Oral delivery of DNA-enzyme nanoparticles ameliorates inflammation in a murine model of ulcerative colitis
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Baker, Nusaiba
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Abstract
Ulcerative colitis (UC) is a chronic relapsing disease characterized by
epithelial barrier damage and disruption of immune homeostasis in the colon.
Incidence is increasing every year, affecting 1-2 of every thousand persons
in developed countries. Current treatments aim to alleviate inflammation as
well as heal the damaged mucosa. Current therapeutic strategies include
5-aminosalicylates, corticosteroids, immunosuppressants, or biologics.
However, these treatments result in numerous off-target effects, and
immunosuppression can be fatal.
A major cause of inflammatory symptoms is the release of cytokines from
immune cells. These cytokines, such as IL-4, IL-5, TNF-a, and IFN-g signal to the body to cause symptoms such as fever, fatigue, swelling, and cachexia.
GATA3, a transcriptional activator, is involved in T lymphocyte
differentiation and signaling, and regulates the expression of cytokines such
as IL-4, IL-5, and IL-13. Accordingly, knock down of GATA3 and subsequent
cytokine expression is a promising strategy for treatment of inflammatory
disease. A range of antisense and RNAi technologies have been tested, and
among these approaches, DNA enzymes (Dzs) have shown the greatest promise in
animal models and Phase 1 clinical trials.
Dzs are canonical DNA oligonucleotides that catalytically degrade a specific
complementary RNA sequence. Despite the success of soluble Dzs as a
therapeutic intervention, delivering highly charged oligonucleotides across
the plasma membrane, and preventing nuclease degradation are major
challenges. To address these problems, we have developed GATA3 DNAzyme
nanoparticle conjugates delivered via an oral hydrogel method that elucidate
the stability and delivery issues. Preliminary evidence shows that
conjugating ~100 Dzs to a 14-nm gold particle forms a complex (DzNP) that
improves airway function in mouse models of asthma. Importantly, DzNPs use
one order of magnitude lower Dz dose compared to their soluble counterparts.
By delivering the DzNPs via an alginate-based hydrogel, the therapeutic
DNA-coated nanoparticles survive the acidic environment of the stomach and
are degraded in the small intestine. Thus, we have established a novel method
of gene regulation using a synthetic biomaterial. This research will provide
a foundation for future development of nanoparticle-based therapeutic
strategies for numerous diseases.
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Date
2018-11-07
Extent
03:15 minutes
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