Advancing novel therapies for ichthyoses

Short abstract

Linked Article: Valentin et al. Br J Dermatol 2021; 184:1123–1131.

Sequencing technology increasingly allows for clarification of the genetic basis of disease pathogenesis in rare genodermatoses such as the ichthyoses. While there has been great progress in the discovery of genetic variations underlying ichthyoses and the elucidation of the pathomechanisms, therapeutic developments have been sparse. Too often, no therapeutic benefit follows from research advances in the field, and, to date, there are few examples for targeted therapy that address the molecular cause of the disease. Thus, patient options are still mostly limited to keratolytics, topical anti‐inflammatory agents, rather unspecific emollient therapies, and topical and systemic retinoids.

However, it is likely that this will change. An increasing number of researchers are dedicated to devising new, targeted therapies based on progress in the understanding of disease pathogenesis, and powerful advances are being made in the area of genodermatoses. With regard to the ichthyoses, therapeutic intervention can take multiple and diverse forms. It remains unclear if a single one of the strategies will prevail. A competitive ‘best athlete approach’ is likely to yield optimal benefit for patients. Some examples of mechanism‐targeted treatments currently being developed are listed in Table 1.

Table 1.

Targeted therapies for ichthyoses

At the DNA level, mutations can be excised or corrected, or expression vectors can be introduced 3 , 4

Small molecules modulate relevant signalling pathways, e.g. nitric oxide synthase inhibitors or Janus kinase inhibitors improve tissue models of harlequin ichthyosis 5

Protease inhibitors are being developed to antagonize protease overactivity in Netherton syndrome 6

Monoclonal antibodies neutralize mediators of skin inflammation in patients with ichthyosis 7 , 8

Deficient lipid components that are essential for the epidermal barrier have been exogenously added and shown to improve the scaling phenotype in ichthyosis 9

Decreased or absent proteins can be delivered to diseased skin grafts 2 , 10

In 2010, Oji et al. reported that permeability barrier impairment in peeling skin syndrome 1 (PSS‐1) is caused by corneodesmosin deficiency, resulting in a distinct ichthyosis phenotype, which includes decreased corneocyte coherence, food allergies and failure to thrive. ¹ As in other related ichthyoses, this disease has a significant impact on patient quality of life and years lost due to disability, and there are no good therapies.

In this issue, Dr Oji’s group presents compelling evidence of successful liposome‐based delivery of recombinantly synthesized corneodesmosin to patient‐derived PSS‐1 keratinocytes both in monolayer and in three‐dimensional (3D) cultures. ² Aside from choosing protein supplementation as the method of disease modification, the efficient and precise delivery of the compounds to the crime scene – the tissue or the cell – represents a major hurdle. The carrier system used by Valentin et al. consists of 1‐palmitoyl‐2‐oleoyl‐glycero‐3‐phosphocholine, mimicking cellular lipid membranes. Lamellar vesicles were optimized in size for efficient uptake of the corneodesmosin cargo, and for good penetration properties. Importantly, liposomes loaded with corneodesmosin and tagged with the lipopeptide P2K12 showed a localization at the plasma membrane of the keratinocytes. Consequently, corneodesmosin was successfully delivered to the cytoplasm of keratinocytes, and functional studies showed improvements of histopathological alterations and epidermal barrier function in 3D human skin equivalents.

As demonstrated, delivery remains a major hurdle to overcome when trying to deliver nucleic acids or peptides/proteins to viable epidermal cells. The skin barrier, as created by the stratum corneum, normally prevents large molecules from entering the body. Multiple strategies to penetrate the skin barrier for delivery of bioactive therapeutic molecules have shown promise. Other than the liposomes and cationic lipopeptide described here, additional carrier options include nanocarriers such as thermoresponsive nanogels or spherical nucleic nanoparticle conjugates. Also effective are disruptive biophysical interventions such as iontophoresis, sonophoresis, electroporation, laser abrasion, microneedles, high‐velocity jets, intradermal injections and – most invasive – skin transplants. Optimization for enhanced delivery must be carried out for each specific cargo and each specific entity.

Although liposome‐based corneodesmosin delivery to PSS‐1 skin appears highly attractive, the approach requires replication, refinement and in vivo confirmation. Nevertheless, the work is seminal and will be followed by more detailed descriptions of in vivo efficacy and potential adverse effects. This is a very exciting area of investigation, which opens up possibilities for treatment of PSS‐1 and related disorders of cornification, i.e. ichthyoses.

Author Contribution

Matthias Schmuth: Conceptualization (lead). Julia Reichelt: Data curation (equal); Validation (equal); Writing‐review & editing (equal). Robert Gruber: Formal analysis (equal); Methodology (equal); Writing‐review & editing (equal).