Successful gene therapy via intraarticular injection of adenovirus vector containing CTLA4IgG in a murine model of type II collagen-induced arthritis

• Published in: Human gene therapy Vol. 12; no. 9; p. 1063
• Main Authors: Ijima, K, Murakami, M, Okamoto, H, Inobe, M, Chikuma, S, Saito, I, Kanegae, Y, Kawaguchi, Y, Kitabatake, A, Uede, T
• Format: Journal Article
• Language: English
• Published: United States 10.06.2001
• Subjects: Abatacept; Adenoviridae - genetics; Animals; Antigens, CD; Antigens, Differentiation - administration & dosage; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - genetics; Antigens, Differentiation - therapeutic use; Arthritis, Experimental - genetics; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Arthritis, Experimental - therapy; Collagen - administration & dosage; Collagen - immunology; CTLA-4 Antigen; Disease Progression; Female; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Immunity, Innate - genetics; Immunoconjugates; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - biosynthesis; Immunoglobulin Fc Fragments - genetics; Immunoglobulin G - administration & dosage; Immunoglobulin G - biosynthesis; Immunoglobulin G - genetics; Immunoglobulin G - therapeutic use; Injections, Intra-Articular; Injections, Intramuscular; Injections, Intravenous; Injections, Subcutaneous; Mice; Mice, Inbred DBA; Severity of Illness Index
• ISSN: 1043-0342
• DOI: 10.1089/104303401750214285

We previously constructed an adenovirus vector carrying a gene encoding a soluble form of fusion protein, consisting of the extracellular portion of cytotoxic lymphocyte antigen 4 (CTLA4) and the Fc portion of human immunoglobulin G1 (Adex1CACTLA4IgG). Murine type II collagen-induced arthritis (CIA) was treated with Adex1CACTLA4IgG. A single intraarticular injection of 1 x 10(5) PFU was able to support serum CTLA4IgG at more than 10 microg/ml for at least 12 weeks and was able to inhibit the CIA clinically and histologically. In contrast, intravenous, intramuscular, or subcutaneous injection of 1 x 10(5) PFU was unable to support a significant level of serum CTLA4IgG and thus was unable to inhibit the development of arthritis. Thus, we demonstrated that (1) a low-dose intraarticular injection of Adex1CACTLA4IgG was effective in delaying the onset of CIA and reducing the severity of arthritis; (2) an intraarticular (knee joint) injection of Adex1CACTLA4IgG effectively blocked the development of arthritis in distal paws; (3) the inhibitory effect of Adex1CACTLA4IgG lasted at least up to 20 weeks; (4) although serum CTLA4IgG at more than 10 microg/ml persisted for at least 12 weeks, mice treated by intraarticular injection of Adex1CACTLA4IgG were not anergic to adenovirus and were able to mount antibody responses against various antigens.