the nucleic acid sequence encoding for human or mammalian interleukin-1 receptor antagonist (Il-1 Ra) and which is specifically activated by increased levels of immune stimulatory substances.

2 . The adenoviral-based biological delivery and expression system according to claim 1 , wherein the inflammation-inducible promoter is selected from the group consisting of NF-1κ13 promoter, interleukin 6 (Il-6) promoter, interleukin-1 (Il-1) promoter, tumor necrosis factor (TNF) promoter, cyclooxygenase 2 (COX-2) promoter, complement factor 3 (C3) promoter, serum amyloid A3 (SAA3) promoter, macrophage inflammatory protein-1a (MlP-1 α) promoter, or hybrid constructs of the above.

3 . The adenoviral-based biological delivery and expression system according to claim 1 , wherein the helper-dependent adenoviral vector comprises a nucleic acid sequence set forth in SEQ ID NO 2 or SEQ ID NO 3, or a biologically effective part thereof.

4 . The adenoviral-based biological delivery and expression system according to claim 1 , wherein the mammalian interleukin-1 receptor antagonist (Il-1 Ra) is selected from the group consisting of murine Il-1 Ra, equine Il-1 Ra, canine Il-1 Ra, cat Il-1 Ra, rabbit Il-1 Ra, hamster Il-1 Ra, bovine Il-1Ra, camel Il-1 Ra or their homologs in other mammalian species.

5 . The adenoviral-based biological delivery and expression system according to claim 1 , wherein the helper-dependent adenoviral vector further comprises a marker gene that allows monitoring of the vector genome in the synovial cells.

6 . The adenoviral-based biological delivery and expression system according to claim 1 , wherein the helper-dependent vector comprises a nucleic acid sequence set forth in SEQ ID NO 1 or a conserved sequence thereof encoding for the same amino acids.

7 . The adenoviral-based biological delivery and expression system according to claim 1 , wherein the helper-dependent vector has at least 50%, 60%, 80%, 90% sequence homology with the nucleic acid sequence set forth in SEQ ID NO 1.

8 . A pharmaceutical composition, comprising a helper-dependent adenoviral vector containing a nucleic acid sequence encoding for human or mammalian interleukin-1 receptor antagonist (Il-1 Ra), left and right inverted terminal repeats (L ITR and R ITR), an adenoviral packaging signal and non-viral, non-coding stuffer nucleic acid sequences, wherein the expression of the human or mammalian interleukin-1 receptor antagonist (Il-1 Ra) gene within synovial cells is regulated by an inflammation-inducible promoter, which is located upstream of the reading frame of the nucleic acid sequence encoding for human or mammalian interleukin-1 receptor antagonist (Il-1 Ra) and which is specifically activated by increased levels of immune stimulatory substances, for the treatment or prevention of osteoathritis.

9 . The pharmaceutical composition according to claim 8 , wherein the inflammation-inducible promoter is selected from the group consisting of NF-KB promoter, interleukin 6 (11-6) promoter, interleukin-1 (11-1) promoter, tumor necrosis factor (TNF) promoter, cyclooxygenase 2 (COX-2) promoter, complement factor 3 (C3) promoter, serum amyloid A3 (SAA3) promoter, macrophage inflammatory protein-1a (MIP-1a) promoter, or hybrid constructs of the above.

10 . The pharmaceutical composition according to claim 8 , wherein the helper-dependent adenoviral vector comprises a nucleic acid sequence set forth in SEQ ID NO 2 or SEQ ID NO 3, or a biologically effective part thereof.

11 . The pharmaceutical composition according to claim 8 , wherein the mammalian interleukin-1 receptor antagonist (Il-1 Ra) is selected from the group consisting of murine Il-1 Ra, equine Il-1 Ra, canine Il-1 Ra, cat Il-1 Ra, rabbit Il-1 Ra, hamster Il-1 Ra, bovine Il-1 Ra, camel Il-1 Ra or their homologs in other mammalian species.

12 . The pharmaceutical composition according to claim 8 , wherein the helper-dependent adenoviral vector further comprises a marker gene that allows monitoring of the vector genome in the synovial cells.

13 . The pharmaceutical composition according to claim 8 , wherein the helper-dependent vector comprises a nucleic acid sequence set forth in SEQ ID NO 1 or a conserved sequence thereof encoding for the same amino acids.

14 . The pharmaceutical composition according to claim 8 , wherein the helper-dependent vector has at least 50%, 60%, 80%, 90% sequence homology with the nucleic acid sequence set forth in SEQ ID NO 1.

15 . Use of an adenoviral-based biological delivery and expression system according to claim 1 for expressing interleukin-1 receptor antagonist (Il-1 Ra) in synovial cells ex vivo.