Abstract
The skin provides direct protection to the human body from assault by the harsh external environment. The crucial function of this organ is significantly disrupted in genodermatoses patients. Genodermatoses comprise a heterogeneous group of largely monogenetic skin disorders, typically involving mutations in genes encoding structural proteins. Therapeutic options for this debilitating group of diseases, including epidermolysis bullosa, primarily consist of wound management. Genome editing approaches co-opt double-strand break repair pathways to introduce desired sequence alterations at specific loci. Rapid advances in genome editing technologies have the potential to propel novel genetic therapies into the clinic. However, the associated phenotypes of many mutations may be treated via several genome editing strategies. Therefore, for potential clinical applications, implementation of efficient approaches based upon mutation, gene and disease context is necessary. Here, we describe current genome editing approaches for the treatment of genodermatoses, along with a discussion of the optimal strategy for each genetic context, in order to achieve enhanced genome editing approaches.
Highlights
Aside from the ease and cost of and use, all genome editing technologies rely on the formation of specific double-strand breaks (DSBs) generation and use, all genome editing technologies rely on the formation of specific double-strand and their resolution via DSB repair pathways
The majority of genome editing-mediated gene disruption approaches in genodermatoses have targeted keratinopathies. These are a group of disorders including epidermolysis bullosa simplex (EBS), epidermolytic ichthyosis (EI) and pachyonychia congenita (PC), largely caused by dominant-negative mutations in keratins expressed within specific epidermal layers of the skin [54]
Genome editing efficiencies of over 20% were subsequently described in treated primary EI keratinocytes
Summary
The skin is the largest organ of the human body, consisting of three main layers, with differing cellular localization, organization, expression and function (Figure 1) [1]. The deepest of these is the underlying subcutaneous fat layer, which contacts skeletal muscle. The basement membrane is essential for adhesion and signaling between the dermis and the much thinner, outermost layer of the skin—the epidermis [4]. This is a multi-layered, stratified squamous epithelium, largely composed of keratinocytes and capable of continuous regeneration [5]. Type XVII collagen and type VII collagen, are crucial for the integrity and stability of the skin
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