Veterans Affairs

Pharmaceutical compositions for treating autoimmune disorders mediated by T helper 17 cells

This aptamer-facilitated cell-specific delivery of shRNA represents a novel approach for efficient RNAi delivery and has the potential to be developed for therapeutics targeting specific T cells subtypes

Medical & Biotechnology

Scanning electron micrograph of a human T cell from the immune system of a healthy donor. (NIAID photo)

Medical research by the U.S. Department of Veterans Affairs has led to potentially valuable pharmaceutical discoveries. The following describes a patented technology available to companies that would use it to develop new drug therapies.

RNA interfering (RNAi)-mediated gene silencing holds great promise for manipulating, studying, and developing T cell targeted therapeutics.

However, efficient delivery of small interfering RNA (siRNA) into primary T cells represents a major hurdle to the wide use of RNAi technology as T cells are known to be hard to transfect. Several methods of transfection have been applied to T cells with varying degrees of success but the most notable disadvantage of these methods is that they are not suitable for in vivo use.

Many autoimmune and inflammatory diseases are mediated by T helper 17 (Th17) cells. Th17 cells produce several inflammatory cytokines, including IL-17, IL-17F, IL-22, and IL-21 which all have been implicated in mediating the chronic inflammation that is characteristic of a number of autoimmune inflammatory diseases. Blocking IL-17A activity has been proven to be highly effective to treat immune-mediated inflammatory disease models and clinical trials with blocking IL-17 are ongoing with promising results. However, IL-17A and IL-17F are also produced by many other innate immune cells and are important cytokines in host defense. Moreover, it is Th17 cells that are detrimental and are to be blocked for therapeutic purposes. Therefore, it is highly desirable to narrow the target to Th17 cells and spare IL-17 cytokines produced by innate immune cells from being blocked.

The retinoic acid receptor-related orphan receptor gamma 2 gene encodes RORγt which is required for the differentiation of Th17 cells. RORγt is a nuclear transcription factor and the intracellular location of RORγt makes it an undruggable target by monoclonal antibodies. With this background, VA researchers have developed a CD4 aptamer -shRNA chimera specific to RORγt to suppress Th17 cells. By substituting the shRNA for targeted genes, this CD4 aptamer may be used as a universal vehicle to introduce RNAi into CD4+ T cells.

Compared with other vehicles for siRNA delivery into T cells, aptamers have many advantages. The size of aptamers is relatively smaller and less likely to be immunogenic. This is particularly critical for in vivo use as therapeutics. Aptamers can be chemically synthesized and it is relatively less expensive to generate aptamer-shRNA/siRNA.

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