New insights into TNFα aptamers ameliorating inflammation indices in a DTHR humanized TNFα mouse model

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Joseph, N. et al. Biodistribution and function of coupled polymer‑DNA origami nanostructures. Scientific Reports, 2023

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Since the 1980s, monoclonal antibodies have been increasingly incorporated into clinical practice as therapeutic options, particularly in oncology, immunology and inflammatory diseases^1,2. However, they are, to date, still administered systemically, which has led to disqualifying adverse reactions in major clinical trials such as the appearance of tuberculosis or lymphomas, the worsening of heart failure, and increased cardiocytotoxicity^3-6. Antibodies disperse rapidly and only a low percentage of patients exhibit long-lasting complete response to treatments. One solution could be coupling to biocompatible, stable agents with programmable spatial distribution such as polymer‑DNA hybrid nanostructures. The resulting conjugate maintains antibody activity, i.e., binding and neutralization of soluble or membrane-bound targets while restricting the diffusion of the antibody away from its target site or tissue, increasing its concentration there and limiting its occurrence elsewhere. 

Along these lines, a study conducted by a group of researchers at Augmanity Nano Ltd and the faculty of Biotechnology and Food Engineering at Haifa, recently published in Scientific Reports, shed some light on development of DNA origami-based aptamer-TNFα targeting therapeutics. TNFα (tumor necrosis factor alpha) is produced mainly by macrophages, but also by a broad variety of other cell types, including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts and neuronal tissues. TNFα is a pleiotropic cytokine involved in systemic inflammation instrumental for the immune elimination of various infectious agents. Deregulation of TNFα production has been involved in septic shock, as well as several autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, psoriasis, and insulin-dependent diabetes mellitus. A strategy conferring a spatial control over drug activity targeting TNF would be key for a wide range of therapeutic applications.

In order to establish the DNA origami-based aptamer potential to serve as a drug capable to elicit therapeutic effects in a spatially confined manner, humanized TNFα mice, developed by genOway, were treated with TNCB epicutaneous application in order to induce experimental delayed-type hypersensitivity reaction (DTHR). According to this experimental model, inflammation occurs in a challenge area (usually the ear) and results in the subsequent production of proinflammatory cytokines such as TNFα. Interestingly, it was found that humanized TNFα mice treated with long rod nanostructures comprising TNFα aptamers exhibited reduced ear swelling in response to TNCB, compared with mice treated with long rod-no aptamer. The reduced inflammation was similar to treatment with infliximab, a chimeric monoclonal antibody used as a registered drug to treat a number of inflammatory conditions (see figure 1). Notably, these effects were obtained within physiologically relevant concentrations and time ranges.

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Figure 1 in the paper: ear thickness measurements before and at the indicated time points after TNCB challenge of non-sensitized mice (healthy), untreated TNCB-sensitized mice (vehicle), long rod-treated TNCB-sensitized mice before or after TNCB challenge (LR-TNFa after/before), or infliximab-treated TNCB-sensitized mice.

These findings highlight hybrid polymer-DNA nanostructures as significant therapeutic agents with potential novel modality in the field of controllable and personalized medicine with improved precision and functionality.

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References:

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