DNA Delivery for Vaccination and Therapeutics Through the Skin

Abstract

Cutaneous gene therapy and DNA vaccination are potential applications of plasmid delivery methods where a gene for an antigen or a therapeutic protein is inserted in the plasmid and applied to the skin. However, the delivery of the DNA plasmid is a major challenge due to the unusual physicochemical properties of the DNA, the tissue and cellular barriers and expression difficulties. Even though the skin is the most accessible organ of the body and it is an ideal target for gene therapy, the delivery of plasmid DNA across the skin is very difficult due to the specific barrier function of the stratum corneum and the inconsistent transfection rate of keratinocytes and other epidermal cells. To date there is no gene delivery system that was shown to be optimal for cutaneous gene therapy. In order to develop an efficient non-viral delivery vehicle we need to design a system that provides the combined properties of effective DNA condensation, cutaneous permeation, cellular transfection and sufficiently sustained expression. This paper reviews the formulation approaches and delivery methods for DNA through the skin in the context of the barriers both at the tissue and cellular levels for both vaccine and gene therapy applications.

Proteolytic Activation Cascade of the Netherton Syndrome–Defective Protein, LEKTI, in the Epidermis: Implications for Skin Homeostasis

“…Nevertheless, in spite of the encouraging results (Di et al, 2010;Roedl et al, 2011), the ex-vivo gene transfer cannot be envisaged as an imminent therapeutic option. Local delivery through the horny layer, by means of topical application or non-invasive mini-gene transfer (Foldvari et al, 2006) of LEKTI bioactive fragments could attenuate unopposed KLKs activity and counteract the skin barrier impairment of NS patients. Although the efficacy and safety in vivo of the ''putative'' LEKTI fragments studied by others cannot be predicted, it is fair to expect for a beneficial effect by the LEKTI physiological fragments.…”

rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients

“…Such shorter transgenes could possibly being transduced at higher efficacy and the corresponding protein fragments might be sufficient for treating at least some NS patients, but further research is necessary to find out which combination of domains works best for which mutations. A small transgene would also be suitable for non viral topical gene transfer approaches in the sense of a gene cream for instance by using transposon elements forcing stable integration of the transgene and a liposomal formulation that facilitate transcorneal permeation [26].…”

On the Search for Skin Gene Therapy Strategies of Xeroderma Pigmentosum Disease

“…Up to now, they are attractive alternatives for the expression of protein to the antigen presenting cells existing in skin epidermis and dermis, for DNA vaccine purposes. Many recent reviews provide more complete details of non-viral strategies to deliver genes into skin tissues [Hengge and Bardenheur, 2004;Birchall, 2006;Hoffman, 2006;Foldvari et al, 2006], but we will give a brief description of the different approaches, mainly with the specific aim of calling attention to the possibilities of using combined formulations, and eventually improve gene delivery through viral vectors.…”

“…Prof. Lineu Prestes, 1374, Ed. Biomédicas 2, São Paulo, 05508-900, SP,Brazil; limited efficiency, and are detailed in excellent recent reviews [Hengge and Bardenheur, 2004;Birchall, 2006;Hoffman, 2006;Foldvari et al, 2006]. Viral vectors, even though more expensive and complex to generate, appear as effective alternatives that provide gene uptake and expression in many of the skin cells.…”