Messenger RNA delivery of a cartilage-anabolic transcription factor as a disease-modifying strategy for osteoarthritis treatment

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease and a major health problem in the elderly population. No disease-modifying osteoarthritis drug (DMOAD) has been made available for clinical use. Here we present a disease-modifying strategy for OA, focusing on messenger RNA (mRNA) delivery of a therapeutic transcription factor using polyethylene glycol (PEG)-polyamino acid block copolymer-based polyplex nanomicelles. When polyplex nanomicelles carrying the cartilage-anabolic, runt-related transcription factor (RUNX) 1 mRNA were injected into mouse OA knee joints, OA progression was significantly suppressed compared with the non-treatment control. Expressions of cartilage-anabolic markers and proliferation were augmented in articular chondrocytes of the RUNX1-injected knees. Thus, this study provides a proof of concept of the treatment of degenerative diseases such as OA by the in situ mRNA delivery of therapeutic transcription factors; the presented approach will directly connect basic findings on disease-protective or tissue-regenerating factors to disease treatment.

Structurally Programmed Assembly of Translation Initiation Nanoplex for Superior mRNA Delivery

“…The polyamines with one to four side chain aminoethylene repeat units have been previously characterized, demonstrating potent gene delivery in vitro and in vivo. 19–21 Moreover, in this study, an additional polyamine with five aminoethylene repeats was synthesized and characterized (Figure 1A, Supplementary Scheme 1 and Supplementary Figs. 2A–F).…”

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies

“…A number of next‐generation therapeutics are in clinical trial, though few have been developed to a point where regulatory approval has been granted 22. Exciting new approaches, such as the use of poly‐micelle protected Runx1 mRNA,95 demonstrates that, in principle, articular cartilage is amenable to RNA‐based therapeutics. Given that small molecules with Runx1 ‐mediated chondroprotective properties, including kartogenin 96 and TD‐198946,97, 98 have been defined using high‐throughput candidate molecule screens and not systems biology approaches, can systems orientated approaches solve the problem of defining novel therapeutic targets?…”

Design concepts of polyplex micelles for in vivo therapeutic delivery of plasmid DNA and messenger RNA

“…The resulting prolonged protein expression profiles from mRNA complexed with PAsn with an odd number of repeats are beneficial for the treatment of diseases requiring sustainable protein expression. Indeed, polyplex micelles prepared from the block copolymer having PAsn segment with three aminoethylene repeats induced efficient and prolonged protein expression from mRNA after in vivo delivery to the mouse knee joint, leading to effective treatment of osteoarthritis using cartilage‐anabolic transcription factor mRNA . Interestingly, in pDNA delivery, PAsn with an even number of repeats induced much more efficient transgene expression compared to that with an odd number of repeats .…”

“…On the other hand, elongation of the duration of protein expression is required for expanding the range of target diseases, for example, chronic diseases and single gene disorders. In our previous reports, intracellular mRNA degradation was effectively prevented by polycation optimization, leading to prolonged protein expression from mRNA in cultured cells and also in mice . Designing mRNA carriers to control intracellular mRNA stability is further needed, although studies discussing this issue are so far limited.…”