Abstract
Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated virus (AAV) vectors. EP- and AAV-mediated delivery of human interleukin-1 receptor antagonist (hIL-1Ra) was localized performed in the joints of rats following induction of OA. mRNA levels for hIL-1Ra, IL-1β, TNF-α, MMP-13 and ADAMTS-4 in the cartilage and synovial tissues were analyzed. Structural analyses of the subchondral bone at the medial femoral condyle were performed by Micro-CT after treatment. Knee joint specimens were staining with hematoxylin and eosin and Saffron O. Induction of hIL-1Ra by both EP and AAV inhibited inflammatory-induced sub-chondral bone reconstruction, and effectively suppressed IL-1β activity, as evidenced by decreased expression of MMP-13 and ADAMTS-4. Histological analyses revealed significant protection of cartilage, proteoglycan by EP and AAV. hIL-1Ra expression was similar in both the EP and AAV groups. Notably, this gene is not easier degraded transduced by EP compared with AAV. Taken together, these results show that EP offers transfection efficiency comparable to that of AAV, with the potential for longer gene expression, making EP a promising candidate for efficient non-viral delivery of OA gene therapy.
Highlights
Osteoarthritis (OA) is the one of the most common joint diseases, characterized by loss of articular cartilage in combination with underlying bone changes, including sclerosis, bone cysts, subchondral bone sclerosis, and osteophyte formation [1] [2]
Parameter optimization focused on pulse width and plasmid dose, with various levels of each parameter divided into seven experimental groups (Figure 1(b))
Plasmid dose was performed at two different levels, and pulse width at five different levels spanning the entire range of the EP equipment
Summary
Osteoarthritis (OA) is the one of the most common joint diseases, characterized by loss of articular cartilage in combination with underlying bone changes, including sclerosis, bone cysts, subchondral bone sclerosis, and osteophyte formation [1] [2]. Gene therapy is considered a promising new method for the treatment of joint-disorders such as OA, with the possibility of treating disease symptoms by targeting specific pathological mechanisms underlying pathogenesis [3] [4]. Alternative approaches for delivering gene products to the articular cartilage have been used, with viral vectors being the most common method [8]-[11]. While most gene therapy approaches to date have employed viral vectors due to their high transfection efficiency in clinical trials, their potential for fatal defects may prevent any further clinical use, due to the potential for infectivity, oncogenic effects, immunogenicity, and other unexpected complications [7]-[14]. Its low transfection efficiency has limited further application as a non-viral gene delivery vector [18]
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