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Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: Toxicology and pain efficacy assessments
•Proinflammatory cytokines create osteoarthritis pathology and pain.•Treatments for osteoarthritis have not previously targeted these cytokines.•We developed a novel plasmid DNA therapy expressing interleukin-10 (IL-10).•This reports the first long-term assessment of its intra-articular use.•This IL...
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Published in: | Brain, behavior, and immunity behavior, and immunity, 2020-11, Vol.90, p.155-166 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | •Proinflammatory cytokines create osteoarthritis pathology and pain.•Treatments for osteoarthritis have not previously targeted these cytokines.•We developed a novel plasmid DNA therapy expressing interleukin-10 (IL-10).•This reports the first long-term assessment of its intra-articular use.•This IL-10 gene therapy decreased pain without adverse effects.
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. |
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ISSN: | 0889-1591 1090-2139 |
DOI: | 10.1016/j.bbi.2020.08.005 |