Compositions and methods for improved adenovirus-based gene therapy utilizing corticosteroid treatment

Abstract

The present disclosure relates to pharmaceutical compositions, kits, methods and their uses, comprising a corticosteroid and an adenovirus-based delivery and expression system.In some embodiments, the compositions, kits, methods and their uses improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to an animal, compared with the administration of the same pharmaceutical composition without a corticosteroid.

Description

[Technical Field]

[0001] Incorporation by reference of sequence listing This application contains a Sequence Listing that has been submitted via EFS-Web in XML format and is incorporated herein by reference in its entirety. The XML copy, created on February 27, 2024, is named "PCRTX_018WO" and is 203,433 bytes in size.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 488,130, filed March 2, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0003] Background to the disclosure The use of adenovirus vectors for gene therapy is increasing. Both adenovirus vectors and helper-dependent adenovirus vectors (HDAds) are being investigated for use in gene therapy. HDAds lack all viral coding sequences and have genomes containing only the inverted terminal repeats (ITRs) required for vector genome replication and the adenovirus packaging signal (Ψ) required for packaging the viral genome into capsids produced by helper adenoviruses. Due to the lack of viral coding sequences, HDAds have a greater cloning capacity than adenovirus vectors and are thought to illicit a weaker host immune response. However, HDAds can be more difficult to produce than adenovirus vectors. Despite advances in the use of adenovirus-based vectors, there remains a need to improve the utility of both adenovirus vectors and HDAd vectors for gene therapy. Summary of the Invention

[0004] Summary of disclosure The present disclosure relates to pharmaceutical compositions, kits, methods and their uses, comprising a corticosteroid and an adenovirus-based delivery and expression system.In some embodiments, the compositions, kits, methods and their uses improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to an animal, compared with the administration of the same pharmaceutical composition without a corticosteroid.

[0005] Embodiments of the present disclosure include the following numbered embodiments: 1. A pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system. 2. The pharmaceutical composition of embodiment 1, wherein the corticosteroid is a glucocorticoid, a mineralocorticoid, or both. 3. The corticosteroid is Beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, ciclesonide, fluticasone, flunisolide, mometasone and mixtures thereof; Beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, and mixtures thereof; Beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and mixtures thereof; Beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone, and mixtures thereof; Betamethasone, dexamethasone, triamcinolone, methylprednisolone and their mixtures; beclomethasone, budesonide, ciclesonide, fluticasone, flunisolide, mometasone and mixtures thereof; and / or Fludrocortisone, deoxycorticosterone, aldosterone, and their mixtures 3. The pharmaceutical composition of embodiment 1 or 2, wherein the pharmaceutical composition is selected from the group consisting of: 4. A pharmaceutical composition described in any one of embodiments 1 to 3, wherein the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, triamcinolone, methylprednisolone, and mixtures thereof; optionally, the corticosteroid is methylprednisolone; optionally, the corticosteroid is methylprednisolone acetate. 5. A pharmaceutical composition described in any one of embodiments 1 to 4, wherein the adenovirus-based delivery and expression system comprises a nucleic acid encoding a protein for expression by the adenovirus-based delivery and expression system; optionally, the protein is a therapeutic protein. 6. A pharmaceutical composition described in any one of embodiments 1 to 5, wherein the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, optionally of the Ad5 serotype. 7. The pharmaceutical composition of embodiment 6, wherein the helper-dependent adenoviral vector comprises a genome comprising or consisting of the nucleic acid sequence encoding the protein, a promoter controlling expression of the nucleic acid sequence encoding the protein, left and right inverted terminal repeats, an adenoviral packaging signal, and non-viral and non-coding stuffer nucleic acid sequences, and optionally, the promoter is located upstream of the open reading frame of the nucleic acid sequence encoding the protein such that expression of the protein is controlled by the promoter. 8. The promoter is a ubiquitous constitutive promoter, optionally selected from the group consisting of elongation factor 1 alpha (EF1 alpha) promoter, cytomegalovirus (CMV) promoter, beta-actin promoter, simian virus 40 (SV40) early promoter, ubiquitin c promoter, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter, and phosphoglycerate kinase (PGK) promoter; or an inflammation-sensitive promoter optionally selected from the group consisting of promoters inducible by NF-κB, interleukin 6 (II-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), cyclooxygenase 2 (COX-2), complement factor 3 (C3), serum amyloid A3 (SAA3), and macrophage inflammatory protein-1a (MIP-1a); 8. The pharmaceutical composition of embodiment 7, wherein the pharmaceutical composition is selected from: 9. The pharmaceutical composition of embodiment 7 or 8, wherein the genome comprises, or consists of, a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, or at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO: 7 or 8, excluding the promoter and the nucleic acid sequence encoding the protein. 10. The nucleic acid encoding the protein is Interleukin-1 receptor antagonist (IL-1Ra), proteoglycan 4 (PRG4), or both IL-1Ra and PRG4, or a biologically active fragment of at least one of the foregoing; IL-1Ra, PRG4, or both IL-1Ra and PRG4; IL-1Ra; or PRG4 10. The pharmaceutical composition of any one of embodiments 5 to 9, wherein the composition encodes: 11. The nucleic acid is mammalian proteins; equine, canine, feline, or murine proteins; or Human proteins Code 11. The pharmaceutical composition of any one of embodiments 5 to 10, wherein optionally the nucleic acid is codon-optimized. 12. The nucleic acid encoding the protein comprises a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or a nucleic acid that is at least ... 12. The pharmaceutical composition of any one of embodiments 5 to 11, wherein the composition consists of a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 14, 17, 18 or 19, or a nucleic acid that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 4, 5, 10, 11, 14, 17, 18 or 19, wherein optionally the sequence is codon-optimized. 13. The pharmaceutical composition of any one of embodiments 7 to 12, wherein the genome comprises or consists of a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, or at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO: 2, 3, 7, 8, 9, or a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO: 2, 3, 7, 8, 9, or a nucleic acid that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO: 2, 3, 7, 8, 9. 14. The nucleic acid comprises an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 12, 13, 17, 18 or 19, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 12, 13, 17, 18 or 19, or is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 12, 13, 17, 18 or 19. 13. The pharmaceutical composition of any one of embodiments 7 to 12, wherein the PRG4 protein comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or a biologically active fragment thereof, or a homolog thereof from any other species. 15. The nucleic acid comprises an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16, or an amino acid sequence that is 80%, 85%, 90%, 90% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16. 13. The pharmaceutical composition according to any one of embodiments 7 to 12, wherein the composition encodes an IL-1Ra protein consisting of an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 6, 15 or 16, or a biologically active fragment thereof, or a homolog thereof from any other species. 16. The pharmaceutical composition of any one of embodiments 7 to 14, wherein the nucleic acid encodes PRG4 and expression of PRG4 is controlled by a ubiquitous constitutive promoter optionally selected from the group consisting of elongation factor 1 alpha (EF1 alpha) promoter, cytomegalovirus (CMV) promoter, beta-actin promoter, simian virus 40 (SV40) early promoter, ubiquitin c promoter, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter, and phosphoglycerate kinase (PGK) promoter. 17. The pharmaceutical composition of any one of embodiments 7 to 13 or 15, wherein the nucleic acid encodes IL-1Ra and expression of IL-1Ra is controlled by an inflammation-sensitive promoter, optionally selected from the group consisting of promoters inducible by NF-κB, interleukin 6 (II-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), cyclooxygenase 2 (COX-2), complement factor 3 (C3), serum amyloid A3 (SAA3), and macrophage inflammatory protein-1a (MIP-1a). 18. A pharmaceutical composition described in any one of embodiments 7 to 17, wherein the promoter is located upstream of the reading frame of the nucleic acid sequence encoding the protein so that expression of the protein is controlled by the promoter. 19. The pharmaceutical composition of any one of embodiments 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding an IL-1Ra protein of an animal, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding an IL-1Ra protein of the animal is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the IL-1Ra protein of the animal, and optionally the animal is a horse, dog, cat, or mouse. 20. The pharmaceutical composition of any one of embodiments 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and wherein expression of the nucleic acid sequence encoding the human IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human IL-1Ra protein. 21. The pharmaceutical composition of any one of embodiments 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding an animal PRG4 protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding the animal PRG4 protein is controlled by an EF1 alpha-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the animal PRG4 protein, and optionally, the animal is a horse, dog, cat, or mouse. 22. A pharmaceutical composition described in any one of embodiments 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding human PRG4 protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and the expression of the nucleic acid sequence encoding human PRG4 protein is controlled by an EF1 alpha-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding human PRG4 protein. 23. A pharmaceutical composition described in any one of embodiments 1 to 22, wherein the pharmaceutical composition is formulated for localized administration, optionally topically, by injection, by inhalation, intraocularly, or intraaurally. 24. A pharmaceutical composition described in any one of embodiments 1 to 23, wherein the pharmaceutical composition is formulated for injection into an articular joint, optionally intratendinous, intramuscular, intraarticular, or subacromial injection. 25. A pharmaceutical composition described in any one of embodiments 1 to 24, wherein the pharmaceutical composition is formulated for intra-articular injection into a joint of a human, and optionally the joint is the knee. 26. A pharmaceutical composition described in any one of embodiments 1 to 23, wherein the pharmaceutical composition is formulated for injection into an intervertebral disc, optionally wherein the injection is an intradiscal injection, optionally into the nucleus pulposus (NP) region of the intervertebral disc. 27. A pharmaceutical composition described in any one of embodiments 1 to 23, wherein the pharmaceutical composition is not formulated for administration into an intervertebral disc, and optionally the administration is by intradiscal injection into the nucleus pulposus (NP) or central gelatinous nucleus pulposus (NP) region of the intervertebral disc, as appropriate. 28. A pharmaceutical composition described in any one of embodiments 1 to 27, wherein the pharmaceutical composition is a liquid. 29. The pharmaceutical composition of any one of embodiments 1 to 28, wherein the adenovirus-based delivery and expression system is present in a buffer comprising TRIS 10 mM, NaCl 75 mM, polysorbate 80 0.02% (v / v), sucrose 5% (w / v), MgCl2 1.0 mM, EDTA 100 μM, ethanol 0.5% (v / v), and L-histidine 10 mM. 30. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×109 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10of, if necessary, at least 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The following, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11The pharmaceutical composition according to any one of embodiments 1 to 29, which is a recombinant adenoviral vector or a helper-dependent adenoviral vector with the following genome copies (GC): 31. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8, 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The pharmaceutical composition according to any one of embodiments 1 to 30, which is a recombinant adenoviral vector or a helper-dependent adenoviral vector of the following viral particles (VP): 32. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml, is 1.0, 2.0, 2.5 or 5.0 ml as appropriate, is 5.0 ml as appropriate, is at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or is a range defined by at least any two of the foregoing values ​​as appropriate, is at least 0. 1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 5.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9 A pharmaceutical composition described in any one of embodiments 1 to 31, which is a liquid having a volume that is equal to or less than 0.5, 10 ml, or equal to or less than a range defined by any two of the preceding values, optionally equal to or less than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally equal to or less than 1.0, 2.0, 2.5 or 5.0 ml, optionally equal to or less than 5.0 ml. 33. The pharmaceutical composition of any one of embodiments 1-32, wherein the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or a range defined by any two of the foregoing values, as appropriate, 10%-90%, 10%-50%, 30%-80%, 50%-90%, of the typical and / or publicly disclosed concentration of said recombinant adenovirus vector or helper-dependent adenovirus vector for administration by the same route of administration to an animal of the same species for treatment of the same or a similar disease or disorder. 34. A pharmaceutical composition described in any one of embodiments 1 to 33, wherein the concentration of the corticosteroid is sufficient to improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to an animal compared to administration of the same pharmaceutical composition without the corticosteroid. 35. The pharmaceutical composition described in embodiment 34, wherein the improvement includes an improvement in the amount or duration of a measure of transduction or expression. 36. A pharmaceutical composition described in embodiment 34 or 35, wherein said improvement in transfection and / or expression is measured in vitro. 37. A pharmaceutical composition described in any one of embodiments 34 to 36, wherein the improvement in safety includes a reduction in the number, severity, or duration of adverse events, and optionally the adverse events are selected from pain, swelling, oozing, inflammation, headache, fever, chills, and flu-like symptoms. 38. A pharmaceutical composition described in any one of embodiments 34 to 37, wherein the improved efficacy includes an improvement in the onset, amount and / or duration of the therapeutic effect of the adenovirus-based delivery and expression system. 39. The pharmaceutical composition of embodiment 38, wherein the therapeutic effect comprises a reduction in a symptom measure or marker of the disease or disorder, and optionally the symptom is pain in a joint of the animal, optionally measured using the Western Ontario-McMaster Universities Osteoarthritis Index Pain Score (WOMAC-A). 40. The improvement is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000%, or 5000%, or a range defined by any two of the foregoing values, optionally 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%, as compared to the same pharmaceutical composition without the corticosteroid. 40. The pharmaceutical composition of any one of embodiments 34-39, wherein the α-aspartate aminotransferase activity is at most 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by at least any two of the foregoing values, optionally at least 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%. 41. The concentration of the corticosteroid is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 3 The pharmaceutical composition may have a concentration of 0-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by at least any two of the foregoing values, optionally at least 0.001-50 00, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml of the pharmaceutical composition, optionally at least 40 mg / ml of the pharmaceutical composition, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by any two of the preceding values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml or less, optionally 40 mg / ml or less. 42. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml, and optionally is 1.0, 2.0, 2.5 or 5.0 ml as appropriate, is 1.0 ml as appropriate, is at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml as appropriate, or is a range defined by at least any two of the foregoing values ​​as appropriate, is at least 0. 1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9 A pharmaceutical composition described in any one of embodiments 1 to 41, which is a liquid having a volume that is equal to or less than 0.5, 10 ml, or equal to or less than a range defined by any two of the preceding values, optionally equal to or less than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally equal to or less than 1.0, 2.0, 2.5 or 5.0 ml, optionally equal to or less than 1.0 ml. 43. A pharmaceutical composition described in any one of embodiments 1 to 42, wherein the amount of the adenovirus-based biological delivery and expression system is a therapeutically effective amount. 44. A pharmaceutical composition described in any one of embodiments 1 to 43, wherein the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system, such that the corticosteroid can be administered before or after the adenovirus-based biological delivery and expression system. 45. A pharmaceutical composition described in any one of embodiments 1 to 42, wherein the corticosteroid is in the same dosage form as the adenovirus-based biological delivery and expression system, and optionally, the dosage form is a single fluid, such that the corticosteroid is administered simultaneously with the adenovirus-based biological delivery and expression system. 46. ​​The pharmaceutical composition of embodiment 45, wherein the dosage form comprising the corticosteroid and the adenovirus-based biological delivery and expression system is prepared by combining a composition comprising the corticosteroid with a composition comprising the adenovirus-based biological delivery and expression system. 47. A kit comprising the pharmaceutical composition of embodiment 44, the kit comprising a first container containing the corticosteroid in a first dosage form and a second container containing the adenovirus-based biological delivery and expression system in a second dosage form. 48. A kit for use in preparing the pharmaceutical composition of embodiment 46, the kit comprising a composition comprising the corticosteroid in a first container and a composition comprising the adenovirus-based biological delivery and expression system in a second container. 49. A method comprising administering to an animal a pharmaceutical composition described in any one of embodiments 1 to 46. 50. The method described in embodiment 49, wherein administration of the pharmaceutical composition infects cells of the animal with the adenovirus-based delivery and expression system, resulting in expression of the protein encoded by the nucleic acid of the adenovirus-based delivery and expression system. 51. The method of embodiment 49, wherein administration of the pharmaceutical composition infects articular cells of a joint affected by osteoarthritis in a human in need of administration of the pharmaceutical composition, and optionally, the joint is a knee joint. 52. The method of any one of embodiments 49 to 51, wherein the concentration of the corticosteroid is sufficient to improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to the animal compared to administration of the same pharmaceutical composition without the corticosteroid. 53. The method of embodiment 52, wherein the improvement comprises an improvement in the amount or duration of a measure of transduction or expression. 54. The method of embodiment 52 or 53, wherein said improvement in transfection and / or expression is measured in vitro. 55. The method of any one of embodiments 52-54, wherein the improvement in safety comprises a reduction in the number, severity, or duration of adverse events, and optionally the adverse events are selected from pain, swelling, oozing, inflammation, headache, fever, chills, and flu-like symptoms. 56. The method of any one of embodiments 49 to 55, wherein the improvement in efficacy includes an improvement in the onset, amount, or duration of the therapeutic effect of the adenovirus-based delivery and expression system. 57. The method of embodiment 56, wherein the therapeutic effect comprises a reduction in a symptom measure or marker of the disease or disorder, and optionally the symptom is pain in a joint of the animal, optionally measured using the Western Ontario-McMaster Universities Osteoarthritis Index Pain Score (WOMAC-A). 58. The method of any one of embodiments 56-57, wherein said improvement in efficacy comprises an improvement in the onset and / or amount of reduction in a joint pain scale in said animal. 59. The method of any one of embodiments 56 to 58, wherein said improvement in efficacy comprises an improvement in the likelihood that said animal will experience at least a 50% reduction in a joint pain scale. 60. The improvement is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000%, or 5000%, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, compared to administration of the same pharmaceutical composition without the corticosteroid. , 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by any two of the foregoing values, optionally 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%. 61. The corticosteroid is administered for a period of 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or 0.0-0.01 hours, prior to administration of the adenovirus-based delivery and expression system. 61. The method of any one of embodiments 49-60, wherein the dose is administered to the animal for a period of time that is not more than 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or not more than a range defined by any two of the foregoing values, optionally not more than 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or 0.0-0.01 hours. 62. The corticosteroid is administered for a period of 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or 0.0-0.01 hours, following administration of the adenovirus-based delivery and expression system. 62. The method of any one of embodiments 49-61, wherein the dose is administered to the animal for a period of time that is equal to or less than 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or equal to or less than a range defined by any two of the foregoing values, optionally equal to or less than 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or 0.0-0.01 hours. 63. The method of any one of embodiments 49 to 62, wherein the corticosteroid is administered to the animal no more than 3 hours before administration of the adenovirus-based delivery and expression system and no more than 30 minutes after administration of the adenovirus-based delivery and expression system, or the corticosteroid is administered to the animal no more than 30 minutes before administration of the adenovirus-based delivery and expression system and no more than 30 minutes after administration of the adenovirus-based delivery and expression system, or the corticosteroid is administered to the animal no more than 5 minutes before administration of the adenovirus-based delivery and expression system and no more than 5 minutes after administration of the adenovirus-based delivery and expression system. 64. The method of any one of embodiments 49 to 63, wherein the corticosteroid is administered to the animal simultaneously with the adenovirus-based delivery and expression system. 65. The method of embodiment 64, wherein the corticosteroid and the adenovirus-based delivery and expression system are in a single dosage form. 66. The animal is 2, 3, 4, 5, 6, 12, 18, 24, 48, or 72 hours, or a range defined by any two of the foregoing values, optionally 2-72, 3-72, 4-72, 5-72, 2-24, 3-24, 5-24, 2-48, 3-48, 4-48, 5-48, 6-72, 6-48, 12-72, or 18-72 hours, or at least 2, 3, 4, 5, 6, 12, 18, 24, 48, or 72 hours, prior to administration of the adenovirus-based delivery and expression system. 66. The method of any one of embodiments 49-65, wherein the patient has not administered a corticosteroid other than the corticosteroid of the pharmaceutical composition for a period of 4, 48 or 72 hours, or a range defined by at least any two of the foregoing values, optionally at least 2-72, 3-72, 4-72, 5-72, 2-24, 3-24, 5-24, 2-48, 3-48, 4-48, 5-48, 6-72, 6-48, 12-72 or 18-72 hours. 67. The method of any one of embodiments 49 to 66, wherein the method comprises systemic administration of the corticosteroid of the pharmaceutical composition and local administration of the adenovirus-based delivery and expression system of the pharmaceutical composition. 68. A method according to any one of embodiments 49 to 66, wherein the method comprises administering the corticosteroid of the pharmaceutical composition and an adenovirus-based delivery and expression system locally to the same location in the animal. 69. The method of embodiment 68, wherein the method comprises administering the corticosteroid of the pharmaceutical composition and an adenovirus-based delivery and expression system topically, by injection, by inhalation, intraocularly, or intraaurally. 70. The method of embodiment 68, wherein the method comprises administering the corticosteroid and adenovirus-based delivery and expression system of the pharmaceutical composition by injection, wherein the administration of the corticosteroid and the adenovirus-based delivery and expression system is via the same needle, the needle being maintained at the same site during administration of both the corticosteroid and the adenovirus-based delivery and expression system, and, optionally, the needle being flushed with fluid between administration of the corticosteroid and administration of the adenovirus-based delivery and expression system. 71. The method of any one of embodiments 68 to 70, wherein the method comprises injection into a joint of the animal, optionally by intratendinous, intramuscular, intraarticular or subacromial injection. 72. The method of embodiment 71, wherein the injection is an intra-articular injection, and optionally the joint is the knee. 73. The method of any one of embodiments 68 to 70, wherein the method comprises an injection into an intervertebral disc, optionally wherein the injection is an intradiscal injection, optionally into the nucleus pulposus (NP) region of the intervertebral disc. 74. The method of any one of embodiments 49 to 72, wherein the method does not include administration into the intervertebral disc, the method does not include administration by intradiscal injection, or the method does not include intradiscal injection into the nucleus pulposus (NP) or central gelatinous nucleus pulposus (NP) region of the intervertebral disc. 75. The method of any one of embodiments 49-74, wherein the method comprises treating a disease or condition. 76. The method of embodiment 75, wherein the method comprises identifying the animal as suffering from the disease or condition being treated or as being at risk of suffering from the disease or condition being treated prior to administration of the pharmaceutical composition. 77. The disease or condition is: Camptodactyly-arthrosis-coxa vara-pericarditis (CACP) syndrome; musculoskeletal disease or condition; joint disease or condition; pulmonary disease or condition; eye disease or condition; ear disease or condition; Arthropathy, arthritis or arthritis-related conditions; osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, Reiter's syndrome or tendinopathy including tendinitis, tendinosis and tenosynovitis; synovial disorders, including synovitis; bursal disorders, including bursitis; or Equine musculoskeletal disorders including hock tumors, navicular syndrome and coronoid phalangeal neuropathy 77. The method of embodiment 75 or 76, wherein 78. The method of embodiment 75 or 76, wherein the disease or symptom is degenerative disc disease (DDD) or a symptom associated with DDD. 79. The method of embodiment 75 or 76, wherein the disease or symptom is not degenerative disc disease (DDD) or a symptom associated with DDD. 80. The method of embodiment 75 or 76, wherein the disease or condition is osteoarthritis or a symptom of osteoarthritis, optionally of the knee. 81. The method of any one of embodiments 49 to 80, wherein the animal is a mammal. 82. The method of any one of embodiments 49 to 80, wherein the animal is a human. 83. The method of any one of embodiments 49 to 80, wherein the animal is a horse, dog, or cat. 84. The method of any one of embodiments 49 to 83, wherein the amount of vector administered to the animal is reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or a range defined by any two of the foregoing values, as appropriate, 10% to 90%, 10% to 50%, 30% to 80%, 50% to 90%, of the typical and / or publicly disclosed amount of the recombinant adenoviral vector or helper-dependent adenoviral vector administered to an animal of the same species by the same route of administration for the treatment of the same or similar disease or disorder. 85. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of at least 1.4 x 10 5, 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, at least 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7, 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The following, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 The method according to any one of embodiments 49 to 84, wherein the recombinant adenoviral vector or helper-dependent adenoviral vector has the following genome copies (GC): 86. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×106 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×109 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12, 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The method of any one of embodiments 49 to 84, wherein the recombinant adenoviral vector or helper-dependent adenoviral vector is a viral particle (VP): 87. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml. , optionally 2.0, 2.5 or 5.0 ml; optionally 5.0 ml; at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml; or a range defined by at least any two of the foregoing values; optionally at least Also, the volume may be 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml, or at least 2.0, 2.5, or 5.0 ml, or at least 5.0 ml, as appropriate, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9. 87. The method of any one of embodiments 49 to 86, wherein the liquid has a volume that is equal to or less than 0, 9.5, 10 ml, or equal to or less than a range defined by any two of the preceding values, optionally equal to or less than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally equal to or less than 2.0, 2.5 or 5.0 ml, optionally equal to or less than 5.0 ml. 88. The pharmaceutical composition is a liquid, and the amount of pharmaceutical composition administered to the animal is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7 ml. 0.5 or 4.0-6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 5.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by at least any two of the foregoing values; Optionally, at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml; Optionally, at least 1.0, 2.0, 2.5, or 5.0 ml; Optionally, at least 5.0 ml; or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8 The method of any one of embodiments 49 to 87, wherein the liquid has a volume of 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml or less, optionally 1.0, 2.0, 2.5 or 5.0 ml or less, optionally 5.0 ml or less. 89. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the amount of vector administered to the animal is 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×107 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of at least 1.4 x 10 5 , 1.4×106 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, at least 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, at least 5.6 x 10 9 , 7.0×109 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The following, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×1010 , 1.4×10 11 or 1.4 x 10 12 The following, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 The method according to any one of embodiments 49 to 88, wherein the recombinant adenoviral vector or helper-dependent adenoviral vector has the following genome copies (GC): 90. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the amount of vector administered to the animal is 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×105 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×1013 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, at least 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, at least 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×1013 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The following, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 The following, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 The method of any one of embodiments 49 to 88, wherein the recombinant adenoviral vector or helper-dependent adenoviral vector is a viral particle (VP): 91. The concentration of the corticosteroid is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, The pharmaceutical composition may have a concentration of 30-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by at least any two of the foregoing values, optionally at least 0.001 5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml of the pharmaceutical composition, optionally at least 40 mg / ml of the pharmaceutical composition, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 25 91. The method of any one of embodiments 49-90, wherein the pharmaceutical composition is at or below 0.001 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml or less, optionally 40 mg / ml or less. 92. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml; Optionally, 1.0, 2.0, 2.5, or 5.0 ml; optionally, 1.0 ml; at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml; or a range defined by at least any two of the foregoing values; optionally, at least 0 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 92. The method of any one of embodiments 49 to 91, wherein the liquid has a volume that is equal to or less than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml, optionally equal to or less than 1.0, 2.0, 2.5, or 5.0 ml, optionally equal to or less than 1.0 ml. 93. The pharmaceutical composition is a liquid, and the amount of pharmaceutical composition administered to the animal is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7. 0.5 or 4.0-6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by at least any two of the foregoing values; Optionally, at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml; Optionally, at least 1.0, 2.0, 2.5, or 5.0 ml; Optionally, at least 1.0 ml; or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8 The method of any one of embodiments 49 to 92, wherein the liquid has a volume of 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml or less, optionally 1.0, 2.0, 2.5 or 5.0 ml or less, optionally 1.0 ml or less, or optionally 1.0 ml or less. 94. The amount of corticosteroid administered to the animal is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, or, as appropriate, 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-1 00, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg, optionally 40 mg, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by at least any two of the preceding values, optionally At least 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg, or at least 40 mg, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750 mg, if necessary , 1000, 2500 or 5000 mg or less, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg or less, optionally 40 mg or less. 95. The method comprises identifying a human subject as suffering from osteoarthritis of the knee; administering the pharmaceutical composition to the human subject by intra-articular injection into the knee joint affected by osteoarthritis; Including, the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system; administering the corticosteroid comprises an intra-articular injection of 1 ml of a formulation containing 40 mg / ml of the corticosteroid; Administration of the adenovirus-based biological delivery and expression system is optionally 2.8 x 10 per ml of the adenovirus-based biological delivery and expression system 9 , 2.8×10 10 , 2.8×10 11 an intra-articular injection of 2, 2.5 or 5 ml of a dosage form comprising The amount of adenovirus-based biological delivery and expression system delivered to the knee is 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 a recombinant adenoviral vector or a helper-dependent adenoviral vector containing a genome copy (GC) of administration of the corticosteroid and the adenovirus-based delivery and expression system is via the same needle, the needle being maintained at the same site during administration of both the corticosteroid and the adenovirus-based delivery and expression system, and optionally the needle being flushed with fluid during administration of the corticosteroid and the adenovirus-based delivery and expression system; the corticosteroid is administered no more than 0-15 minutes, and optionally no more than 0-5 minutes, prior to administration of the adenoviral-based delivery and expression system; The method according to any one of embodiments 49 to 94. 96. The method of embodiment 95, wherein the adenovirus-based delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and wherein expression of the nucleic acid sequence encoding the human IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human IL-1Ra protein. 97. The method of embodiment 96, wherein the genome of the helper-dependent adenoviral vector has the nucleic acid sequence of SEQ ID NO: 7. 98. The method of any one of embodiments 95 to 97, wherein the corticosteroid is methylprednisolone. 99. The method of any one of embodiments 49 to 98, wherein the amount of the adenovirus-based biological delivery and expression system administered to the animal is a therapeutically effective amount. 100. Use of a composition or kit described in any one of embodiments 1 to 48 for use in a method for treating a disease or condition, the method comprising a method described in any one of embodiments 49 to 98. 101. A kit comprising a first container containing a corticosteroid in a first dosage form and a second container containing an adenovirus-based biological delivery and expression system in a second dosage form. 102. The kit described in embodiment 101, wherein the corticosteroid or the adenovirus-based biological delivery and expression system is provided as described in any one of embodiments 1 to 46. 103. A pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system according to any one of embodiments 1 to 46, for use as a medicament, or a kit comprising a first container comprising a corticosteroid in a first dosage form and a second container comprising an adenovirus-based biological delivery and expression system in a second dosage form, according to any one of embodiments 101 to 102. 104. A pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system according to any one of embodiments 1 to 46, or a kit comprising a first container comprising a corticosteroid in a first dosage form and a second container comprising an adenovirus-based biological delivery and expression system in a second dosage form, according to any one of embodiments 101 to 102, for use in the prevention or treatment of a disease or condition. 105. The symptoms of the disease are: Camptodactyly-arthrosis-coxa vara-pericarditis (CACP) syndrome; musculoskeletal disease or condition; joint disease or condition; pulmonary disease or condition; eye disease or condition; ear disease or condition; Arthrosis, arthritis and arthritis-related conditions; osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, Reiter's syndrome or tendinopathy including tendinitis, tendinosis and tenosynovitis; synovial disorders, including synovitis; bursal disorders, including bursitis; or Equine musculoskeletal disorders including hock tumors, navicular syndrome and coronoid phalangeal neuropathy 105. The pharmaceutical composition or kit for use according to embodiment 104, selected from the group consisting of: 106. A pharmaceutical composition or kit for use according to embodiment 104, wherein the disease or symptom is degenerative disc disease (DDD) or a symptom associated with DDD. 107. A pharmaceutical composition or kit for use according to embodiment 104, wherein the disease or symptom is not degenerative disc disease (DDD) or a symptom associated with DDD. 108. The pharmaceutical composition, kit, method, or use of any one of the preceding embodiments, wherein the adenovirus-based biological delivery and expression system is PCRX201, and optionally, the amount of the corticosteroid and / or the PCRX is a therapeutically effective amount.

[0006] Unless otherwise specified, or unless the embodiments are mutually exclusive, any of the above numbered embodiments can be combined with any other numbered embodiment, even if not explicitly stated. [Brief explanation of the drawings]

[0007] [Figure 1]FIG. 1 illustrates one embodiment of a genomic map of human takinogen hexanoate (FX201, also referred to herein as PCRX-201 or PCRX201). ITR = inverted terminal repeat (5' top 1-103 bp; 3' top 29,158-29,260 bp), Ψ = packaging signal (240-375 bp), HPRT stuffer = human hypoxanthine phosphoribosyltransferase (463-16,518 bp), human cosmid insert = human cosmid (16,532-27,637 bp), SV40 polyA = simian virus 40 polyA (27,750-28,020 bp), huIL-1Ra = human interleukin-1 receptor antagonist, genome of interest (28,033-28,566 bp), NF-κB5-ELAM promoter = NΦ-κBινδυχιβλε promoter (28,581-28,842 bp).

[0008] [Figure 2] Figure 2 illustrates one embodiment of a basic genetic map of a helper-dependent adenoviral vector of the present disclosure. The vector backbone (excluding the transgene and promoter cDNAs) consists of left and right inverted terminal repeats (ITRs), an adenoviral packaging signal (Ψ), and a non-coding, non-viral stuffer sequence (the remaining unmarked sequence present between the ITRs). The cDNA for the protein to be expressed (transgene), e.g., equine IL-1Ra (GQ-201), mouse IL-1Ra, or human IL-1Ra (alternatively, equine PRG4, canine PRG4, feline PRG4, or mouse PRG4, not shown), is cloned between the left and right viral ITRs of the adenoviral vector used. Expression of IL-1Ra is typically regulated by the inflammation-sensitive NF-KB5-ELAM promoter. Expression of PRG4 is typically regulated by an EF1 alpha-inducible promoter (not shown).

[0009] [Figure 3]FIG. 3 illustrates one embodiment of a photomicrograph of X-Gal staining in 116 cells after treatment with HDAd-LacZ at 100 viral particles / cell in combination with 0.36 μg / ml or 428.5 μg / ml of the corticosteroid triamcinolone acetonide (TAC), or without TAC.

[0010] [Figure 4] FIG. 4 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0011] [Figure 5] FIG. 5 illustrates one embodiment of a photograph of X-Gal staining in HEK293 cells after treatment with HDAd-LacZ at 100, 30, or 10 viral particles / cell in combination with 0.36 μg / ml or 428.5 μg / ml of TAC or without TAC.

[0012] [Figure 6] FIG. 6 illustrates one embodiment of a photomicrograph of the well in FIG.

[0013] [Figure 7] FIG. 7 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0014] [Figure 8] FIG. 8 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0015] [Figure 9] Figure 9 illustrates one embodiment of a photomicrograph of X-Gal staining in HEK293 cells after treatment with HDAd-LacZ and TAC (rows A-K: 2.88 μg / mL to 0.0028125 μg / mL; row L: 0 ng / mL).

[0016] [Figure 10]FIG. 10 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0017] [Figure 11] FIG. 11 illustrates one embodiment of a photomicrograph of X-Gal staining in HEK293 cells after treatment with HDAd-LacZ and TAC (rows B-K: 2.8125 ng / mL to 0.005493164 ng / mL; row L: 0 ng / mL).

[0018] [Figure 12] FIG. 12 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0019] [Figure 13] Figure 13 illustrates one embodiment of photographs of X-Gal staining in HEK293 cells after treatment with HDAd-LacZ and TAC using different timings of TAC relative to HDAd-LacZ treatment (rows A-F: 360 ng / mL to 0.35 ng / mL; row G: 0 ng / mL; row H: 360 ng / mL). "Before" refers to TAC treatment 3 hours before HDAd-LacZ infection, "simultaneous" refers to TAC treatment and HDAd-LacZ infection simultaneously, and "after" refers to TAC treatment 3 hours after HDAd-LacZ infection.

[0020] [Figure 14] FIG. 14 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0021] [Figure 15]Figure 15 illustrates one embodiment of photomicrographs of X-Gal wells in Figure 13 using different timings of TAC relative to HDAd-LacZ treatment (rows A-F: 360 ng / mL to 0.35 ng / mL; row G: 0 ng / mL; row H: 360 ng / mL). "Before" refers to TAC treatment 3 hours before HDAd-LacZ infection, "simultaneous" refers to TAC treatment and HDAd-LacZ infection simultaneously, and "after" refers to TAC treatment 3 hours after HDAd-LacZ infection.

[0022] [Figure 16] FIG. 16 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0023] [Figure 17] FIG. 17 illustrates one embodiment of photographs of X-Gal staining in HEK293 cells after treatment with HDAd-LacZ plus various concentrations of betamethasone or dexamethasone (rows A-K: 4000 ng / mL to 0.0038 ng / mL betamethasone or dexamethasone; L: no betamethasone or dexamethasone (-)).

[0024] [Figure 18] FIG. 18 illustrates one embodiment of a photomicrograph of the X-Gal wells in FIG. 17 (rows A-K: 4000 ng / mL to 0.0038 ng / mL betamethasone or dexamethasone, L: no betamethasone or dexamethasone (-)).

[0025] [Figure 19] FIG. 19 illustrates one embodiment of a preliminary semi-quantitative measurement of the X-Gal staining in FIG.

[0026] [Figure 20]Figure 20 illustrates one embodiment of preliminary semi-quantitative measurements of the percentage of total length of rat knee synovial membrane expressing X-Gal staining after intra-articular co-administration of HDAd-LacZ and TAC. HDAd was administered at four doses: 5x10, 5x10, 5x10, and 5x10, with or without 0.06 mg TAC (+TAC).

[0027] [Figure 21] 21 illustrates one embodiment of preliminary semi-quantitative measurements of the percentage of total tissue area of ​​rat knee synovial membrane expressing X-Gal staining after intra-articular co-administration of HDAd-LacZ and TAC. HDAd was administered at four doses: 5×10, 5×10, 5×10, and 5×10, with or without 0.06 mg TAC (+TAC).

[0028] [Figure 22] Figure 22 illustrates one embodiment of preliminary semi-quantitative measurements of synovial / periarticular inflammation in rat knee joints following intra-articular co-administration of HDAd-LacZ and TAC. HDAd was administered at four doses: 5x10, 5x10, 5x10, and 5x10, with or without 0.06 mg of TAC (+TAC).

[0029] [Figure 23] FIG. 23 illustrates one embodiment of a graphical representation of the mean percent change in the WOMAC-A pain index in human subjects treated with low (1.4E10 genome copies (GC) / knee), medium (1.4E11 GC / knee), or high (1.4E12 GC / knee) doses administered by intra-articular injection into osteoarthritis-affected knees, either with or without administration of 40 mg of methylprednisolone by intra-articular injection through the same needle immediately prior to the injection of PCRX201.

[0030] [Figure 24]Figure 24 illustrates an embodiment of another graphical representation of the mean percent change in the WOMAC-A pain index shown in Figure 23, with additional time points. "No pretreatment" means no methylprednisolone treatment, and "with pretreatment" means administration of 40 mg of methylprednisolone by intra-articular injection through the same needle immediately prior to injection of PCRX201.

[0031] [Figure 25] 25 illustrates one embodiment of a graphical representation of the percentage of patients with a 50% or greater reduction from baseline in the WOMAC-A pain index. "No methylprednisolone" refers to the absence of methylprednisolone treatment, and "methylprednisolone" refers to the administration of 40 mg of methylprednisolone by intra-articular injection through the same needle immediately prior to the injection of PCRX201. DETAILED DESCRIPTION OF THE INVENTION

[0032] Detailed Description of Disclosure The present disclosure provides pharmaceutical compositions, kits, methods and uses thereof, comprising a corticosteroid and an adenovirus-based delivery and expression system.In some embodiments, the compositions, kits, methods and uses thereof improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to an animal, compared with the administration of the same pharmaceutical composition without a corticosteroid.

[0033] Pharmaceutical Compositions In some embodiments, in any one of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises a corticosteroid, and an adenovirus-based delivery and expression system is disclosed.As used herein, "pharmaceutical composition" has its plain and ordinary meaning as understood by those skilled in the art in light of this disclosure.The pharmaceutical composition does not need to be a single dosage form; in some embodiments, the corticosteroid and the adenovirus-based delivery and expression system are in separate dosage forms (e.g., two separate liquids) so that they can be administered separately.In some embodiments, the pharmaceutical composition is a single dosage form (e.g., liquid) containing both the corticosteroid and the adenovirus-based delivery and expression system.

[0034] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the corticosteroid is a glucocorticoid, a mineralocorticoid, or both. For example, the corticosteroid may have primarily glucocorticoid or mineralocorticoid activity, or the corticosteroid's activity may be both glucocorticoid and mineralocorticoid. In some embodiments, the corticosteroid is a combination of one or more glucocorticoids, a combination of one or more mineralocorticoids, or a combination of both glucocorticoids and mineralocorticoids. In some embodiments, the corticosteroid is selected from the group consisting of beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, and mixtures thereof. In some embodiments, the corticosteroid is selected from the group consisting of beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, ciclesonide, fluticasone, flunisolide, mometasone, and mixtures thereof. In some embodiments, the corticosteroid is selected from the group consisting of beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and mixtures thereof. In some embodiments, the corticosteroid is selected from the group consisting of beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone, and mixtures thereof. In some embodiments, the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, triamcinolone, methylprednisolone, and mixtures thereof.In some embodiments, the corticosteroid is selected from the group consisting of beclomethasone, budesonide, ciclesonide, fluticasone, flunisolide, mometasone, and mixtures thereof. In some embodiments, the corticosteroid is selected from the group consisting of fludrocortisone, deoxycorticosterone, aldosterone, and mixtures thereof. In some embodiments, the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, triamcinolone, methylprednisolone, and mixtures thereof. In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the corticosteroid is methylprednisolone acetate.In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the concentration of corticosteroid is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001 ~0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, 40 mg / ml if necessary, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000 mg / ml, or at least A range defined by any two of the preceding values, as appropriate, of at least 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, as appropriate, of at least 40 mg / ml, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 8 The pharmaceutical composition is a pharmaceutical composition having a concentration of not more than 0, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml or, optionally, 40 mg / ml or less.In some embodiments, the pharmaceutical composition has a volume of 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0 to 6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or within a range defined by at least any two of the preceding values. or less, optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5, or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 , 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml or less, or a range defined by any two of the preceding values, optionally 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml or less, optionally 1.0, 2.0, 2.5 or 5.0 ml or less, optionally 1.0 ml or less.

[0035] In some embodiments, in any one of the pharmaceutical compositions disclosed herein, the adenovirus-based delivery and expression system comprises a nucleic acid encoding a protein for expression by the adenovirus-based delivery and expression system, and optionally, the protein is a therapeutic protein. In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector. In some embodiments, the recombinant adenovirus vector or helper-dependent adenovirus vector is an Ad5 serotype. In some embodiments, the helper-dependent adenovirus vector comprises a genome comprising or consisting of a nucleic acid sequence encoding a protein, a promoter controlling expression of the nucleic acid sequence encoding the protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and optionally, the promoter is located upstream of the open reading frame of the nucleic acid sequence encoding the protein so that expression of the protein is controlled by the promoter. In some embodiments, the promoter is a ubiquitous constitutive promoter. In some embodiments, the promoter is selected from the group consisting of elongation factor 1 alpha (EF1 alpha) promoter, cytomegalovirus (CMV) promoter, beta-actin promoter, simian virus 40 (SV40) early promoter, ubiquitin c promoter, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter, and phosphoglycerate kinase (PGK) promoter. In some embodiments, the promoter is an inflammation-sensitive promoter. In some embodiments, the promoter is selected from the group consisting of promoters inducible by NF-κB, interleukin 6 (II-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), cyclooxygenase 2 (COX-2), complement factor 3 (C3), serum amyloid A3 (SAA3), and macrophage inflammatory protein-1a (MIP-1a).In some embodiments, the genome comprises, consists of, or is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:7 or 8, excluding the sequence of the promoter and protein-encoding nucleic acid sequence from a comparison between the genome and SEQ ID NO:7 or 8. In some embodiments, the genome comprises or consists of a nucleic acid, and the nucleic acid sequences of the left and right inverted terminal repeats, adenoviral packaging signal, and non-viral and non-coding stuffer portions of the genome are 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:7 or 8, or are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:7 or 8.

[0036] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the protein-encoding nucleic acid encodes a therapeutic protein. In some embodiments, the protein-encoding nucleic acid encodes interleukin-1 receptor antagonist (IL-1Ra), proteoglycan 4 (PRG4), or both IL-1Ra and PRG4, or at least one biologically active fragment of the foregoing. In some embodiments, the protein-encoding nucleic acid encodes IL-1Ra, PRG4, or both IL-1Ra and PRG4. In some embodiments, the protein-encoding nucleic acid encodes IL-1Ra. In some embodiments, the protein-encoding nucleic acid encodes PRG4. In some embodiments, the nucleic acid encodes a mammalian protein. In some embodiments, the nucleic acid encodes an equine, canine, feline, or murine protein. In some embodiments, the nucleic acid encodes a human protein. In some embodiments, the protein-encoding nucleic acid is codon-optimized. In some embodiments, the nucleic acid encoding the protein comprises a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or a nucleic acid that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or a nucleic acid that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 1, 4, 5, 10, 11, 14, 17, 18 or 19, optionally wherein the sequence is codon optimized.In some embodiments, the genome comprises or consists of a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, or at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO:2, 3, 7, 8, 9. In some embodiments, the nucleic acid comprises an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or is also SEQ ID NOs: 12, 13, 17, 18 or 19, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or a biologically active fragment thereof, or a homolog thereof from any other species.In some embodiments, the nucleic acid comprises an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16, or a sequence selected from SEQ ID NO: 6, 15 or 16. In some embodiments, the nucleic acid encodes an IL-1Ra protein consisting of an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 6, 15 or 16, or a biologically active fragment thereof, or a homolog thereof from any other species. In some embodiments, the nucleic acid encodes PRG4, and expression of PRG4 is controlled by a ubiquitous constitutive promoter. In some embodiments, the nucleic acid encodes PRG4, and expression of PRG4 is controlled by a promoter selected from the group consisting of elongation factor 1 alpha (EF1 alpha) promoter, cytomegalovirus (CMV) promoter, beta-actin promoter, simian virus 40 (SV40) early promoter, ubiquitin c promoter, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter, and phosphoglycerate kinase (PGK) promoter. In some embodiments, the nucleic acid encodes IL-1Ra, and expression of IL-1Ra is controlled by an inflammation-sensitive promoter. In some embodiments, the nucleic acid encodes IL-1Ra, and expression of IL-1Ra is controlled by an inflammation-sensitive promoter selected from the group consisting of promoters inducible by NF-κB, interleukin 6 (II-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), cyclooxygenase 2 (COX-2), complement factor 3 (C3), serum amyloid A3 (SAA3), and macrophage inflammatory protein-1a (MIP-1a).In some embodiments, the pharmaceutical composition of any one of embodiments 7 to 17, wherein the promoter is located upstream of the open reading frame of the nucleic acid sequence encoding the protein such that expression of the protein is controlled by the promoter.

[0037] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding an animal IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding the animal IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the animal IL-1Ra protein. In some embodiments, the animal is a horse, dog, cat, or mouse.

[0038] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding the human IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human IL-1Ra protein.

[0039] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding an animal PRG4 protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding the animal PRG4 protein is controlled by an EF1 alpha-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the animal PRG4 protein. In some embodiments, the animal is a horse, dog, cat, or mouse.

[0040] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human PRG4 protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein the expression of the nucleic acid sequence encoding the human PRG4 protein is controlled by an EF1 alpha-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human PRG4 protein.

[0041] In some embodiments, in any one of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is formulated for localized administration. In some embodiments, the pharmaceutical composition is formulated for localized administration, such as topical, injection, inhalation, intraocular, or intraaural administration. In some embodiments, the pharmaceutical composition is formulated for injection into a joint. In some embodiments, the pharmaceutical composition is formulated for injection into a joint, and the injection is intratendinous, intramuscular, intraarticular, or subacromial injection. In some embodiments, the pharmaceutical composition is formulated for intraarticular injection into a human joint. In some embodiments, the joint is the knee.

[0042] In some embodiments, in any one of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is formulated for injection into intervertebral disc.In some embodiments, the pharmaceutical composition is formulated for injection into intervertebral disc, and the injection is intradiscal injection.In some embodiments, the injection is into the nucleus pulposus (NP) region of the intervertebral disc.

[0043] In some embodiments, in any one of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is not formulated for administration into the intervertebral disc.In some embodiments, the pharmaceutical composition is not formulated for administration into the intervertebral disc, and administration is by intradiscal injection.In some embodiments, the pharmaceutical composition is not formulated for administration into the intervertebral disc, and administration is by intradiscal injection into the nucleus pulposus (NP) or central gelatinous nucleus pulposus (NP) region of the intervertebral disc.

[0044] In some embodiments, the pharmaceutical composition of the present disclosure is not a pharmaceutical composition for direct injection into an intervertebral disc, further comprising a small amount of a local anesthetic, such as lidocaine or bupivacaine, in addition to a corticosteroid, such as methylprednisolone, betamethasone, or triamcinolone. In some embodiments, the pharmaceutical composition of the present disclosure is not a pharmaceutical composition for direct injection into an intervertebral disc, further comprising a corticosteroid. In some embodiments, the pharmaceutical composition of the present disclosure is not a pharmaceutical composition for direct injection into an intervertebral disc, further comprising a corticosteroid, wherein the corticosteroid is methylprednisolone, betamethasone, triamcinolone, or a combination thereof. In some embodiments, the pharmaceutical composition of the present disclosure is not a pharmaceutical composition for direct injection into an intervertebral disc, wherein the corticosteroid, for example, methylprednisolone, betamethasone, triamcinolone, or a combination thereof, is in a dosage form separate from the adenovirus-based biological delivery and expression system, so that the corticosteroid can be administered before or after the adenovirus-based biological delivery and expression system. In some embodiments, the pharmaceutical compositions of the present disclosure are not pharmaceutical compositions for direct injection into an intervertebral disc, and the corticosteroid, e.g., methylprednisolone, betamethasone, triamcinolone, or a combination thereof, is in the same dosage form (e.g., a single fluid) as the adenovirus-based biological delivery and expression system such that the corticosteroid is administered simultaneously with the adenovirus-based biological delivery and expression system.

[0045] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the pharmaceutical composition is liquid. In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the adenovirus-based delivery and expression system is present in a buffer containing 10 mM TRIS, 75 mM NaCl, 0.02% (v / v) polysorbate 80, 5% (w / v) sucrose, 1.0 mM MgCl2, 100 μM EDTA, 0.5% (v / v) ethanol, and 10 mM L-histidine. In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4×10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×105 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×108 , 1.4×10 9 ~7.0×10 10 of, if necessary, at least 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The following, if necessary, 2.8 x 10 9 , 2.8×10 10, 2.8×10 11 In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector with a genome copy (GC) of 1.4 x 10 or more per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of at least 1.4 x 105 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8, 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10In some embodiments, the pharmaceutical composition is a recombinant adenoviral vector or helper-dependent adenoviral vector of the following viral particles (VP): 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or is 4.0 to 6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 5.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or within a range defined by at least any two of the preceding values. 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, a liquid having a volume of 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml or less, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml or less, optionally 1.0, 2.0, 2.5, or 5.0 ml or less, optionally 5.0 ml or less. In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is adjusted to 200 ml or less for administration by the same route of administration to an animal of the same species for treatment of the same or similar disease or disorder. The concentration may be reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the typical and / or publicly disclosed concentration of the dependent adenoviral vector, or a range defined by any two of the aforementioned values, as appropriate, 10%-90%, 10%-50%, 30%-80%, 50%-90%, or the like.

[0046] In some embodiments, the concentration of corticosteroid in any one of the pharmaceutical compositions disclosed herein is sufficient to improve one or more of the transduction, expression, efficacy, and / or safety of the adenovirus-based delivery and expression system when administered to an animal compared to administration of the same pharmaceutical composition without the corticosteroid. In some embodiments, the improvement includes an improvement in the amount or duration of a measure of transduction or expression. In some embodiments, the improvement in transfection and / or expression is measured in vitro, for example, in a cell assay. In some embodiments, the improvement in safety includes a reduction in the number, severity, or duration of adverse events, optionally selected from pain, swelling, oozing, inflammation, headache, fever, chills, and flu-like symptoms. In some embodiments, the improvement in efficacy includes an improvement in the onset, amount, and / or duration of the therapeutic effect of the adenovirus-based delivery and expression system. In some embodiments, the therapeutic effect includes a reduction in a measure of a symptom or marker of a disease or disorder. In some embodiments, the symptom is pain in the animal's joints. In some embodiments, pain is a self-reported measure of pain. In some embodiments, pain is measured using the Western Ontario-McMaster Universities Osteoarthritis Index Pain Score (WOMAC-A).In some embodiments, the improvement is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000%, or 5000%, or a range defined by any two of the foregoing values, optionally 10% to 5000%, 10% to 100%, 100% to 5000%, or between 50% and 500%, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by at least any two of the foregoing values, optionally at least 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%.

[0047] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the concentration of corticosteroid is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001 ~0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or at least the foregoing A range defined by any two of the values ​​of, as appropriate, at least 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, as appropriate, at least 40 mg / ml, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 8 The pharmaceutical composition is at or below 0, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml or below.In some embodiments, the pharmaceutical composition has a volume of 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0 to 6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or within a range defined by at least any two of the preceding values. or less, optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5, or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 , 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml or less, or a range defined by any two of the preceding values, optionally 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml or less, optionally 1.0, 2.0, 2.5 or 5.0 ml or less, optionally 1.0 ml or less.

[0048] In some embodiments, in the pharmaceutical compositions of any one of the embodiments disclosed herein, the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system, such that the corticosteroid can be administered before or after the adenovirus-based biological delivery and expression system.

[0049] In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the corticosteroid is in the same dosage form as the adenovirus-based biological delivery and expression system, and optionally the dosage form is a single fluid, such that the corticosteroid is administered simultaneously with the adenovirus-based biological delivery and expression system. In some embodiments, the dosage form comprising the corticosteroid and the adenovirus-based biological delivery and expression system is prepared by combining a composition comprising the corticosteroid with a composition comprising the adenovirus-based biological delivery and expression system.

[0050] method In some embodiments, the method comprises administering to an animal any one of the pharmaceutical compositions of the embodiments disclosed herein. In some embodiments, administration of the pharmaceutical composition infects cells of the animal with an adenovirus-based delivery and expression system, resulting in expression of a protein encoded by the nucleic acid of the adenovirus-based delivery and expression system. In some embodiments, administration of the pharmaceutical composition infects articular cells of a joint affected by osteoarthritis in a human in need of administration of the pharmaceutical composition. In some embodiments, the joint is a knee joint. In some embodiments, the concentration of corticosteroid in the administered pharmaceutical composition is sufficient to improve one or more of the transduction, expression, efficacy, and / or safety of the adenovirus-based delivery and expression system when administered to an animal, compared to administration of the same pharmaceutical composition without the corticosteroid. In some embodiments, the improvement comprises an improvement in the amount or duration of a measure of transduction or expression. In some embodiments, the improvement in transfection and / or expression is measured in vitro. In some embodiments, the improved safety comprises a reduction in the number, severity, or duration of adverse events, optionally selected from pain, swelling, oozing, inflammation, headache, fever, chills, and flu-like symptoms. In some embodiments, the improved efficacy comprises an improvement in the onset, amount, or duration of the therapeutic effect of the adenovirus-based delivery and expression system. In some embodiments, the therapeutic effect comprises a reduction in a symptom measure or marker of a disease or disorder, optionally wherein the symptom is pain in the animal's joints, optionally measured using the Western Ontario-McMaster Universities Osteoarthritis Index Pain Score (WOMAC-A). In some embodiments, the improved efficacy comprises an improvement in the onset and / or amount of reduction in a joint pain measure in the animal. In some embodiments, the improved efficacy comprises an improvement in the likelihood that the animal will experience at least a 50% reduction in a joint pain measure.In some embodiments, the improvement is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000%, or 5000%, or a range defined by any two of the foregoing values, optionally 10% to 5000%, 10% to 100%, 100% to 5000%, if compared to administration of the same pharmaceutical composition without a corticosteroid. or 50%-500%, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by at least any two of the foregoing values, optionally at least 10%-5000%, 10%-100%, 100%-5000%, or 50%-500%.

[0051] In some embodiments, in any one of the methods of the embodiments disclosed herein, the corticosteroid is administered for 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0- The animal is administered for a period of time that is 0.5, 0.0-0.2 or 0.0-0.01 hours, or not more than 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4 or 5 hours, or not more than a range defined by any two of the foregoing values, as appropriate, not more than 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2 or 0.0-0.01 hours. In some embodiments, the corticosteroid is administered for 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours after administration of the adenoviral-based delivery and expression system, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or The adenovirus-based delivery and expression system is administered to the animal for a period of time that is 0.0 to 0.01 hours, or for a period of time that is not greater than 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or for a range defined by any two of the foregoing values, optionally for a period of time that is not greater than 0.0 to 5, 0.0 to 3, 0.0 to 2, 0.0 to 1, 0.0 to 0.5, 0.0 to 0.2, or 0.0 to 0.01 hours. In some embodiments, the adenovirus-based delivery and expression system is administered to the animal for a period of time that is not greater than 3 hours prior to and not greater than 30 minutes after administration of the adenovirus-based delivery and expression system. In some embodiments, the adenovirus-based delivery and expression system is administered to the animal for a period of time that is not greater than 30 minutes prior to and not greater than 30 minutes after administration of the adenovirus-based delivery and expression system.In some embodiments, corticosteroid is administered to animal 5 minutes or less before and 5 minutes or less after the administration of adenovirus-based delivery and expression system.In some embodiments, corticosteroid is administered to animal simultaneously with adenovirus-based delivery and expression system.In some embodiments, corticosteroid and adenovirus-based delivery and expression system are in a single dosage form.

[0052] In some embodiments, in any one of the methods of the embodiments disclosed herein, the animal has not been administered a systemic and / or local corticosteroid other than the corticosteroid of the pharmaceutical composition for a period of 2, 3, 4, 5, 6, 12, 18, 24, 48, or 72 hours, or a range defined by any two of the foregoing values, or for a period of at least 2, 3, 4, 5, 6, 12, 18, 24, 48, or 72 hours, or at least a range defined by any two of the foregoing values. In some embodiments, the animal has not been administered a corticosteroid, other than the corticosteroid of the pharmaceutical composition, for a period of 2-72, 3-72, 4-72, 5-72, 2-24, 3-24, 5-24, 2-48, 3-48, 4-48, 5-48, 6-72, 6-48, 12-72, or 18-72 hours, or at least 2-72, 3-72, 4-72, 5-72, 2-24, 3-24, 5-24, 2-48, 3-48, 4-48, 5-48, 6-72, 6-48, 12-72, or 18-72 hours prior to administration of the adenoviral-based delivery and expression system.

[0053] In some embodiments, in any one of the methods disclosed herein, the method comprises systemic administration of a corticosteroid pharmaceutical composition and local administration of an adenovirus-based delivery and expression system pharmaceutical composition. In some embodiments, the method comprises local administration of a corticosteroid pharmaceutical composition and an adenovirus-based delivery and expression system to the same location on an animal. In some embodiments, the method comprises local administration of a corticosteroid pharmaceutical composition and an adenovirus-based delivery and expression system by injection, by inhalation, intraocularly, or intraauricularly. In some embodiments, the method comprises administration of a corticosteroid pharmaceutical composition and an adenovirus-based delivery and expression system by injection, wherein the administration of the corticosteroid and the adenovirus-based delivery and expression system is via the same needle, and the needle is maintained at the same site during administration of both the corticosteroid and the adenovirus-based delivery and expression system. In some embodiments, the needle is flushed with a fluid, e.g., saline, between administration of the corticosteroid and administration of the adenovirus-based delivery and expression system.

[0054] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method comprises an injection into a joint of an animal, optionally via intratendinous, intramuscular, intraarticular, or subacromial injection. In some embodiments, the injection is an intraarticular injection. In some embodiments, the joint is a knee.

[0055] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method comprises an injection into an intervertebral disc. In some embodiments, the injection is an intradiscal injection. In some embodiments, the intradiscal injection is into the nucleus pulposus (NP) region of the intervertebral disc.

[0056] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method does not include administration into the intervertebral disc. In some embodiments, in any one of the methods of the embodiments disclosed herein, the method does not include administration by intradiscal injection. In some embodiments, in any one of the methods of the embodiments disclosed herein, the method does not include intradiscal injection into the nucleus pulposus (NP) or central gelatinous nucleus pulposus (NP) region of the intervertebral disc.

[0057] In some embodiments, the method does not include expressing IL-IRA in cells of one or more intervertebral discs of a subject suffering from degenerative disc disease (DDD) or a symptom associated with DDD, and the method comprises: a) infecting cells of one or more intervertebral discs of a subject in need thereof with a pharmaceutical composition comprising an adenovirus-based biological delivery and expression system comprising a nucleic acid encoding an interleukin-1 receptor antagonist (IL-1Ra) protein, and b) expressing IL-1Ra in cells of the one or more intervertebral discs. In some embodiments, the method does not comprise administering a corticosteroid and / or a local anesthetic into the subject's intervertebral disc. In some embodiments, the method does not include a method in which the corticosteroid and / or local anesthetic are present in a single pharmaceutical formulation with the adenovirus-based biological delivery and expression system, such that the corticosteroid and / or local anesthetic are administered into the subject's intervertebral disc simultaneously with the adenovirus-based biological delivery and expression system. In some embodiments, the method does not include a method in which the corticosteroid and / or local anesthetic are not present in a single pharmaceutical formulation with the adenovirus-based biological delivery and expression system, such that the corticosteroid and / or local anesthetic are administered into the subject's intervertebral disc before and / or after the adenovirus-based biological delivery and expression system. In some embodiments, the method does not include intradiscal injection of the corticosteroid and / or local anesthetic and / or fluid.

[0058] In some embodiments, the method does not further comprise administering a corticosteroid, such as methylprednisolone, betamethasone, triamcinolone, or a combination thereof, into the subject's intervertebral disc.In some embodiments, the method does not comprise a corticosteroid formulated in a single pharmaceutical composition with an adenovirus-based biological delivery and expression system, so that the corticosteroid is administered into the subject's intervertebral disc simultaneously with the adenovirus-based biological delivery and expression system.In some embodiments, the method does not comprise a corticosteroid in a dosage form separate from the adenovirus-based biological delivery and expression system, so that the corticosteroid can be administered into the subject's intervertebral disc before or after administering the adenovirus-based biological delivery and expression system into the subject's intervertebral disc.In some embodiments, the method does not further comprise administering both a corticosteroid and a local anesthetic into the subject's intervertebral disc. In some embodiments, the method does not include one or both of the corticosteroid and the local anesthetic formulated in a single pharmaceutical composition with the adenovirus-based biological delivery and expression system, such that the corticosteroid and / or the local anesthetic are administered into the subject's intervertebral disc simultaneously with the adenovirus-based biological delivery and expression system. In some embodiments, the method does not include one or both of the corticosteroid and the local anesthetic in a dosage form(s) separate from the adenovirus-based biological delivery and expression system, such that the corticosteroid and / or the local anesthetic can be administered before or after administration of the adenovirus-based biological delivery and expression system to the subject's intervertebral disc.

[0059] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method comprises treating a disease or condition. In some embodiments, the method comprises identifying the animal as suffering from or at risk of suffering from the disease or condition to be treated prior to administering the pharmaceutical composition. In some embodiments, the disease or condition is camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome; a musculoskeletal disease or condition; a joint disease or condition; a pulmonary disease or condition; an eye disease or condition; an ear disease or condition; arthropathy, arthritis, or an arthritis-related condition; osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, Reiter's syndrome, or tendinopathy, including tendinosis and tenosynovitis; synovial disorders, including synovitis; bursal disorders, including bursitis; or equine musculoskeletal disorders, including hock enlargement, navicular syndrome, and coronoid phalangeal cyst. In some embodiments, the disease or condition is degenerative disc disease (DDD) or a condition associated with DDD.

[0060] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method includes treating a disease or condition, wherein the disease or condition is not degenerative disc disease (DDD) or a condition associated with DDD.

[0061] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method includes treating a disease or condition, wherein the disease or condition is osteoarthritis or a symptom of osteoarthritis, optionally of the knee. In some embodiments, the animal is a mammal. In some embodiments, the animal is a human. In some embodiments, the animal is a horse, dog, or cat. In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×106 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8, 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of, if necessary, at least 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10, 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 The following, if necessary, 2.8 x 10 9 , 2.8×10 10 , 2.8×10 11The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector with a genome copy (GC) of 10% to 90%, 10% to 50%, 30% to 80%, 50% to 90%, or 10% to 50% of the typical and / or publicly disclosed amount of a recombinant adenovirus vector or a helper-dependent adenovirus vector administered to an animal of the same species by the same route of administration for the treatment of the same or similar disease or disorder. In some embodiments, the amount of vector administered to an animal is reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or a range defined by any two of the foregoing values, as appropriate, 10% to 90%, 10% to 50%, 30% to 80%, or 50% to 90%, or 10% to 50% of the typical and / or publicly disclosed amount of a recombinant adenovirus vector or a helper-dependent adenovirus vector administered to an animal of the same species by the same route of administration for the treatment of the same or similar disease or disorder. In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12, 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×109 ~7.0×10 10 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10The recombinant adenoviral vector or helper-dependent adenoviral vector is a viral particle (VP) of: In some embodiments, the pharmaceutical composition is liquid and has a volume of 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0 up to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally 2.0, 2.5 or 5.0 ml, optionally 5.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or at least the aforementioned or less than a range defined by any two of the values, optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml, optionally at least 2.0, 2.5, or 5.0 ml, optionally at least 5.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4 or less than 0.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or less than a range defined by any two of the preceding values, or less than 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0-6.0 ml, or less than 2.0, 2.5 or 5.0 ml, or less than 10 ml, or less than 10 ml, or less than 20 ml, or less than 50 ml, or less than 10 ... In some embodiments, the pharmaceutical composition is a liquid and the amount of pharmaceutical composition administered to the animal is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10 , 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 5.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or at least the aforementioned values. It is equal to or less than a range defined by any two of the above, optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 5.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5 0.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml, optionally 1.0, 2.0, 2.5, or 5.0 ml, optionally 5.0 ml or less. In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the amount of vector administered to the animal is 1.4x10 5 , 1.4x10 6 , 2.8x10 6 , 7.0x10 6 , 1.4x10 7 , 2.8x10 7 , 7.0x107 , 1.4x10 8 , 2.8x10 8 , 7.0x10 8 , 1.4x10 9 , 2.8x10 9 , 7.0x10 9 , 1.4x10 10 , 2.8x10 10 , 7.0x10 10 , 1.4x10 11 , 2.8x10 11 , 7.0x10 11 , 1.4x10 12 , 2.8x10 12 , 7.0x10 12 , 1.4x10 13 , 2.8x10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 , 1.4 x 10, if necessary 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 , 5.6 x 10, if necessary 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 of, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×109 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8, 1.4×10 9 ~7.0×10 10 , 1.4 x 10, if necessary 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 , 5.6 x 10, if necessary 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 ,,Atata is 1.4 x 10 12 of, if necessary, at least 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, at least 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12, 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 , 1.4 x 10, if necessary 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 , 5.6 x 10, if necessary 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 The following, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 The following, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12In some embodiments, the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the amount of vector administered to the animal is 1.4 x 10 genome copies (GC). 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or in a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 , 1.4 x 10, if necessary 5 , 1.4×10 7, 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 , 5.6 x 10, if necessary 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 of, if necessary, 1.4 x 10 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, if necessary, 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of at least 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×10 10 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13of, or at least in the range defined by any two of the preceding values, as appropriate, at least 1.4 × 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 , 1.4 x 10, if necessary 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 , 5.6 x 10, if necessary 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 of, if necessary, at least 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12 of, or 1.4 x 10 5 , 1.4×10 6 , 2.8×10 6 , 7.0×10 6 , 1.4×10 7 , 2.8×10 7 , 7.0×10 7 , 1.4×10 8 , 2.8×10 8 , 7.0×10 8 , 1.4×10 9 , 2.8×10 9 , 7.0×10 9 , 1.4×10 10 , 2.8×1010 , 7.0×10 10 , 1.4×10 11 , 2.8×10 11 , 7.0×10 11 , 1.4×10 12 , 2.8×10 12 , 7.0×10 12 , 1.4×10 13 , 2.8×10 13 , 7.0×10 13 or a range defined by any two of the preceding values, as appropriate, 1.4 x 10 5 ~7.0×10 13 , 1.4×10 5 ~7.0×10 12 , 1.4×10 5 ~7.0×10 11 , 1.4×10 5 ~7.0×10 10 , 1.4×10 5 ~7.0×10 9 , 1.4×10 5 ~7.0×10 8 , 1.4×10 9 ~7.0×10 10 , 1.4 x 10, if necessary 5 , 1.4×10 7 , 5.6×10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12 , 5.6 x 10, if necessary 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 , or 1.4 × 10 12In some embodiments, the concentration of the corticosteroid in the pharmaceutical composition is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1- 100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, 40 mg / ml if necessary, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or at least any two of the preceding values A range defined by the above, as appropriate, at least 0.001 to 5000, 0.001 to 0.1, 0.001 to 10, 0.1 to 100, 1.0 to 100, 1.0 to 50, 30 to 300, 25 to 60, 30 to 50, 100 to 1000, 500 to 5000 mg / ml, as appropriate, at least 40 mg / ml, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, Not more than 90, 100, 250, 500, 750, 1000, 2500, or 5000, or not more than a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml or less.In some embodiments, the pharmaceutical composition is a liquid and has a volume of 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml. ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or at least equal to or less than a range defined by any two of the foregoing values, optionally at least 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 1.0 ml, or not more than 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or not more than a range defined by any two of the foregoing values, optionally not more than 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml, optionally not more than 1.0, 2.0, 2.5, or 5.0 ml, optionally not more than 1.0 ml.In some embodiments, the pharmaceutical composition is a liquid and the amount of pharmaceutical composition administered to the animal is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10 , 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml, optionally 1.0, 2.0, 2.5, or 5.0 ml, optionally 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or at least the aforementioned values. is equal to or less than a range defined by any two of the following: optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5, or 4.0 to 6.0 ml; optionally at least 1.0, 2.0, 2.5, or 5.0 ml; optionally at least 1.0 ml; or optionally at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5 or less than 0.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or less than a range defined by any two of the preceding values; optionally, 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml; optionally, 1.0, 2.0, 2.5, or 5.0 ml; optionally, 1.0 ml or less.In some embodiments, the amount of corticosteroid administered to the animal is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0 1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg, or, as appropriate, 40 mg, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or at least any of the aforementioned values A range defined by two, if necessary, of at least 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg, if necessary, of at least 40 mg, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, Not more than 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or not more than a range defined by any two of the foregoing values, or, as appropriate, 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg or less, or, as appropriate, 40 mg or less.

[0062] In some embodiments, in any one of the methods of the embodiments disclosed herein, the method comprises identifying a human subject as suffering from osteoarthritis of the knee; administering to said human subject a pharmaceutical composition by intra-articular injection into the knee joint affected by osteoarthritis, wherein the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system, wherein administering the corticosteroid comprises intra-articular injection of 1 ml of a dosage form comprising 40 mg / ml of corticosteroid, and wherein administering the adenovirus-based biological delivery and expression system comprises intra-articular injection of 2.8 x 10 per ml of the adenovirus-based biological delivery and expression system, if desired. 9 , 2.8×10 10 , 2.8×10 11 and the amount of adenovirus-based biological delivery and expression system delivered to the knee is 5.6 x 10 9 , 7.0×10 9 , 1.4×10 10 , 1.4×10 11 or 1.4 x 10 12The adenoviral vector is a recombinant adenoviral vector or a helper-dependent adenoviral vector of a genome copy (GC) of a corticosteroid, wherein the administration of the corticosteroid and the adenoviral-based delivery and expression system is via the same needle, the needle is maintained at the same site during administration of both the corticosteroid and the adenoviral-based delivery and expression system, and, if necessary, the needle is flushed with fluid between administration of the corticosteroid and the adenoviral-based delivery and expression system, and the corticosteroid is administered 0 to 15 minutes or less before administration of the adenoviral-based delivery and expression system. In some embodiments, the corticosteroid is administered 0 to 5 minutes or less before administration of the adenoviral-based delivery and expression system. In some embodiments, the adenovirus-based delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding the human IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human IL-1Ra protein. In some embodiments, the genome of the helper-dependent adenovirus vector has the nucleic acid sequence of SEQ ID NO: 7. In some embodiments, the corticosteroid is methylprednisolone.

[0063] Uses and Kits In some embodiments, a kit comprises any one of the pharmaceutical compositions of the embodiments disclosed herein, wherein the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system, and the kit comprises a first container comprising the corticosteroid in a first dosage form and a second container comprising the adenovirus-based biological delivery and expression system in a second dosage form.

[0064] In some embodiments, a kit for use in preparing any one of the pharmaceutical compositions of the embodiments disclosed herein, wherein the corticosteroid is in the same dosage form as an adenovirus-based biological delivery and expression system, the kit comprising a composition comprising the corticosteroid in a first container and a composition comprising the adenovirus-based biological delivery and expression system in a second container.

[0065] In some embodiments, the composition or kit of any one of the embodiments disclosed herein is for use in a method for treating a disease or condition, including any one of the methods disclosed in any one of the embodiments disclosed herein. In some embodiments, the kit comprises a first container containing a corticosteroid in a first dosage form and a second container containing an adenovirus-based biological delivery and expression system in a second dosage form. In some embodiments, the corticosteroid or the adenovirus-based biological delivery and expression system is provided as disclosed in any embodiment disclosed herein. In some embodiments, the pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system according to any one of the embodiments disclosed herein is for use as a medicament. In some embodiments, the kit comprises a first container containing a corticosteroid in a first dosage form and a second container containing an adenovirus-based biological delivery and expression system in a second dosage form according to any one of the embodiments disclosed herein is for use as a medicament. In some embodiments, a pharmaceutical composition comprising a corticosteroid according to any one of the embodiments disclosed herein and an adenovirus-based delivery and expression system is for use in the prevention or treatment of a disease or condition. In some embodiments, a kit comprising a first container comprising a first dosage form of a corticosteroid according to any one of the embodiments disclosed herein and a second container comprising a second dosage form of an adenovirus-based biological delivery and expression system is for use in the prevention or treatment of a disease or condition.In some embodiments, the disease or condition is selected from the group consisting of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome; a musculoskeletal disease or condition; a joint disease or condition; a pulmonary disease or condition; an eye disease or condition; an ear disease or condition; arthropathy, arthritis, and arthritis-related conditions; osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, Reiter's syndrome, or tendinopathy, including tendinosis and tenosynovitis; synovial disorders, including synovitis; bursal disorders, including bursitis; or equine musculoskeletal disorders, including hock enlargement, navicular syndrome, and ball and foot ulcer. In some embodiments, the disease or condition is degenerative disc disease (DDD) or a condition associated with DDD. In some embodiments, the disease or condition is not degenerative disc disease (DDD) or a condition associated with DDD.

[0066] PCRX201 In some embodiments, in the pharmaceutical composition, kit, method, or use according to any one of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system is PCRX 201. In some embodiments, in the pharmaceutical composition, kit, method, or use according to any one of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system is a helper-dependent adenovirus, the genome of which consists of the nucleic acid of SEQ ID NO: 7.

[0067] In some embodiments, in the pharmaceutical composition, kit, method, or use according to any one of the embodiments disclosed herein, the adenovirus-based biological delivery and expression system provides long-term expression of IL-1Ra in cells in human joints for the treatment and prevention of osteoarthritis. In some embodiments, the adenovirus-based biological delivery and expression system for IL-1Ra gene therapy is PCRX201 (humantakinogene hadenovec, also referred to herein as FX201 or PCRX-201) for intra-articular (IA) administration, which is being developed for the treatment of osteoarthritis or osteoarthritis symptoms in patients / animals. PCRX201 is a helper-dependent adenovirus (HDAd) that delivers a nucleic acid sequence encoding human IL-1Ra under the control of a nuclear factor-κB (NF-κB)-inducible promoter for IA administration to patients / animals with osteoarthritis or osteoarthritis symptoms. After intravenous injection, PCRX201 infects cells in the joint and produces IL-1Ra locally in response to inflammation. PCRX201 is a non-replicating, non-integrating HDAd vector engineered to carry the gene coding sequence for IL-1Ra, but without any viral coding sequence. Only the adenoviral packaging signal and inverted terminal repeats (ITRs) remain in the PCRX201 genome, as they are required for production. Transcription is regulated by an inflammation-sensitive NF-κB-inducible promoter, which drives the expression of IL-1Ra in response to an inflammatory environment.

[0068] PCRX201 can be administered as a single dose via intravenous injection. The expected clinical benefits are sustained symptomatic relief, including both pain reduction and improved or restored function, as well as beneficial alterations of the underlying disease process in patients with osteoarthritis or osteoarthritis symptoms in human joints. Advantageously, the adenoviral delivery and expression system of the present disclosure specifically localizes to the joint when administered intra-articularly. Most importantly, no measurable concentrations of vector sequences were detected in the livers of mice treated with the adenoviral system of the present disclosure. Therefore, IL-1Ra concentrations are expected to be highest in joints injected with the vector of the present disclosure, while no significant side effects are expected in any other organs. The properties of PCRX201 are described below. Administration of the corticosteroids disclosed herein improves one or more measures of the efficacy and / or safety of PCRX201.

[0069] Vector backbone: PCRX201 is a non-replicating, non-integrating HDAd vector. The genomic components consist of double-stranded linear DNA approximately 29.3 kilobases (kb) in size. Annotated sequences obtained by next-generation sequencing confirm the essential elements in the PCRX201 genome. The PCRX201 genome contains the minimal adenoviral elements required for amplification and packaging to enable its production: left and right inverted terminal repeats (hereafter referred to as "L ITR" and "R ITR," respectively) and a packaging signal (Ψ). Approximately 1.1 kb of the PCRX201 genome consists of a nucleic acid sequence encoding human IL-1Ra inserted in a reverse (right-to-left) orientation at the right end of the genome, with a promoter located immediately preceding the R ITR. The promoter is a repeat sequence of NF-κB binding motifs conserved in five species fused to the proximal promoter region of the human ELAM gene, which responds to proinflammatory cytokines (Schindler 1994). Approximately 27 kb of the PCRX201 genome consists of human hypoxanthine phosphoribosyltransferase (HPRT) and a non-coding stuffer sequence composed of a human cosmid insert, which was inserted to expand the PCRX201 genome to a size that allows efficient packaging of the vector genome into each viral particle. An embodiment of a genome map for PCRX201 is presented in Figure 1.

[0070] Gene of interest: The PCRX201 genome contains a 534 base pair (bp) sequence of human IL-1Ra, which is controlled by a 262 bp sequence of an NF-κB inducible promoter.

[0071] A genetic map of PCRX201, an embodiment of the HDAd vector of the present disclosure, is disclosed herein ( FIG. 2 ). All three vectors contain an inflammation-sensitive NF-κB5-ELAM promoter upstream of the IL-1Ra cDNA set forth in any one of SEQ ID NOs: 1 or 4, as well as ITRs and an adenovirus packaging signal. The complete vector sequences of GQ-201, HDAd-mIL-Ra, and HDAd-human IL-1Ra are shown in SEQ ID NOs: 2, 3, and 7, respectively. The only difference between the three vectors is that GQ-201 carries the equine variant of IL-1Ra, HDAd-mIL-Ra has the murine IL-1Ra variant, and HDAd-huIL-1Ra carries human IL-1Ra. As an example, the HDAd-mIL-Ra of the nucleic acid sequence set forth in SEQ ID NO: 3 can contain a nucleic acid encoding the murine IL-1Ra set forth in SEQ ID NO: 1. As an example, the HDAd-mIL-Ra of the nucleic acid sequence set forth in SEQ ID NO: 7 can contain a nucleic acid encoding the murine IL-1Ra set forth in SEQ ID NO: 4. These vectors can be prepared by methods known in the art, for example, as disclosed in this disclosure and in WO 2021 / 0055860, the disclosure of which is incorporated herein by reference in its entirety.

[0072] In some embodiments, the helper-dependent adenoviral vector of the present disclosure, such as PCRX201, does not carry any viral sequences except for the L ITR, R ITR, and adenoviral packaging signal. Exemplary helper-dependent adenoviral vectors used in embodiments of the present disclosure are based on the helper virus and helper-dependent backbone system developed by Palmer and Ng (Palmer, D., and Ng, P. (2003). Improved system for helper-dependent adenoviral vector production. Mol Ther 8, 846-852.) and Toietta et al. (Toietta, G., Pastore, L., Cerullo, V., Finegold, M., Beaudet, AL, and Lee, B. (2002). Generation of helper-dependent adenoviral vectors by homologous recombination. Mol Ther 5, 204-210.). In some embodiments, an adenoviral delivery and expression system according to the present disclosure can comprise a nucleic acid sequence, or a biologically effective portion thereof, of an adenovirus-based biological delivery and expression system comprising a promoter, a nucleic acid sequence encoding IL-1Ra, left and right inverted terminal repeats, an adenoviral packaging signal, and a non-viral non-coding stuffer nucleic acid sequence, as set forth in SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:7. The nucleic acid sequence of SEQ ID NO:2 describes a mouse helper-dependent adenoviral vector, the sequence set forth in SEQ ID NO:3 describes an equine helper-dependent adenoviral vector, and the sequence set forth in SEQ ID NO:7 describes a human helper-dependent adenoviral vector, all three vectors carrying either a mouse, equine, or human IL-1Ra gene, respectively. In some embodiments, the system of the present disclosure has at least 96%, 97%, 98%, or 99% sequence identity to the vector set forth in SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:7.

[0073] "Long-term expression," in the context of the present disclosure, has its ordinary and customary meaning when read in light of the present disclosure, and includes the meaning that the gene product of the adenoviral delivery and expression system (e.g., IL-1Ra) is expressed for at least 3 months, 6 months, or 12 months in the joint(s) infected with the helper-dependent adenoviral vector of the present disclosure. In some embodiments, IL-1Ra is expressed for at least 3 months in the joint(s) infected with the helper-dependent adenoviral vector of the present disclosure.

[0074] In some embodiments, the helper-dependent adenoviral vector of the present disclosure contains a nucleic acid sequence encoding IL-1Ra under the control of an inflammation-sensitive promoter. Although IL-1Ra contains a species-specific nucleic acid sequence, the adenoviral vector can express interleukin-1 receptor antagonist (IL-1Ra) from any mammalian species or human. In some embodiments, the mammalian interleukin-1 receptor antagonist (IL-1Ra) cDNA used for cloning is a cDNA selected from the group consisting of human IL-1Ra, mouse IL-1Ra, equine IL-1Ra, canine IL-1Ra, feline IL-1Ra, rabbit IL-1Ra, hamster IL-1Ra, bovine IL-1Ra, camel IL-1Ra, or their homologs in other mammalian species.

[0075] In some embodiments, to monitor the presence of genomic vector sequences in synovial cells, the helper-dependent adenoviral vectors of the present disclosure can further comprise a sequence encoding a visually or instrumentally detectable marker gene. In some embodiments, the marker gene is green fluorescent protein (GFP), LacZ, or luciferase enzyme.

[0076] In some embodiments, the nucleic acid sequence of human IL-1Ra used in the present disclosure is set forth in the sequence listing as SEQ ID NO:4. As stated herein, in some embodiments, a nucleic acid sequence resulting in a human biologically active IL-1Ra protein is used in the context of the present disclosure. In some embodiments, a conserved nucleic acid sequence encoding the same amino acid, polypeptide, or protein is used in an embodiment of the present disclosure. In some embodiments, a helper-dependent adenoviral vector according to the present disclosure contains a nucleic acid sequence (e.g., a cDNA) of IL-1Ra having at least 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:4. In some embodiments, the nucleic acid sequence encodes a human IL-1Ra protein whose amino acid sequence is identical to SEQ ID NO:6 or at least 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0077] In some embodiments, a pharmaceutical composition comprising a corticosteroid and an adenovirus-based biological delivery and expression system is provided for the treatment of osteoarthritis or osteoarthritis symptoms in a human joint, or for the prevention of osteoarthritis or osteoarthritis symptoms in a human identified as being at risk for developing such symptoms. In some embodiments, the adenovirus-based biological delivery and expression system is PCRX201. In some embodiments, the adenovirus-based biological delivery and expression system is: a) 1.4x10 per ml; 8 ~1.4x10 12 a) helper-dependent adenoviral vectors of GC (GC / ml); b) less than 15% helper virus particles; c) less than 10% empty capsids; d) less than 100 μg / ml host cell protein; e) less than 20 ng / ml host cell nucleic acid; f) less than 35 EU / ml endotoxin; and g) 300 GC / TCID 50 The following viral particle to infectious unit ratios are included:

[0078] In some embodiments, PCRX201 can quantify vectors using Droplet Digital™ polymerase chain reaction (ddPCR). In some embodiments, Table 1 below can be used to convert GC / dose to VP / dose, or vice versa. Table 1: Comparison of VP / dose and GC / dose [Table 1]

[0079] Pharmaceutical preparations In some embodiments, in any one of the pharmaceutical compositions of the embodiments disclosed herein, the composition is formulated using methods known in the art, such as those disclosed in this disclosure and WO 2021 / 0055860, which is incorporated herein by reference in its entirety. Such compositions typically comprise a helper-dependent adenoviral vector virus particle disclosed herein, a helper adenovirus, and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" has its ordinary and customary meaning when read in light of the present disclosure and may include any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with the intended route of administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference in its entirety. In some embodiments, examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used.The use of such media and agents for pharmaceutically active substances is well known in the art.Except when conventional media or agents are incompatible with active compounds, they are contemplated for some embodiments to be used in compositions.In some embodiments, auxiliary active compounds are also incorporated into compositions.

[0080] In some embodiments, any one of the pharmaceutical compositions of the embodiments disclosed herein is formulated to be compatible with its intended route of administration as disclosed herein. Examples of routes of administration, some of which are used in the embodiments disclosed herein, include parenteral, e.g., intraarticular, intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Examples of solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citrate, or phosphate, and an agent for adjusting isotonicity, such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0081] In some embodiments, pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In some embodiments, the composition must be sterile and fluid to the extent that easy syringability exists. In some embodiments, the composition is stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi. In some embodiments, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, the prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0082] In some embodiments, sterile injectable solution can be prepared by incorporating the active compound in the required amount in suitable solvent with one or combination of the above-listed components as needed, and then sterilize by filtration.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components that are required from the above-listed components.For the preparation of sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which makes the powder of active ingredient plus any additional desired components from the solution that has been previously sterilized and filtered.

[0083] Chemical Characteristics of the Adenoviral Expression and Delivery System of the Present Disclosure In some embodiments, the capsid of any embodiment of the adenovirus-based biological delivery and expression system disclosed herein, such as PCRX201, is not enveloped and can contain 29.3 kb of double-stranded DNA. In some embodiments, the theoretical molecular weight of the capsid can be 103.9 megadaltons (MDa), and the genome can be 18.1 MDa. In some embodiments, the capsid of PCRX201 can have a diameter of approximately 100 nm.

[0084] Formulation: In some embodiments, PCRX201 is formulated in a buffer consisting of about 1-20 mM TRIS, about 50-100 mM NaCl, 0.01-1% weight / volume (w / v) polysorbate 80, 1-10% (w / v) sucrose, 0.1-10 mM MgCl2, 50-500 μM EDTA, 1-5% volume / volume (v / v) ethanol, and 5-50 mM L-histidine. In some embodiments, PCRX201 may be formulated in a buffer composed of 10 mM TRIS, 75 mM NaCl, 0.02% (weight / volume (w / v)) polysorbate 80, 5% (w / v) sucrose, 1.0 mM MgCl, 100 μM EDTA, 0.5% (volume / volume (v / v) ethanol), and 10 mM L-histidine. In some embodiments, the product may be a clear to slightly opalescent, colorless suspension containing no visible particulates. In some embodiments, the formulation further comprises a corticosteroid. In some embodiments, the concentration of the steroid is 5-10 or 8 mg / ml.

[0085] Storage Conditions and Stability: In some embodiments, PCRX201 is stored as a frozen liquid at -65°C or below. In some embodiments, PCRX201 formulations are stable for at least 3 months, at least 6 months, or at least 12 months when stored at -65°C. Once thawed, the product should be stored at 2-8°C and used within 7 days. PCRX201 can be kept at room temperature (RT) for some period of time. Once the vial is ready for use, PCRX201 can be kept at RT in the vial for no more than 7 hours (vials kept at RT cannot be returned to refrigeration for later use). Once the PCRX201 dose is prepared in the syringe, it should be kept at RT and used within 4 hours.

[0086] Treatment Monitoring In some embodiments, in any one of the methods disclosed herein, the method improves one or more of the transduction, expression, efficacy, and / or safety of the adenovirus-based delivery and expression system when administered to an animal compared to administration of the same pharmaceutical composition without a corticosteroid. In some embodiments, the improvement is an improvement in one or more measures of pain, physical function, patient global assessment, or joint imaging in a human requiring treatment. In some embodiments, the improvement is an improvement in the efficacy or progression of treatment of osteoarthritis or symptoms of osteoarthritis in a human joint, such as an improvement in a measure of osteoarthritis using the Western Ontario-McMaster Universities Osteoarthritis (WOMAC) index, e.g., WOMAC-A. In some embodiments, the improvement is an improvement in a measure of osteoarthritis using the Knee Injury and Osteoarthritis Outcome Score (KOOS). In some embodiments, the improvement is an improvement in a measure of osteoarthritis using the average daily pain (ADP) scoring system. In some embodiments, the improvement is an improvement in a measure of osteoarthritis using the WOMAC, KOOS, and ADP. In some embodiments, the improvement is an improvement in a measure of osteoarthritis using a human joint physical examination requiring a physical examination of the joint for any one or all of joint pain, joint stiffness, crepitus, redness, tenderness, Baker's cysts, and joint swelling, or a combination thereof. In some embodiments, the improvement is an improvement in a measure of depression, sleep deprivation, hyperalgesia, central sensitization, and catastrophizing, or a combination thereof, in a human subject. In some embodiments, the improvement is an improvement in a measure of osteoarthritis using radiography to assess osteophyte formation and joint space narrowing (JSN). In some embodiments, the improvement is an improvement in a measure of osteoarthritis using any one or combination of magnetic resonance imaging (MRI), ultrasound (US), and optical coherence tomography (OCT).In some embodiments, the improvement is an improvement in measurements of interleukin-1 receptor antagonist (IL-1Ra) and interleukin-1β (IL-1β) protein concentrations in the treated knee. In some embodiments, the improvement is an improvement in a measure of the immunological response to the helper-dependent adenoviral vector (HDAd) of the present disclosure. In some embodiments, the improvement is an improvement in a measure of osteoarthritis using blood samples from humans treated with the pharmaceutical compositions or methods of the present disclosure for the presence of anti-capsid and anti-IL-1Ra antibodies. In some embodiments, the improvement is an improvement in a measure of osteoarthritis using IL-1Ra and IL-1β protein concentrations in IA synovial fluid samples from humans treated with the pharmaceutical compositions or methods of the present disclosure.

[0087] Subjects, osteoarthritis and osteoarthritis symptoms In some embodiments, in any one of the methods disclosed herein, the method comprises treating a human suffering from osteoarthritis or osteoarthritis symptoms. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms is between 30 and 80 years old. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms is over 80 years old. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has osteoarthritis of a joint. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has osteoarthritis of the shoulder, hip, ankle, knee, hand, or spine. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has osteoarthritis of the knee (OAK). In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has painful OA of the index knee with Kellgren-Lawrence (KL) grade 2, 3, or 4. In some embodiments, the human suffers from osteoarthritis or osteoarthritis symptoms caused by aging, sex-related (female) predisposition, obesity, metabolic disease, joint injury, repetitive stress on the joint, genetic predisposition, or bone deformity, or a combination thereof. In some embodiments, the human suffers from osteoarthritis or osteoarthritis symptoms caused by joint injury leading to cartilage tear, joint dislocation, or ligament injury, or a combination thereof. In some embodiments, the human suffers from osteoarthritis or osteoarthritis symptoms caused by anterior cruciate ligament (ACL) strain and tear. In some embodiments, the human suffers from osteoarthritis or osteoarthritis symptoms caused by meniscus strain and tear.

[0088] In some embodiments, a human suffering from osteoarthritis or symptoms of osteoarthritis has a blood cholesterol level of 40 kilograms per meter squared (kg / m 2) or less. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has symptoms associated with OA in the index knee for 12 months or more. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has index knee pain for more than 15 days in the most recent month prior to treatment with a pharmaceutical composition or method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has any one or a combination of the following characteristics defined by the American College of Rheumatology (ACR) criteria (clinical and radiological) for OA: a) knee pain, b) at least one of: (i) age > 50 years; (ii) morning stiffness < 30 minutes; and (iii) creaking knee during movement, and c) bone spurs.

[0089] In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has failed two or more conservative treatments for index knee osteoarthritis. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms may have failed a structured land-based exercise program. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has failed previous treatment with a topical nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has failed previous treatment with a topical nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has failed previous treatment with a nonselective NSAID or COX-2 inhibitor. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has failed one prior type of conservative treatment and at least one prior index knee IA treatment (corticosteroids or hyaluronic acid).

[0090] In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has a Kellgren-Lawrence (KL) grade of 2 in the index knee based on x-rays and physical examination. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has a Kellgren-Lawrence (KL) grade of 3 in the index knee based on x-rays and physical examination. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has a Kellgren-Lawrence (KL) grade of 4 in the index knee based on x-rays and physical examination.

[0091] In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has an index knee, and the area intended for injection of the pharmaceutical composition of the present disclosure does not contain any signs of local or joint infection. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has a Western Ontario-McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a 0-10 numeric rating scale [NRS] scale) in the index knee between 4.0 and 9.0, inclusive. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms is a non-pregnant female or a female who is able to use one or more methods of contraception at the time of or for at least 12 months after treatment with a pharmaceutical composition or method of the present disclosure.

[0092] In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms does not have a current or previous diagnosis of reactive arthropathy, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms does not have current clinical signs and symptoms of active crystal disease, including gout, calcium pyrophosphate deposition disease, in the index knee. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms does not have current clinical signs and symptoms of active crystal disease within three months prior to treatment with a pharmaceutical composition or method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms is not unable to undergo magnetic resonance imaging (MRI) due to the presence of surgical hardware or other foreign material in the index knee. In some embodiments, the human suffering from osteoarthritis or symptoms of osteoarthritis does not have an unstable index knee joint.

[0093] In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not received prior treatment with intra-articular (IA) drugs / biologics in the index knee within 6 months of treatment with the pharmaceutical composition or method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not received treatment with any one or combination of corticosteroids, hyaluronic acid, platelet-rich plasma, stem cells, prolotherapy, and amniotic fluid injections within 6 months of treatment with the pharmaceutical composition or method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not received cold or radiofrequency nerve ablation of the index knee within 12 months of treatment with the pharmaceutical composition or method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not received arthroscopic or open surgery on the index knee within 12 months of treatment with the pharmaceutical composition or method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not planned or anticipated surgery on the index knee within 12 months of treatment with a pharmaceutical composition or by a method of the present disclosure, hi some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not suffered from loss of skin integrity over the index knee where the intra-articular injection is given.

[0094] In some embodiments, a human suffering from osteoarthritis or osteoarthritis symptoms may not have any clinical laboratory evidence of infection with human immunodeficiency virus (HIV), a positive test for hepatitis B surface antigen (HBsAg), or positive serology for hepatitis C virus (HCV) with a positive test for hepatitis C viral ribonucleic acid (HCV RNA).

[0095] In some embodiments, a human suffering from osteoarthritis or osteoarthritis symptoms may not exhibit any ECG abnormalities. In some embodiments, a human suffering from osteoarthritis or osteoarthritis symptoms has not received or used an immunomodulatory agent, immunosuppressant, or chemotherapeutic agent within 5 years of treatment with a pharmaceutical composition or by a method of the present disclosure. In some embodiments, a human suffering from osteoarthritis or osteoarthritis symptoms has not received any previous investigational or approved gene therapy treatment and has no active or history of malignancy within 5 years of treatment with a pharmaceutical composition or by a method of the present disclosure, except for resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively controlled cervical intraepithelial carcinoma.

[0096] In some embodiments, the person suffering from osteoarthritis or osteoarthritis symptoms has not received active pharmacological treatment for depression, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and nonselective serotonin reuptake inhibitors (NSRIs), or tricyclic drugs, unless the dose / regimen has been stable for at least six months prior to treatment with the pharmaceutical composition or method of the present disclosure. In some embodiments, the person suffering from osteoarthritis or osteoarthritis symptoms has not engaged in active substance abuse (drugs or alcohol) or has a history of substance abuse within 12 months prior to treatment with the pharmaceutical composition or method of the present disclosure. In some embodiments, the person suffering from osteoarthritis or osteoarthritis symptoms has not received any investigational drug, biologic, or device within three months prior to treatment with the pharmaceutical composition or method of the present disclosure.

[0097] In some embodiments, the human suffering from osteoarthritis or symptoms of osteoarthritis does not have any systemic or localized bacterial or viral infection that requires an intravenous (IV) antibiotic or antiviral within four weeks prior to treatment with a pharmaceutical composition or by a method of the present disclosure, or an oral antibiotic or antiviral within two weeks prior to treatment with a pharmaceutical composition or by a method of the present disclosure.

[0098] In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has bilateral knee OA and pain in the contralateral knee is not 4.0 or greater (NRS scale of 0-10) within one month prior to treatment with a pharmaceutical composition or by a method of the present disclosure. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms has not undergone previous total or partial knee arthroplasty in the index knee. In some embodiments, the human suffering from osteoarthritis or osteoarthritis symptoms may not have a body temperature above 99.5°F at the time of treatment with a pharmaceutical composition or by a method of the present disclosure.

[0099] In some embodiments, a person suffering from osteoarthritis or symptoms of osteoarthritis may not have a prothrombin time (PT) / international normalized ratio (INR) > 1.5. In some embodiments, a person suffering from osteoarthritis or symptoms of osteoarthritis may not have an activated partial thromboplastin time (aPTT) greater than 5 seconds above the upper limit of normal (ULN).

[0100] In some embodiments, a person suffering from osteoarthritis or symptoms of osteoarthritis may not have alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 1.5 x ULN, alkaline phosphatase (ALP) > 1.5 x ULN, and total bilirubin outside the normal range. In some embodiments, a person suffering from osteoarthritis or symptoms of osteoarthritis may not have a known allergy or sensitivity to acetaminophen.

[0101] In some embodiments, a person suffering from osteoarthritis or osteoarthritis symptoms may not have any clinically significant acute or chronic medical conditions that would prevent the use of IA injection or compromise the person's safety. In some embodiments, a person suffering from osteoarthritis or osteoarthritis symptoms may not have any bleeding disorders.

[0102] In some embodiments, a person suffering from osteoarthritis or osteoarthritis symptoms is administered aspirin for cardioprotection at a maximum dose of 81 milligrams (mg) per day, provided that the dose is stable for three months prior to treatment with the pharmaceutical composition or by the method of the present disclosure. In some embodiments, a person suffering from osteoarthritis or osteoarthritis symptoms is administered a medical treatment for depression, including an SSRI, SNRI, and NSRI, or a tricyclic drug, provided that the dose / regimen is stable for six months prior to treatment with the pharmaceutical composition or by the method of the present disclosure. In some embodiments, a person suffering from osteoarthritis or osteoarthritis symptoms is administered any treatment or rescue medication for adverse effects associated with treatment with the pharmaceutical composition or by the method of the present disclosure.

[0103] In some embodiments, the person suffering from osteoarthritis or osteoarthritis symptoms has never received any oral NSAIDs, and the local treatment applied to the index knee cannot be any one of topical NSAIDs, capsaicin, lidocaine patch, cannabinoids, aspirin at a dose of more than 325 mg per day, centrally acting analgesics, opioids, muscle relaxants, any intravascular injections in the index knee, cryo- or radiofrequency nerve ablation in the index knee, any investigational drug, device or biologic, any immunomodulatory drug, immunosuppressant or chemotherapeutic agent, or a combination thereof. In some embodiments, the person suffering from osteoarthritis or osteoarthritis symptoms has never received pregabalin or gabapentin. In some embodiments, the person suffering from osteoarthritis or osteoarthritis symptoms has never received oxycodone, hydrocodone, codeine, morphine, or tramadol. In some embodiments, the human suffering from osteoarthritis or symptoms of osteoarthritis has not been administered cyclobenzaprine, tetrazepam, or diazepam, hi some embodiments, the human suffering from osteoarthritis or symptoms of osteoarthritis has not been administered local anesthetics, corticosteroids, hyaluronic acid, platelet-rich plasma, stem cells, prolotherapy, or amniotic fluid injections.

[0104] In some embodiments, a therapeutically effective amount of an adenovirus-based biological delivery and expression system and a corticosteroid is used in any one of the pharmaceutical compositions, methods, kits or uses disclosed herein.As used herein, the "therapeutically effective amount" or "effective amount" of the adenovirus-based biological delivery and expression system and / or a corticosteroid of the present disclosure has its plain and ordinary meaning as understood by those skilled in the art in light of the present disclosure, and generally refers to the amount required to achieve a therapeutic purpose.In some embodiments, this may be a complete to partial recovery from osteoarthritis or osteoarthritis symptoms in the joints of a human subject in need of such a complete to partial recovery.In some embodiments, this may be a partial or complete prevention of the development of osteoarthritis or osteoarthritis symptoms in the progression of osteoarthritis in the joints of a human subject in need of such a partial or complete prevention.

[0105] As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The terms "optional" or "optionally" mean that the subsequently described event or circumstance can or cannot occur, and that the statement includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, a phrase that a composition may optionally include a combination means that the composition may or may not include a combination of different molecules, such that the statement includes both the combination and the absence of the combination (i.e., individual members of the combination). Ranges may be expressed herein as from about one particular value and / or to about another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0106] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art when read in light of the present disclosure. In this disclosure, the singular includes the plural unless the context clearly dictates otherwise. By way of example, the terms "a," "an," and "the" are understood to be singular or plural, and the term "or" is understood to be inclusive. By way of example, "an element" means one or more elements. Throughout this specification, the word "comprising" or variations such as "comprises" or "comprising" are understood to mean the inclusion of the listed element, integer, or step or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step or group of elements, integers, or steps. About can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term "about."

[0107] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The references cited herein are not admitted to be prior art to the claimed disclosure. In the event of a conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. The following references disclose methods, compositions, dosages, administration routes, and sequences related to the present disclosure, and their disclosures are incorporated herein by reference, and each of these references is incorporated herein by reference in its entirety: WO 2013 / 114199, WO 2014 / 115022, WO 2021 / 055860, and PCT / US2022 / 075358.

[0108] The present disclosure is further illustrated by the following non-limiting examples, the teachings and disclosures of which can be generalized and combined with the disclosures set forth above. [Example]

[0109] Example 1: HDAd-mediated gene expression in combination with TAC in vitro Methods: 116 or HEK293 cells were seeded in 12- or 96-well plates in standard cell culture medium. One day later, the cells were infected with the gene therapy vector HDAd-LacZ (a helper-dependent adenovirus vector expressing β-galactosidase (LacZ) under the control of the constitutive CMV promoter) at different multiplicities of infection (MOIs; viral particles per seeded cell) mixed with different amounts / concentrations of the corticosteroids triamcinolone acetonide (TAC; TriamHEXAL®, Hexal AG, Holzkirchen, Germany), betamethasone (Celestan®, MSD, Kenilworth, NJ, USA), or dexamethasone (Lipotalon®, Recordati, Milan, Italy). HDAd-LacZ was produced by GeneQuine Biotherapeutics GmbH (HDAd-LacZ was originally supplied by Baylor College of Medicine, USA). In experiments evaluating different timing or administration of corticosteroids relative to HDAd-LacZ administration, cells were pretreated with TAC 3 hours before infection with HDAd-LacZ (pre-treatment), TAC treatment and HDAd-LacZ infection were performed simultaneously as described above (co-treatment), or cells were treated with TAC 3 hours after infection with HDAd-LacZ (post-treatment). One day later, the supernatant was aspirated, and the cell monolayer was stained for LacZ expression using an X-Gal staining kit according to the manufacturer's instructions (OZ Bioscience, Marseille, France). Macroscopic and microscopic (4x or 10x magnification) photographs of the stained monolayer were taken (blue staining indicates LacZ expression). A preliminary measure of the intensity of staining was semi-quantitatively measured using ImageJ software by converting images to an 8-bit gray scale and drawing a region of interest around the area to be measured. The mean intensity value (on a 0-255 scale; 0 is black and 255 is white) was subtracted from 255, divided by 255, and multiplied by 100. Reported values ​​are on a 0-100 scale (0 is white and 100 is black), with higher values ​​indicating more intense (darker) staining.

[0110] Results: HDAd-mediated LacZ expression was significantly increased by simultaneous exposure to TAC in 116 and HEK293 cells at 428.5 μg / mL (similar to the dose used in humans for intra-articular treatment) and 0.36 μg / mL (a dose extrapolated from humans to rat joints). Figure 3 shows photomicrographs (4x magnification) of 116 cells, and Figure 4 represents a preliminary semiquantitative quantification of LacZ expression in the photographs in Figure 3. Figures 5 and 6 show macroscopic and microscopic (10x magnification) photographs of HEK293 cells. Figures 7 and 8 represent preliminary semiquantitative quantification of LacZ expression in the photographs in Figures 5 and 6, respectively.

[0111] When a dose range of TAC was evaluated in HEK293 cells, enhancement of HDAd-mediated LacZ expression appeared to begin at a concentration of 0.18 ng / mL. Figure 9 shows photomicrographs (10x magnification) of HEK293 cells exposed to various concentrations of TAC (Groups A-K: 2.88 μg / mL to 0.0028125 μg / mL; Group L: 0 ng / mL TAC), and Figure 10 shows preliminary semiquantitative quantification of LacZ expression in the photo from Figure 9. Figure 11 shows photomicrographs (10x magnification) of HEK293 cells exposed to various concentrations of TAC (Groups B-K: 2.8125 ng / mL to 0.005493164 ng / mL; Group L: 0 ng / mL TAC), and Figure 12 shows preliminary semiquantitative quantification of LacZ expression in the photo from Figure 11.

[0112] The enhanced gene expression induced by TAC was most pronounced when HEK293 cells were treated simultaneously with TAC and HDAd-LacZ, compared with 3-hour pretreatment with TAC and treatment with TAC after HDAd-LacZ infection. Figure 13 shows macroscopic photographs, and Figure 14 represents a preliminary semiquantitative quantification of LacZ expression from the photograph in Figure 13. Figure 15 shows a microscope (10x magnification) of the plate shown in Figure 13, and Figure 16 represents a preliminary semiquantitative quantification of LacZ expression from the microscope photograph in Figure 15. Preliminary assessment indicates that simultaneous administration improves staining compared with pretreatment 3 hours before infection, and that pretreatment 3 hours before infection improves staining compared with posttreatment 3 hours after infection.

[0113] Two additional corticosteroids were tested: betamethasone and dexamethasone both increased HDAd-mediated LacZ expression. Figures 17 and 18 are macroscopic and photomicrographs, respectively, and Figure 19 represents a preliminary semiquantitative quantification of LacZ expression from the photomicrograph in Figure 18. For both betamethasone and dexamethasone, enhancement appeared to begin at a concentration of 3.9 ng / mL.

[0114] Example 2: HDAd-mediated gene expression in combination with TAC in rat joints in vivo In vivo studies were performed at Bolder BioPATH (now Inotiv), Boulder, Colorado, USA. The study design and animal use were approved by the Institutional Animal Care and Use Committee (IACUC) at Bolder BioPATH.

[0115] Rats obtained from Envigo (Indianapolis, IN) were housed four per cage in polycarbonate cages. After 4 days of acclimation, animals (average body weight 310 g) were randomly assigned to weight-based groups with six animals per group on study day 0. After randomization, test article administration was performed via intra-articular injection of 50 μL per joint. In each group, animals were treated with 5E7 VP HDAd-LacZ, 5E8 VP HDAd-LacZ, 5E9 VP HDAd-LacZ, 5E10 VP HDAd-LacZ, 5E7 VP HDAd-LacZ + 0.06 mg TAC, 5E8 VP HDAd-LacZ + 0.06 mg TAC, 5E9 VP HDAd-LacZ + 0.06 mg TAC, 5E10 VP HDAd-LacZ + 0.06 mg TAC, or vehicle.

[0116] For the group co-treated with HDAd-LacZ and TAC, a TAC suspension was prepared by diluting a commercially available injection suspension (Kenalog 10, Bristol-Myers Squibb) with isotonic saline solution and added to the HDAd-LacZ preparation (i.e., a 50 μL injection volume of the test article + TAC mixture contained 0.06 mg of TAC).

[0117] At necropsy on study day 4, rats were anesthetized with isoflurane. After knee lavage, knees were harvested and fixed in chilled 2% paraformaldehyde (PFA) for 1 hour, then washed three times with PBS. Joints were incubated in 1.2 mg / mL X-gal solution (pH 7.4) at 37°C for 8 hours (or until the blue color fully developed). Knee joints were photographed, further dissected if necessary, and fixed in 10% neutral buffered formalin (NBF) for an additional 48 hours. Preserved knee joints were decalcified in formic acid, embedded in paraffin, sectioned, and stained with Nuclear Fast Red (NFR) stain. Three sections were cut from each joint.

[0118] Investigators microscopically evaluated tissues for inflammation and X-gal staining in a blinded fashion. An ocular micrometer was used to measure the approximate length of the medial and lateral synovium. The length of the X-gal-stained area was measured, and the length of staining (%) relative to the total area was determined. The width of X-gal labeling extending beyond the synovial lining into the subsynovial periarticular tissue was estimated to approximate the total area (%) of staining. If staining was limited to the synovial lining and immediate subsynovial area, a width metric value of 0.5 units was given. Any width metric value greater than 0.5 indicated that periarticular connective tissue cells (primarily fibroblasts) had staining (extending beyond the lining) in addition to possible synovial cell staining.

[0119] The results of X-gal staining evaluation indicate that intra-articular co-administration of HDAd-LacZ and TAC resulted in increased transduction and higher LacZ expression in synovial tissue, the primary target tissue for HDAd-mediated intra-articular gene therapy (Figures 20 and 21). Figure 22 shows that co-administration of TAC reduced HDAd-LacZ-mediated inflammation. Interestingly, the results of X-gal staining (Figure 20) indicate that co-injection with TAC can result in increased transduction and expression to levels similar to those at 10-fold higher dose levels (31.43% in the 5E10 VP group vs. 32.40% in the 5E9 + TAC group; 23.43% in the 5E9 VP group vs. 21.49% in the 5E8 + TAC group). This finding indicates that co-administration of HDAd vectors with TAC or other corticosteroids can significantly reduce the dose for clinical use. This can reduce production requirements, cost per dose, total viral load to the patient, and drug-related adverse events, if any.

[0120] Example 3: Improved Efficacy and Safety of PCRX201 (also known as FX201) Combined with Corticosteroid Treatment for Knee Osteoarthritis Methods: This Phase 1, open-label, proof-of-concept, single-ascending-dose study enrolled adults aged 30-80 years with moderate to severe knee osteoarthritis (OA) (NCT04119687). Additional inclusion criteria included a Western Ontario-McMaster Universities Osteoarthritis Index pain score (WOMAC-A) ≥ 4.0 and ≤ 9.0, Kellgren-Lawrence (KL) grade 2-4, and prior failure of two or more other treatments for OA. The first half of patients received ultrasound-guided intra-articular injections of 5 ml of PCRX201 into the knee joint at escalating doses of 2.8E9 genome copies (GC) / mL (1.4E10 GC / knee) (low dose), 2.8E10 GC / mL (1.4E11 / knee) (medium dose), and 2.8E11 GC / mL (1.4E12 / knee) (high dose). The second half of patients received a 1 ml intra-articular injection of methylprednisolone (40 mg / ml) immediately before PCRX201 administration at the above dose. Methylprednisolone was administered first, followed by PCRX201 through the same needle without removing the needle from the subject's knee between doses. The primary endpoint was safety, which included adverse event (AE) monitoring, repeated index knee assessments, clinical laboratory evaluations, and biodistribution samples. Efficacy was assessed using change from baseline in pain (WOMAC-A). The current data represent preliminary results based on available data up to 6 months after the last patient treatment dose, without imputation of missing values.

[0121] Results: Seventy-two patients were enrolled and treated, with 36 patients in each cohort (non-methylprednisolone and methylprednisolone). The first patient was dosed in March 2020, and the last in December 2021. As of May 2022, 33% of patients had discontinued the study. Low-, medium-, and high-dose PCRX201 were given to 12, 16, and 8 patients, respectively, in the non-methylprednisolone cohort, and low-, medium-, and high-dose PCRX201 were given to 13, 15, and 8 patients, respectively, in the methylprednisolone cohort. Index knee effusions considered related to PCRX201 were dose-dependent (50%, 56%, and 100% with increasing dose in the non-methylprednisolone cohort and 31%, 27%, and 63% with increasing dose in the methylprednisolone cohort). There were five grade 3 knee events (14%) in the non-methylprednisolone cohort and one (7%) in the methylprednisolone cohort. Most index knee AEs were treated conservatively with rest, ice, acetaminophen, and aspiration of synovial fluid. In the high-dose group, four patients experienced self-limited chills without fever (two in each cohort), and two had concurrent headache (one in each cohort). One patient (high-dose) in the methylprednisolone cohort had flu-like symptoms, and one patient (medium-dose) in the non-methylprednisolone cohort had a self-limited fever at the time of the onset of the knee AE. One patient (medium-dose) in the methylprednisolone cohort experienced severe pain during PCRX201 administration, resulting in premature termination of the injection. There were no other PCRX201-related AEs. Baseline adenovirus status did not predict index knee AEs, and there was no clinical evidence of biodistribution. Pain improvement, assessed by percent change from baseline in WOMAC-A scores, was observed for each dose group within each cohort (Figures 23 and 24). Figure 23 compares methylprednisolone-treated patients with non-methylprednisolone-treated patients for each of the three doses of PCRX201 tested.Figure 24 includes additional data, but is grouped by methylprednisolone treatment status, with pre-treatment referring to administration of methylprednisolone immediately prior to PCRX201, as discussed above. Of note is the overall higher response and onset rate in the methylprednisolone cohort, at least at low and medium doses of PCRX201. Figure 25 shows the incidence of WOMAC-A 50% responders over time for the methylprednisolone-treated and non-treated groups. Of note is the 100% rate of 50% responders in the methylprednisolone cohort at week 52, compared with only a 50% rate in the non-methylprednisolone cohort.

[0122] Conclusions: PCRX201 was generally well tolerated, with a reduction in the incidence and severity of index knee events in the methylprednisolone cohort compared with the non-methylprednisolone cohort. Preliminary efficacy results were promising, suggesting substantial improvement in pain across all doses examined in this phase 1, open-label study, with a faster onset and greater overall response rate observed in the methylprednisolone cohort.

Claims

1. A pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system.

2. 2. The pharmaceutical composition of claim 1, wherein the corticosteroid is a glucocorticoid, a mineralocorticoid, or both.

3. The corticosteroid is Beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, ciclesonide, fluticasone, flunisolide, mometasone and mixtures thereof; Beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, and mixtures thereof; Beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and mixtures thereof; Beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone, and mixtures thereof; Betamethasone, dexamethasone, triamcinolone, methylprednisolone and mixtures thereof; beclomethasone, budesonide, ciclesonide, fluticasone, flunisolide, mometasone and mixtures thereof; and / or Fludrocortisone, deoxycorticosterone, aldosterone, and their mixtures 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is selected from the group consisting of:

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, triamcinolone, methylprednisolone, and mixtures thereof; optionally, the corticosteroid is methylprednisolone; optionally, the corticosteroid is methylprednisolone acetate.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the adenovirus-based delivery and expression system comprises a nucleic acid encoding a protein for expression by the adenovirus-based delivery and expression system; optionally, the protein is a therapeutic protein.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, optionally of the Ad5 serotype.

7. 7. The pharmaceutical composition of claim 6, wherein the helper-dependent adenoviral vector comprises a genome comprising or consisting of the nucleic acid sequence encoding the protein, a promoter controlling the expression of the nucleic acid sequence encoding the protein, left and right inverted terminal repeats, an adenoviral packaging signal, and non-viral and non-coding stuffer nucleic acid sequences, and optionally, the promoter is located upstream of the open reading frame of the nucleic acid sequence encoding the protein so that the expression of the protein is controlled by the promoter.

8. The promoter is a ubiquitous constitutive promoter optionally selected from the group consisting of elongation factor 1 alpha (EF1 alpha) promoter, cytomegalovirus (CMV) promoter, beta-actin promoter, simian virus 40 (SV40) early promoter, ubiquitin c promoter, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter, and phosphoglycerate kinase (PGK) promoter; or an inflammation-sensitive promoter optionally selected from the group consisting of promoters inducible by NF-κB, interleukin 6 (II-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), cyclooxygenase 2 (COX-2), complement factor 3 (C3), serum amyloid A3 (SAA3), and macrophage inflammatory protein-1a (MIP-1a); The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is selected from

9. 9. The pharmaceutical composition of claim 7 or 8, wherein the genome comprises, or consists of, a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, or at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO: 7 or 8, excluding the promoter and the nucleic acid sequence encoding the protein.

10. the nucleic acid encoding the protein Interleukin-1 receptor antagonist (IL-1Ra), proteoglycan 4 (PRG4), or both IL-1Ra and PRG4, or at least one biologically active fragment of the foregoing; IL-1Ra, PRG4, or both IL-1Ra and PRG4; IL-1Ra; or PRG4 The pharmaceutical composition according to any one of claims 5 to 9, which encodes:

11. The nucleic acid mammalian proteins; equine, canine, feline, or murine proteins; or Human proteins Code The pharmaceutical composition of any one of claims 5 to 10, wherein the nucleic acid is optionally codon-optimized.

12. The nucleic acid encoding the protein comprises a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or a nucleic acid that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or 12. The pharmaceutical composition of any one of claims 5 to 11, consisting of a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 4, 5, 10, 11, 14, 17, 18 or 19, or a nucleic acid that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 1, 4, 5, 10, 11, 14, 17, 18 or 19, optionally wherein the sequence is codon optimized.

13. 13. The pharmaceutical composition of any one of claims 7 to 12, wherein the genome comprises or consists of a nucleic acid that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, or at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to, SEQ ID NO:2, 3, 7, 8, 9.

14. The nucleic acid comprises an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19.

13. The pharmaceutical composition of any one of claims 7 to 12, encoding a PRG4 protein consisting of an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to, a sequence selected from SEQ ID NOs: 12, 13, 17, 18 or 19, or a biologically active fragment thereof, or a homolog thereof from any other species.

15. The nucleic acid comprises an amino acid sequence that is 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16, or an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16, or 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NO: 6, 15 or 16.

13. The pharmaceutical composition of any one of claims 7 to 12, encoding an IL-1Ra protein consisting of an amino acid sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical or homologous to a sequence selected from SEQ ID NOs: 6, 15 or 16, or a biologically active fragment thereof, or a homolog thereof from any other species.

16. 15. The pharmaceutical composition of any one of claims 7 to 14, wherein the nucleic acid encodes PRG4, and expression of PRG4 is controlled by a ubiquitous constitutive promoter, optionally selected from the group consisting of elongation factor 1 alpha (EF1 alpha) promoter, cytomegalovirus (CMV) promoter, beta-actin promoter, simian virus 40 (SV40) early promoter, ubiquitin c promoter, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter, and phosphoglycerate kinase (PGK) promoter.

17. 16. The pharmaceutical composition of any one of claims 7 to 13 or 15, wherein the nucleic acid encodes IL-1Ra, and expression of IL-1Ra is controlled by an inflammation-sensitive promoter, optionally wherein the inflammation-sensitive promoter is selected from the group consisting of promoters inducible by NF-κB, interleukin 6 (II-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), cyclooxygenase 2 (COX-2), complement factor 3 (C3), serum amyloid A3 (SAA3), and macrophage inflammatory protein-1a (MIP-1a).

18. 18. The pharmaceutical composition according to any one of claims 7 to 17, wherein the promoter is located upstream of the open reading frame of the nucleic acid sequence encoding the protein such that expression of the protein is controlled by the promoter.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding an animal IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and non-viral and non-coding stuffer nucleic acid sequences, wherein expression of the nucleic acid sequence encoding the animal IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the animal IL-1Ra protein, and optionally the animal is a horse, dog, cat, or mouse.

20. 19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and wherein expression of the nucleic acid sequence encoding the human IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human IL-1Ra protein.

21. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding an animal's PRG4 protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, wherein expression of the nucleic acid sequence encoding the animal's PRG4 protein is controlled by an EF1 alpha-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the animal's PRG4 protein, and optionally the animal is a horse, dog, cat, or mouse.

22. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein the adenovirus-based biological delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human PRG4 protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and wherein expression of the nucleic acid sequence encoding the human PRG4 protein is controlled by an EF1 alpha-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human PRG4 protein.

23. 23. The pharmaceutical composition of any one of claims 1 to 22, wherein the pharmaceutical composition is formulated for localized administration, optionally topically, by injection, by inhalation, intraocularly, or intraaurally.

24. 24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the pharmaceutical composition is formulated for injection into an articular space, optionally intratendinous, intramuscular, intraarticular or subacromial injection.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein the pharmaceutical composition is formulated for intra-articular injection into a joint of a human, optionally the joint being the knee.

26. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein the pharmaceutical composition is formulated for injection into an intervertebral disc, optionally the injection being an intradiscal injection, optionally into the nucleus pulposus (NP) region of the intervertebral disc.

27. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein the pharmaceutical composition is not formulated for administration into an intervertebral disc, and optionally the administration is by intradiscal injection into the nucleus pulposus (NP) or central gelatinous nucleus pulposus (NP) region of the intervertebral disc, as appropriate.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the pharmaceutical composition is a liquid.

29. The adenovirus-based delivery and expression system was formulated as follows: TRIS 10 mM, NaCl 75 mM, polysorbate 80 0.02% (v / v), sucrose 5% (w / v), MgCl ２ 29. The pharmaceutical composition of any one of claims 1 to 28, which is present in a buffer containing 1.0 mM EDTA, 100 μM EDTA, 0.5% (v / v) ethanol and 10 mM L-histidine.

30. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , if necessary, 2.8 × 10 ９ , 2.8 × 10 １０ , 2.8 × 10 １１ of at least 1.4 × 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by at least any two of the foregoing values, optionally at least 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , optionally at least 2.8×10 ９ , 2.8 × 10 １０ , 2.8 × 10 １１ of, or 1.4 x 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or less, or a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ The following, as needed, 2.8 x 10 ９ , 2.8 × 10 １０ , 2.8 × 10 １１ The pharmaceutical composition according to any one of claims 1 to 29, which is a recombinant adenoviral vector or a helper-dependent adenoviral vector with the following genome copies (GC):

31. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ of at least 1.4 × 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by at least any two of the foregoing values, optionally at least 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ of, or 1.4 x 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or less, or a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ The pharmaceutical composition according to any one of claims 1 to 30, which is a recombinant adenoviral vector or a helper-dependent adenoviral vector of the following viral particles (VP):

32. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml. Optionally, it is 1.0, 2.0, 2.5 or 5.0 ml, optionally it is 5.0 ml, it is at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by at least any two of the foregoing values, optionally at least 0. 1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 5.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9 32. The pharmaceutical composition of any one of claims 1 to 31, which is a liquid having a volume that is not more than 0.5, 10 ml, or not more than a range defined by any two of the preceding values, optionally not more than 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0-6.0 ml, optionally not more than 1.0, 2.0, 2.5 or 5.0 ml, optionally not more than 5.0 ml.

33. 33. The pharmaceutical composition of any one of claims 1 to 32, wherein the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or a range defined by any two of the foregoing values, optionally 10%-90%, 10%-50%, 30%-80%, 50%-90%, of the typical and / or publicly disclosed concentration of said recombinant adenovirus vector or helper-dependent adenovirus vector for administration by the same route of administration to an animal of the same species for the treatment of the same or a similar disease or disorder.

34. 34. The pharmaceutical composition of any one of claims 1 to 33, wherein the concentration of the corticosteroid is sufficient to improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to an animal compared to administration of the same pharmaceutical composition without the corticosteroid.

35. 35. The pharmaceutical composition of claim 34, wherein the improvement comprises an improvement in the amount or duration of a measure of transduction or expression.

36. 36. The pharmaceutical composition of claim 34 or 35, wherein said improvement in transfection and / or expression is measured in vitro.

37. 37. The pharmaceutical composition of any one of claims 34 to 36, wherein the improved safety comprises a reduction in the number, severity or duration of adverse events, optionally wherein the adverse events are selected from pain, swelling, oozing, inflammation, headache, fever, chills and flu-like symptoms.

38. 38. The pharmaceutical composition of any one of claims 34 to 37, wherein said improved efficacy comprises improved onset, amount and / or duration of therapeutic effect of said adenoviral-based delivery and expression system.

39. 39. The pharmaceutical composition of claim 38, wherein the therapeutic effect comprises a reduction in a symptom measure or marker of the disease or disorder, optionally wherein the symptom is pain in a joint of the animal, optionally measured using the Western Ontario McMaster Universities Osteoarthritis Index Pain Score (WOMAC-A).

40. The improvement is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by any two of the foregoing values, optionally 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%, as compared to the same pharmaceutical composition without the corticosteroid.

40. The pharmaceutical composition of any one of claims 34 to 39, wherein the α-aspartate aminotransferase activity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by at least any two of the foregoing values, optionally at least 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%.

41. The concentration of the corticosteroid is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 3 0-50, 100-1000, 500-5000 mg / ml of said pharmaceutical composition, optionally 40 mg / ml of said pharmaceutical composition, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by at least any two of the foregoing values, optionally at least 0.001-5 000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml of the pharmaceutical composition, optionally at least 40 mg / ml of the pharmaceutical composition, 41. The pharmaceutical composition of any one of claims 1 to 40, wherein the pharmaceutical composition is at or below 0 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml.

42. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 ml. Optionally, it is 1.0, 2.0, 2.5 or 5.0 ml, optionally it is 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by at least any two of the foregoing values, optionally at least 0. 1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9 42. The pharmaceutical composition of any one of claims 1 to 41, which is a liquid having a volume that is not more than 0.5, 10 ml, or not more than a range defined by any two of the preceding values, optionally not more than 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0-6.0 ml, optionally not more than 1.0, 2.0, 2.5 or 5.0 ml, optionally not more than 1.0 ml.

43. 43. The pharmaceutical composition of any one of claims 1 to 42, wherein the amount of the adenovirus-based biological delivery and expression system is a therapeutically effective amount.

44. 44. The pharmaceutical composition of any one of claims 1 to 43, wherein the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system such that the corticosteroid can be administered before or after the adenovirus-based biological delivery and expression system.

45. 43. The pharmaceutical composition of any one of claims 1 to 42, wherein the corticosteroid is in the same dosage form as the adenovirus-based biological delivery and expression system, optionally in a single fluid dosage form, such that the corticosteroid is administered simultaneously with the adenovirus-based biological delivery and expression system.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the dosage form comprising the corticosteroid and the adenovirus-based biological delivery and expression system is prepared by combining a composition comprising the corticosteroid with a composition comprising the adenovirus-based biological delivery and expression system.

47. 45. A kit comprising the pharmaceutical composition of claim 44, the kit comprising a first container comprising the corticosteroid in a first dosage form and a second container comprising the adenovirus-based biological delivery and expression system in a second dosage form.

48. 47. A kit for use in preparing the pharmaceutical composition of claim 46, the kit comprising a composition comprising the corticosteroid in a first container and a composition comprising the adenovirus-based biological delivery and expression system in a second container.

49. A method comprising administering to an animal a pharmaceutical composition according to any one of claims 1 to 46.

50. 50. The method of claim 49, wherein administration of the pharmaceutical composition infects cells of the animal with the adenovirus-based delivery and expression system, resulting in expression of the protein encoded by the nucleic acid of the adenovirus-based delivery and expression system.

51. 50. The method of claim 49, wherein administration of the pharmaceutical composition infects articular cells of a joint affected by osteoarthritis in a human in need of administration of the pharmaceutical composition, optionally wherein the joint is a knee joint.

52. 52. The method of any one of claims 49-51, wherein the concentration of the corticosteroid is sufficient to improve one or more of the transduction, expression, efficacy and / or safety of the adenovirus-based delivery and expression system when administered to the animal compared to administration of the same pharmaceutical composition without the corticosteroid.

53. 53. The method of claim 52, wherein the improvement comprises an improvement in the amount or duration of a measure of transduction or expression.

54. 54. The method of claim 52 or 53, wherein said improvement in transfection and / or expression is measured in vitro.

55. 55. The method of any one of claims 52-54, wherein said improved safety comprises a reduction in the number, severity or duration of adverse events, optionally wherein said adverse events are selected from pain, swelling, oozing, inflammation, headache, fever, chills and flu-like symptoms.

56. 56. The method of any one of claims 49 to 55, wherein the improved efficacy comprises an improved onset, amount or duration of therapeutic effect of the adenoviral-based delivery and expression system.

57. 57. The method of claim 56, wherein the therapeutic effect comprises a reduction in a symptom measure or marker of the disease or disorder, optionally wherein the symptom is pain in a joint of the animal, optionally measured using the Western Ontario McMaster Universities Osteoarthritis Index Pain Score (WOMAC-A).

58. 58. The method of any one of claims 56-57, wherein said improved efficacy comprises improved onset and / or amount of reduction in a joint pain scale in said animal.

59. 59. The method of any one of claims 56 to 58, wherein said improved efficacy comprises an improved likelihood that said animal will experience at least a 50% reduction in a joint pain scale.

60. the improvement is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000%, or 5000%, or at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or more, compared to administration of the same pharmaceutical composition without the corticosteroid , 80%, 90%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 1000% or 5000%, or a range defined by any two of the foregoing values, optionally 10% to 5000%, 10% to 100%, 100% to 5000%, or 50% to 500%.

61. the corticosteroid is administered for a period of 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or 0.0-0.01 hours prior to administration of the adenoviral-based delivery and expression system; or 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4 or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2 or 0.0-0.01 hours or less.

62. the corticosteroid is administered for a period of 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2, or 0.0-0.01 hours after administration of the adenoviral-based delivery and expression system; or 0.00, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4 or 5 hours, or a range defined by any two of the foregoing values, optionally 0.0-5, 0.0-3, 0.0-2, 0.0-1, 0.0-0.5, 0.0-0.2 or 0.0-0.01 hours or less.

63. 63. The method of any one of claims 49-62, wherein the corticosteroid is administered to the animal no more than 3 hours prior to administration of the adenovirus-based delivery and expression system and no more than 30 minutes after administration of the adenovirus-based delivery and expression system, or the corticosteroid is administered to the animal no more than 30 minutes prior to administration of the adenovirus-based delivery and expression system and no more than 30 minutes after administration of the adenovirus-based delivery and expression system, or the corticosteroid is administered to the animal no more than 5 minutes prior to administration of the adenovirus-based delivery and expression system and no more than 5 minutes after administration of the adenovirus-based delivery and expression system.

64. 64. The method of any one of claims 49 to 63, wherein the corticosteroid is administered to the animal simultaneously with the adenovirus-based delivery and expression system.

65. 65. The method of claim 64, wherein the corticosteroid and the adenovirus-based delivery and expression system are in a single dosage form.

66. The animal is 2, 3, 4, 5, 6, 12, 18, 24, 48, or 72 hours, or a range defined by any two of the foregoing values, optionally 2-72, 3-72, 4-72, 5-72, 2-24, 3-24, 5-24, 2-48, 3-48, 4-48, 5-48, 6-72, 6-48, 12-72, or 18-72 hours, or at least 2, 3, 4, 5, 6, 12, 18, 24, 48, or 72 hours prior to administration of the adenoviral-based delivery and expression system.

66. The method of any one of claims 49-65, wherein the patient has not administered a corticosteroid other than the corticosteroid of the pharmaceutical composition for a period of 4, 48 or 72 hours, or at least a range defined by any two of the foregoing values, optionally at least 2-72, 3-72, 4-72, 5-72, 2-24, 3-24, 5-24, 2-48, 3-48, 4-48, 5-48, 6-72, 6-48, 12-72 or 18-72 hours.

67. 67. The method of any one of claims 49-66, wherein the method comprises systemic administration of the corticosteroid of the pharmaceutical composition and local administration of the adenovirus-based delivery and expression system of the pharmaceutical composition.

68. 67. The method of any one of claims 49 to 66, wherein the method comprises administering the corticosteroid of the pharmaceutical composition and an adenovirus-based delivery and expression system locally to the same location in the animal.

69. 69. The method of claim 68, wherein the method comprises administering the corticosteroid of the pharmaceutical composition and an adenovirus-based delivery and expression system topically, by injection, by inhalation, intraocularly, or intraaurally.

70. 69. The method of claim 68, wherein the method comprises administering the corticosteroid and the adenovirus-based delivery and expression system of the pharmaceutical composition by injection, wherein the administration of the corticosteroid and the adenovirus-based delivery and expression system is via the same needle, the needle being maintained at the same site during administration of both the corticosteroid and the adenovirus-based delivery and expression system, and, optionally, the needle being flushed with fluid between administration of the corticosteroid and administration of the adenovirus-based delivery and expression system.

71. 71. The method of any one of claims 68 to 70, wherein the method comprises injection into a joint of the animal, optionally by intratendinous, intramuscular, intraarticular or subacromial injection.

72. 72. The method of claim 71, wherein the injection is an intra-articular injection, and optionally the joint is a knee.

73. 71. The method of any one of claims 68 to 70, wherein the method comprises injection into an intervertebral disc, optionally the injection is an intradiscal injection, optionally into the nucleus pulposus (NP) region of the intervertebral disc.

74. 73. The method of any one of claims 49-72, wherein the method does not include administration into an intervertebral disc, the method does not include administration by intradiscal injection, or the method does not include intradiscal injection into the nucleus pulposus (NP) or central gelatinous nucleus pulposus (NP) region of the intervertebral disc.

75. 75. The method of any one of claims 49 to 74, wherein the method comprises treating a disease or condition.

76. 76. The method of claim 75, wherein the method comprises identifying the animal as suffering from or at risk of suffering from the disease or condition being treated prior to administration of the pharmaceutical composition.

77. The disease or condition is Camptodactyly-arthrosis-coxa vara-pericarditis (CACP) syndrome; musculoskeletal disease or condition; joint disease or condition; pulmonary disease or condition; eye disease or condition; ear disease or condition; Arthropathy, arthritis or arthritis-related conditions; osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, Reiter's syndrome or tendinopathy including tendinitis, tendinosis and tenosynovitis; synovial disorders, including synovitis; bursal disorders, including bursitis; or Equine musculoskeletal disorders including hock tumors, navicular syndrome and coronoid phalangeal neuropathy 77. The method of claim 75 or 76, wherein:

78. 77. The method of claim 75 or 76, wherein the disease or condition is degenerative disc disease (DDD) or a condition associated with DDD.

79. 77. The method of claim 75 or 76, wherein the disease or condition is not degenerative disc disease (DDD) or a condition associated with DDD.

80. 77. The method of claim 75 or 76, wherein the disease or condition is osteoarthritis or a symptom of osteoarthritis, optionally of the knee.

81. 81. The method of any one of claims 49 to 80, wherein the animal is a mammal.

82. 81. The method of any one of claims 49 to 80, wherein the animal is a human.

83. 81. The method of any one of claims 49 to 80, wherein the animal is a horse, dog or cat.

84. 84. The method of any one of claims 49 to 83, wherein the amount of vector administered to the animal is reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or a range defined by any two of the foregoing values, optionally 10%-90%, 10%-50%, 30%-80%, 50%-90%, of the typical and / or publicly disclosed amount of the recombinant adenoviral vector or helper-dependent adenoviral vector administered to an animal of the same species by the same route of administration for the treatment of the same or a similar disease or disorder.

85. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , if necessary, 2.8 × 10 ９ , 2.8 × 10 １０ , 2.8 × 10 １１ of at least 1.4 × 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by at least any two of the foregoing values, optionally at least 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , optionally at least 2.8×10 ９ , 2.8 × 10 １０ , 2.8 × 10 １１ of, or 1.4 x 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or less, or a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ The following, as needed, 2.8 x 10 ９ , 2.8 × 10 １０ , 2.8 × 10 １１ The method according to any one of claims 49 to 84, wherein the adenoviral vector is a recombinant adenoviral vector or a helper-dependent adenoviral vector with the following genome copies (GC):

86. The adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the concentration of the vector is 1.4 x 10 per ml of pharmaceutical composition. ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ of at least 1.4 × 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by at least any two of the foregoing values, optionally at least 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ of, or 1.4 x 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or less, or a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ The method according to any one of claims 49 to 84, wherein the adenoviral vector is a recombinant adenoviral vector or a helper-dependent adenoviral vector of the following viral particles (VP):

87. The pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0-6.0 ml. optionally 2.0, 2.5 or 5.0 ml; optionally 5.0 ml; at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml; or a range defined by at least any two of the foregoing values; optionally at least and optionally at least 5.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76 87. The method of any one of claims 49 to 86, wherein the liquid has a volume that is not more than 0, 9.5, 10 ml, or not more than a range defined by any two of the preceding values, optionally not more than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally not more than 2.0, 2.5 or 5.0 ml, optionally not more than 5.0 ml.

88. The pharmaceutical composition is a liquid, and the amount of pharmaceutical composition administered to the animal is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7 0.5 or 4.0-6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 5.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by at least any two of the foregoing values. optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 5.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 88. The method of any one of claims 49 to 87, wherein the liquid has a volume that is not more than 8.5, 9.0, 9.5, 10 ml, or not more than a range defined by any two of the preceding values, optionally not more than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally not more than 1.0, 2.0, 2.5 or 5.0 ml, optionally not more than 5.0 ml.

89. the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the amount of vector administered to the animal is 1.4×10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , 1.4 × 10 as needed ５ , 1.4 × 10 ７ , 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ , 5.6 x 10 as needed ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ of at least 1.4 × 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by at least any two of the foregoing values, optionally at least 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , optionally at least 1.4×10 ５ , 1.4 × 10 ７ , 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ , optionally at least 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ of, or 1.4 x 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or less, or a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ The following, as needed, 1.4 x 10 ５ , 1.4 × 10 ７ , 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ The following, as needed, 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ The method according to any one of claims 49 to 88, wherein the adenoviral vector is a recombinant adenoviral vector or a helper-dependent adenoviral vector with the following genome copies (GC):

90. the adenovirus-based delivery and expression system is a recombinant adenovirus vector or a helper-dependent adenovirus vector, and the amount of vector administered to the animal is 1.4×10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , 1.4 × 10 as needed ５ , 1.4 × 10 ７ , 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ , 5.6 x 10 as needed ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ of at least 1.4 × 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or in a range defined by at least any two of the foregoing values, optionally at least 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ , optionally at least 1.4×10 ５ , 1.4 × 10 ７ , 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ , optionally at least 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ of, or 1.4 x 10 ５ , 1.4 × 10 ６ , 2.8 × 10 ６ , 7.0 × 10 ６ , 1.4 × 10 ７ , 2.8 × 10 ７ , 7.0 × 10 ７ , 1.4 × 10 ８ , 2.8 × 10 ８ , 7.0 × 10 ８ , 1.4 × 10 ９ , 2.8 × 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 2.8 × 10 １０ , 7.0 × 10 １０ , 1.4 × 10 １１ , 2.8 × 10 １１ , 7.0 × 10 １１ , 1.4 × 10 １２ , 2.8 × 10 １２ , 7.0 × 10 １２ , 1.4 × 10 １３ , 2.8 × 10 １３ , 7.0 × 10 １３ or less, or a range defined by any two of the foregoing values, as appropriate, 1.4 x 10 ５ ~7.0 x 10 １３ , 1.4 × 10 ５ ~7.0 x 10 １２ , 1.4 × 10 ５ ~7.0 x 10 １１ , 1.4 × 10 ５ ~7.0 x 10 １０ , 1.4 × 10 ５ ~7.0 x 10 ９ , 1.4 × 10 ５ ~7.0 x 10 ８ , 1.4 × 10 ９ ~7.0 x 10 １０ The following, as needed, 1.4 x 10 ５ , 1.4 × 10 ７ , 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ The following, as needed, 5.6 x 10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ Or 1.4 x 10 １２ The method according to any one of claims 49 to 88, wherein the adenoviral vector is a recombinant adenoviral vector or a helper-dependent adenoviral vector of the following viral particles (VP):

91. the concentration of the corticosteroid is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500, or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml of said pharmaceutical composition, optionally 40 mg / ml of said pharmaceutical composition, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by at least any two of the foregoing values, optionally at least 0.001 5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml of the pharmaceutical composition, optionally at least 40 mg / ml of the pharmaceutical composition, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2 91. The method of any one of claims 49-90, wherein the pharmaceutical composition is at or below 500 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / ml, optionally 40 mg / ml.

92. the pharmaceutical composition is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5 or 4.0-6.0 ml; Optionally, the volume is 1.0, 2.0, 2.5, or 5.0 ml; optionally, the volume is 1.0 ml; optionally, the volume is at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml; or a range defined by at least any two of the foregoing values; optionally, at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.

92. The method of any one of claims 49 to 91, wherein the liquid has a volume that is not more than 0, 9.5, 10 ml, or not more than a range defined by any two of the preceding values, optionally not more than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally not more than 1.0, 2.0, 2.5 or 5.0 ml, optionally not more than 1.0 ml.

93. The pharmaceutical composition is a liquid, and the amount of pharmaceutical composition administered to the animal is 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the foregoing values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7 0.5 or 4.0-6.0 ml, optionally 1.0, 2.0, 2.5 or 5.0 ml, optionally 1.0 ml, at least 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by at least any two of the foregoing values. optionally at least 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally at least 1.0, 2.0, 2.5 or 5.0 ml, optionally at least 1.0 ml, or 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 93. The method of any one of claims 49 to 92, wherein the liquid has a volume that is not more than 8.5, 9.0, 9.5, 10 ml, or not more than a range defined by any two of the preceding values, optionally not more than 0.1 to 10, 0.1 to 5, 1.0 to 10, 1.0 to 5.0, 2.5 to 7.5 or 4.0 to 6.0 ml, optionally not more than 1.0, 2.0, 2.5 or 5.0 ml, optionally not more than 1.0 ml.

94. The amount of corticosteroid administered to the animal is 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by any two of the foregoing values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-1 00, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg, optionally 40 mg, at least 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2500 or 5000, or a range defined by at least any two of the foregoing values, optionally at least 0.001 to 5000, 0.001 to 0.1, 0.001 to 10, 0.1 to 100, 1.0 to 100, 1.0 to 50, 30 to 300, 25 to 60, 30 to 50, 100 to 1000, 500 to 5000 mg, and optionally at least 40 mg, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 75 94. The method of any one of claims 49 to 93, wherein the amount is not more than 0, 1000, 2500 or 5000, or a range defined by any two of the foregoing values, optionally 0.001 to 5000, 0.001 to 0.1, 0.001 to 10, 0.1 to 100, 1.0 to 100, 1.0 to 50, 30 to 300, 25 to 60, 30 to 50, 100 to 1000, 500 to 5000 mg, optionally 40 mg or less.

95. the method comprising: identifying a human subject as suffering from osteoarthritis of the knee; administering the pharmaceutical composition to the human subject by intra-articular injection into the knee joint affected by osteoarthritis; Including, the corticosteroid is in a dosage form separate from the adenovirus-based biological delivery and expression system; administering the corticosteroid comprises an intra-articular injection of 1 ml of a formulation containing 40 mg / ml of the corticosteroid; Administration of the adenovirus-based biological delivery and expression system is optionally 2.8 x 10 per ml of the adenovirus-based biological delivery and expression system ９ , 2.8 × 10 １０ , 2.8 × 10 １１ and a 2, 2.5 or 5 ml intra-articular injection of a dosage form comprising The amount of adenoviral-based biological delivery and expression system delivered to the knee is 5.6×10 ９ , 7.0 × 10 ９ , 1.4 × 10 １０ , 1.4 × 10 １１ or 1.4 x 10 １２ a recombinant adenoviral vector or a helper-dependent adenoviral vector of a genome copy (GC) of administration of the corticosteroid and the adenovirus-based delivery and expression system is via the same needle, the needle being maintained at the same site during administration of both the corticosteroid and the adenovirus-based delivery and expression system, and optionally the needle being flushed with fluid during administration of the corticosteroid and the adenovirus-based delivery and expression system; the corticosteroid is administered no more than 0-15 minutes, and optionally no more than 0-5 minutes, prior to administration of the adenoviral-based delivery and expression system; 95. The method of any one of claims 49 to 94.

96. 96. The method of claim 95, wherein the adenovirus-based delivery and expression system comprises a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding a human IL-1Ra protein, left and right inverted terminal repeats, an adenovirus packaging signal, and a non-viral and non-coding stuffer nucleic acid sequence, and wherein expression of the nucleic acid sequence encoding the human IL-1Ra protein is controlled by an NF-κB-inducible promoter located upstream of the open reading frame of the nucleic acid sequence encoding the human IL-1Ra protein.

97. 97. The method of claim 96, wherein the genome of the helper-dependent adenoviral vector has the nucleic acid sequence of SEQ ID NO:

7.

98. 98. The method of any one of claims 95 to 97, wherein the corticosteroid is methylprednisolone.

99. 99. The method of any one of claims 49 to 98, wherein the amount of the adenovirus-based biological delivery and expression system administered to the animal is a therapeutically effective amount.

100. 99. Use of a composition or kit according to any one of claims 1 to 48 for use in a method for treating a disease or condition, said method comprising a method according to any one of claims 49 to 98.

101. A kit comprising a first container containing a corticosteroid in a first dosage form and a second container containing an adenovirus-based biological delivery and expression system in a second dosage form.

102. 102. The kit of claim 101, wherein the corticosteroid or the adenovirus-based biological delivery and expression system is provided as described in any one of claims 1 to 46.

103. 103. A pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system according to any one of claims 1 to 46 for use as a medicament, or a kit comprising a first container containing a corticosteroid in a first dosage form and a second container containing an adenovirus-based biological delivery and expression system in a second dosage form according to any one of claims 101 to 102.

104. 103. A pharmaceutical composition comprising a corticosteroid and an adenovirus-based delivery and expression system according to any one of claims 1 to 46, or a kit comprising a first container containing a corticosteroid in a first dosage form and a second container containing an adenovirus-based biological delivery and expression system in a second dosage form according to any one of claims 101 to 102, for use in the prevention or treatment of a disease or condition.

105. Symptoms of the disease include: Camptodactyly-arthrosis-coxa vara-pericarditis (CACP) syndrome; musculoskeletal disease or condition; joint disease or condition; pulmonary disease or condition; eye disease or condition; ear disease or condition; Arthrosis, arthritis and arthritis-related conditions; osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, Reiter's syndrome or tendinopathy including tendinitis, tendinosis and tenosynovitis; synovial disorders, including synovitis; bursal disorders, including bursitis; or Equine musculoskeletal disorders including hock tumors, navicular syndrome and coronoid phalangeal neuropathy 105. The pharmaceutical composition or kit for use according to claim 104, wherein the pharmaceutical composition or kit is selected from the group consisting of:

106. 105. The pharmaceutical composition or kit for use according to claim 104, wherein the disease or condition is degenerative disc disease (DDD) or a condition associated with DDD.

107. 105. The pharmaceutical composition or kit for use according to claim 104, wherein the disease or condition is not degenerative disc disease (DDD) or a condition associated with DDD.

108. 10. The pharmaceutical composition, kit, method or use of any one of the preceding claims, wherein the adenovirus-based biological delivery and expression system is PCRX201, and optionally, the amount of the corticosteroid and / or the PCRX is a therapeutically effective amount.

109. 10. The pharmaceutical composition, kit, method or use of any one of the preceding claims, wherein the corticosteroid is selected from the group consisting of beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, ciclesonide, fluticasone, flunisolide, mometasone, or mixtures thereof.

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