Effective doses of adenovirus-based biological delivery and expression system for treatment of human osteoarthritis and compositions comprising same
A technology of biological delivery and expression system, applied in the direction of drug combination, biochemical equipment and methods, virus, etc.
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Embodiment 1
[0262] Purpose of the study: This article describes studies to determine year-long long-term gene expression in the joints of mice injected intra-articularly with the expression of firefly luciferase (luc) under the control of the CMV promoter. Invented helper-dependent adenoviral vector (HDAd) and first-generation adenoviral (Ad) vectors for comparison.
[0263] Method: intra-articular injection of 10 8 Luciferase-expressing helper-dependent adenoviral vector (HDAd-luc) or the corresponding first-generation adenoviral vector (Ad-luc) expressing viral particles (VP). Injection into two knee joints of four mice per group. Three days later, mice were imaged using an MS 200 series imaging system (Caliper Life Sciences, Hopkinton, MA). Repeated bioluminescent imaging was performed following mouse luciferase expression and quantified using Living Image 2.5 software (Caliper Life Sciences).
[0264] Results: Strong bioluminescence signals were detected in joints injected with HDA...
Embodiment 2
[0267] This article describes studies used to evaluate HDAd transduction in the joints of mice in detail, in which mice were injected intra-articularly with 10 8 or 10 9 VP HDAd expressing LacZ. in use 10 9 Strong expression of LacZ was seen in both synovium and chondrocytes of VP LacZ-expressing HDAd-infected joints ( Figure 5B ), while at 10 8 No staining was observed in chondrocytes in VP-infected joints ( Figure 5A ). The livers of these animals were analyzed to assess whether the virus escaped from the joints or spilled out during injection. Most importantly, detectable carrier concentrations above background could not be measured by quantitative PCR (data not shown). Thus, the vector is specifically localized in the joints and remains there, which is of great benefit in the treatment or prevention of osteoarthritic conditions, since it shows minimal side effects.
[0268] Example 4: HDAd-11-1Ra infected cells secrete IL-1Ra. injection.
[0269] Purpose of the ...
Embodiment 3
[0272] Conclusions: The results disclosed herein demonstrate that cells infected with HDAd-mll-IRa can produce high levels of II-IRa. It has also been shown that IL-1Ra is efficiently secreted from these cells and that inflammatory conditions activate the NF-KB5-ELAM promoter, resulting in increased IL-1Ra levels.
[0273]Acute injury of the anterior cruciate ligament (ACL) is a common cause of post-traumatic OA in humans, and ACL transection (ACLT) in rats and mice is an established animal model of traumatic injury-induced OA. FX201, a helper-dependent adenovirus (HDAd)-based intra-articular (IA) gene therapy candidate designed to induce interleukin (IL)-1 receptors in the presence of inflammation, is being developed as a potential therapeutic agent for OA. production of an antagonist (IL-1Ra). This article describes studies demonstrating that treatment with FX201 or its equivalent HDAd-mIL-IRa is effective in the prevention and treatment of OA.
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