Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.

中文翻译：

---

靶向白细胞介素 10 质粒 DNA 治疗骨关节炎：毒理学和疼痛疗效评估

骨关节炎导致慢性疼痛和功能丧失。促炎细胞因子会导致骨关节炎病理和疼痛。目前的治疗效果不佳，具有显着的副作用，并且没有针对骨关节炎发展和维持的核心细胞因子。Interleukin-10 是一种抗炎细胞因子，可有效且广泛地抑制促炎细胞因子的活性。然而，白细胞介素10蛋白在体内的半衰期短，关节通透性差。为了保持 IL-10 活性，我们开发了一种基于质粒 DNA 的疗法，该疗法表达长效人类白细胞介素 10 变体 (hIL-10var)。在这里，我们描述了这种疗法的 6 个月 GLP 毒理学研究。将 hIL-10var pDNA 关节内注射到犬膝关节最多 1 个。双侧 5 mg 耐受良好且无病理发现。这是首次对关节内 pDNA 治疗进行长期毒理学评估。我们还报告了一项关于关节内 hIL-10var pDNA 对患有自然发生的骨关节炎的伴侣犬（宠物）疼痛测量的影响的小型双盲、安慰剂对照研究的结果。根据兽医和主人的评级，这种基于人类 IL-10 的靶向治疗减少了狗的疼痛程度，没有任何不良发现。hIL-10var pDNA 疗法的这些结果具有良好的耐受性且无毒理学影响，为新型安全有效的 OA 疗法的临床试验奠定了基础。关节内 hIL-10var pDNA 对患有自然发生的骨关节炎的伴侣犬（宠物）疼痛测量的影响的安慰剂对照研究。根据兽医和主人的评级，这种基于人类 IL-10 的靶向治疗减少了狗的疼痛程度，没有任何不良发现。hIL-10var pDNA 疗法的这些结果具有良好的耐受性且无毒理学影响，为新型安全有效的 OA 疗法的临床试验奠定了基础。关节内 hIL-10var pDNA 对患有自然发生的骨关节炎的伴侣犬（宠物）疼痛测量的影响的安慰剂对照研究。根据兽医和主人的评级，这种基于人类 IL-10 的靶向治疗减少了狗的疼痛程度，没有任何不良发现。hIL-10var pDNA 疗法的这些结果具有良好的耐受性且无毒理学影响，为新型安全有效的 OA 疗法的临床试验奠定了基础。