# microRNA target site RNA-directed oligonucleotide topical therapeutics in psoriasis

> **NIH NIH R21** · YALE UNIVERSITY · 2022 · $182,408

## Abstract

Abstract
The IL-17A/IL-23 pro-inflammatory axis has been established as an influential therapeutic target in
psoriasis. However, long-term systemic treatment with IL-17- and IL-23-directed antibody biologics can
be immunosuppressive and should be reserved for the more severe disease manifestations. This
proposal is focused on the development of topical oligonucleotides targeting IL-17A and IL-23
transcripts. Although topical treatments for plaque psoriasis exist, their efficacy is modest. A highly
specific therapy that effectively penetrates plaques for topical treatment of plaque psoriasis continues to
be a significant unmet need. Our therapeutic approach is a novel one, based on an "enhancing
microRNA" mechanism. We have begun developing an innovative platform of target site blocker (TSB)
oligonucleotides that interfere with the enhancing effect of miR466l-3p (miR466) in an individual target
mRNA-specific fashion, thereby repressing expression of only that gene. We have successfully
generated an IL-17A mRNA-specific TSB that is highly effective in IL-17-dependent murine
immune/inflammatory models of multiple sclerosis, autoimmune uveitis, and topically in imiquimod
(IMQ)- induced psoriasis. Our hypothesis that IL-17A- and IL-23- directed TSB oligos, formulated for
highly penetrable topical use, will synergistically represent a novel, highly specific, RNA-directed
treatment in psoriasis. We have assembled an outstanding collaborative team, which includes Dr. Mark
Saltzman, an expert in nucleic acid targeting through nanoparticles, and Dr. Jordan Pober, who has
developed human-to-mouse skin xenograft models. Our team now proposes to: (1) generate an IL-23-
specific TSB oligonucleotide with in vitro and in vivo (IMQ-induced psoriasis) validation, (2) optimize
poly(amine-co-ester) (PACE) nanoparticle (NP)-loaded IL-23 and IL-17A TSBs, with testing in vivo
(IMQ model), and (3) determine the penetrability of the TSB-loaded NPs into human skin, using human-
to-mouse skin xenografting and confocal imaging-based penetration analysis. This molecular,
preclinical model and biomedical nanoparticle engineering promises to develop novel therapeutic
molecules for topical targeting of the IL-17A/23 axis in plaque psoriasis.

## Key facts

- **NIH application ID:** 10426347
- **Project number:** 5R21AR079591-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JEFFREY R. BENDER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $182,408
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426347

## Citation

> US National Institutes of Health, RePORTER application 10426347, microRNA target site RNA-directed oligonucleotide topical therapeutics in psoriasis (5R21AR079591-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10426347. Licensed CC0.

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