Topically-Delivered Targeted Gene Suppression of Immune Activation in Psoriasis

Project: Research project

Project Details

Description

While the pathogenesis of psoriasis is now well understood and this knowledge has translated into targeted systemic therapy, targeted topical therapies have never been developed. Using a new nanotechnology approach, we have generated oligonucleotide nanoconjugates (“spherical nucleic acids” or SNAs) that are able to penetrate psoriatic skin and suppress gene targets locally after topical application. The prototype SNA developed for psoriasis, a TNF-targeting SNA, is highly effective in knocking down TNF and prevents the development of psoriatic changes in the imiquimod (IMQ) mouse model. This TNF-targeting SNA in a gel formulation has passed preclinical safety testing and will shortly begin Phase I human testing. There is now clear evidence, however, that IL-17A or its receptor (IL17RA) is a superior target, based on the spectacular results of IL-17A or IL-17RA antagonism when delivered systemically for psoriasis. In addition, studies have shown that integrative responses to IL-17A and TNF account for the inflammatory activation that leads to psoriasis. This 1-year pilot proposal advances the SNA technology with the hypothesis that a newly engineered SNA that knocks down IL17RA will efficiently suppress the psoriatic phenotype in 3D human and IMQ-induced mouse models. Specifically, our Aims are to:

1) Examine the ability of IL17RA to normalize epidermal differentiation and cytokine expression in a 3D human psoriasis-like model.

2) Evaluate the ability of topically applied IL17RA SNAs prevent and reverse the clinical, histological and transcriptomic features of imiquimod-induced psoriasis-like disease in a mouse model.
StatusFinished
Effective start/end date7/1/166/30/18

Funding

  • National Psoriasis Foundation (AGREEMENT 7/1/16)

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