RNA-Based Antipsoriatic Gene Therapy: An Updated Review Focusing on Evidence from Animal Models

Abstract

Psoriasis presents as a complex genetic skin disorder, characterized by the interaction between infiltrated immune cells and keratinocytes. Substantial progress has been made in understanding the molecular mechanisms of both coding and non-coding genes, which has positively impacted clinical treatment approaches. Despite extensive research into the genetic aspects of psoriasis pathogenesis, fully grasping its epigenetic component remains a challenging endeavor. In response to the pressing demand for innovative treatments to alleviate inflammatory skin disorders, various novel strategies are under consideration. These include gene therapy employing antisense nucleotides, silencing RNA complexes, stem cell therapy, and antibody-based therapy. There is a pressing requirement for a psoriasis-like animal model that replicates human psoriasis to facilitate early preclinical evaluations of these novel treatments. The authors conduct a comprehensive review of various gene therapy in different psoriasis-like animal models utilized in psoriasis research. The animals included in the list underwent skin treatments such as imiquimod application, as well as genetic and biologic injections, and the results of these interventions are detailed. Animal models play a crucial role in translating drug discoveries from the laboratory to clinical practice, and these models aid in improving the reproducibility and clinical applicability of preclinical data. Numerous animal models with characteristics similar to those of human psoriasis have proven to be useful in understanding the development of psoriasis. In this review, the article focuses on RNA-based gene therapy exploration in different types of psoriasis-like animal models to improve the treatment of psoriasis.

Keywords: animal model; gene therapy; miRNA; psoriasis; siRNA.

Figure 1

A simplified diagram illustrating the structural alterations in human skin affected by psoriasis. Normal skin structure (left) and compared with psoriatic skin (right). The formation of scaly, raised, red plaques on the skin, accompanied by I. acanthosis; II. parakeratosis; III. hyperkeratosis; IV. Munro’s microabscess. These plaques can be uncomfortable and itchy, causing pain and irritation.

Figure 2

Gene silencing mechanisms of miRNA. The transcription of miRNA genes occurs in the nucleus via RNA polymerase II, yielding a primary miRNA (pri-miRNA) that is then cleaved by Drosha into a precursor miRNA (pre-miRNA). Exportin 5 mediates the transport of pre-miRNA to the cytoplasm where Dicer cleaves it into mature miRNA. The miRNA is then loaded onto the RISC complex, where the passenger strand is eliminated, and the guide strand directs RISC to partially complementary target mRNA. The binding between the guide strand and target mRNA leads to various modes of target inhibition, including translational repression, degradation, or cleavage.

Figure 3

Gene silencing mechanisms of siRNA. Dicer processes dsRNA (either endogenous or exogenous) into siRNA, which is incorporated into the RISC complex. The passenger strand of siRNA is cleaved by AGO2, a component of RISC, leaving the guide strand to direct the complex to the complementary mRNA target. Upon binding, the guide strand initiates cleavage of the target mRNA, leading to gene silencing.

Figure 4

A summary of various methods used to create animal models for studying psoriasis. Various techniques have been utilized to generate animal models of psoriasis, with each method resulting in chronic inflammatory hyperproliferative skin phenotypes that bear resemblance to psoriasis. These manipulations, which involve different cell types and molecular mechanisms, may induce the development of hyperproliferative inflammatory skin changes, suggesting diverse pathogenic mechanisms (elaborated in the text).