There is still a large unmet medical need for the treatment of ulcerative colitis, despite recent improvements in the understanding of the pathogenic mechanisms of ulcerative colitis.
Simply inhibiting a single inflammatory cytokine or immunological target might not be sufficient to treat ulcerative colitis due to the multifactorial and multistep nature of the disease. It could be necessary to use a combination therapy that targets various ulcerative colitis pathogenic genes and pathways.
Unfortunately, the full potential of combination therapy has not yet been realized for treating ulcerative colitis, and current therapeutic approaches are mostly centered on separate chemical compounds or monoclonal antibodies.
Small interfering RNAs (siRNAs) have the high specificity, efficacy, and adaptability to co-target numerous genes at a single dosage, making siRNA-based treatments an appealing option for combination therapy for ulcerative colitis. However, a significant obstacle to RNAi therapy continues to be the creation of an effective in vivo delivery method for siRNAs.
The liver of male mice was reprogrammed to self-assemble multiple siRNAs into secretory small extracellular vesicles in a recent study published in Nature Communications by a joint research group at Nanjing University led by Professor Chen-Yu Zhang, Xi Chen, and Qipeng Zhang.
This approach combines the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis.
In particular, repeated injections of the multi-targeted genetic circuit intended to simultaneously inhibit TNF-α, B7-1, and integrin α4 rapidly reduced intestinal inflammation. They had a synergistic therapeutic effect against ulcerative colitis by suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells, and preventing T cells from homing to sites of inflammation.
More significantly, they created an AAV-driven genetic circuit to significantly and permanently block TNF-α, B7-1, and integrin α4 with just one injection.
Overall, this study developed a workable combination therapy approach for ulcerative colitis that could serve as an alternative to traditional biological therapies that call for two or more independent chemicals or antibodies.
The following are some reasons why this study is significant:
- The multitargeted genetic circuit is created as a naked DNA plasmid or AAV and is then simply injected intravenously. Subsequently, the liver produces several siRNAs on its own and simultaneously, which are then distributed via the circulatory system of small extracellular vesicles. By redesigning the combination therapy approach and using the body’s own small RNA assembly and transport mechanisms, this design addresses the bottleneck issue in ulcerative colitis combination therapy.
- In vivo self-assembled siRNA reduces ulcerative colitis symptoms more effectively than TNF-α antibody infliximab. In vivo self-assembled siRNA shows tremendous promise of developing into a potential treatment option for patients with ulcerative colitis since monoclonal antibodies suffer from the inherent limitations of antibody medications (such as high costs, serious side effects, and the development of anti-antibody drugs).
- This research lays the framework for siRNA delivery to immune cells and inflamed areas to fine-tune immune responses. In vivo self-assembled siRNA is anticipated to hasten the development of new treatments for various autoimmune disorders because an excessive immune response is a feature of many autoimmune diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis).
Zhou, X., et al. (2022). In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis. Nature Communications. doi.org/10.1038/s41467-022-33436-0