3D model of harlequin ichthyosis reveals inflammatory therapeutic targets

Enjalbert, Florence; Dewan, P.; Caley, Matthew; Jones, Erica; Morse, Mary A.; Kelsell, David P.; Enright, Anton J.; O’Toole, Edel A.

doi:10.1172/jci132987

Cited by 39 publications

(44 citation statements)

References 48 publications

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“…IL-36γ, which has been described as a biomarker of psoriasis 15 and IL-38, an antagonist of IL-36γ, were also detectable in patient's serum at time point 0. Consistently, recently published studies report high expression of IL-36γ in skin samples obtained from ichthyosis 16 and psoriasis patients. 17 Moreover, treatment with secukinumab resulted in reduced systemic and local IL-36γ expression accompanied by an upregulation of IL-38.…”

Section: Discussionsupporting

confidence: 85%

Efficacy and safety of secukinumab for the treatment of severe ABCA12 deficiency‐related ichthyosis in a child

Yogarajah

Gouveia

Iype

et al. 2021

Skin Health and Disease

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Background: Patients with severe autosomal recessive congenital ichthyosis (ARCI) show a T helper 17/interleukin 17 (Th17/IL17) skewing in their skin and serum, resembling the inflammatory profile of psoriatic patients. Secukinumab, an IL-17A inhibitor, has shown clinical efficacy in patients with moderate-to-severe plaque psoriasis. Aims: To test the clinical efficacy and safety of secukinumab in a paediatric patient with ATP-binding cassette subfamily A member 12 deficiencyrelated severe erythrodermic ARCI.Materials & Methods: 6-months therapeutic trial. During the first 4-weeks induction period, the patient received weekly subcutaneous injections of 150 mg secukinumab (five injections in total). During the following 20weeks maintenance period, the patient was given a subcutaneous injection of 150 mg secukinumab every 4 weeks. Result & Discussion: After the 6-months therapy period, there was a 48% reduction from the baseline Ichthyosis-Area-Severity-Index (-Erythema/-Scaling) score. The treatment was well tolerated. Moreover, cytokine analysis revealed a reduction of keratinocyte-derived proinflammatory cytokines and an abrogation of Th17-skewing during therapy. Conclusion: Further studies are needed to evaluate the effects of the use of IL-17A inhibition in ARCI patients. J. Yogarajah and C. Gouveia contributed equally to this study.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionsupporting

confidence: 85%

Efficacy and safety of secukinumab for the treatment of severe ABCA12 deficiency‐related ichthyosis in a child

Yogarajah

Gouveia

Iype

et al. 2021

Skin Health and Disease

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“…Successful editing of ABCA12 was measured by a lack of protein expression. This edited cell line was then confirmed to demonstrate many of the phenotypes of harlequin ichthyosis, including dysregulated KC differentiation and lipid reorganization as well as elevated cytokine production (Enjalbert et al, 2020).…”

Section: Cationic Vectorsmentioning

confidence: 93%

“…In addition, a combination of the cationic vectors, FuGENE 6 and HyperFect transfection reagents, have been used to target genes for modification in N/TERT-1 cells. Again, gene inactivation was detected by western blot analysis of the targeted protein with no genome editing efficiency assessed (Enjalbert et al, 2020).…”

Section: Crispr/cas9-editing Efficiencies Of Epidermal Cells From Different Delivery Methodsmentioning

confidence: 99%

“…Cationic vectors were recently used to develop an in vitro model for the skin disease, harlequin ichthyosis. This disease is known to arise by a mutation in the ABCA12 gene, so to model this in vitro, a combination of the cationic vectors, FuGENE 6 and HyperFect, were used to deliver sgRNA and Cas9 to an immortalized KC line (N/TERT-1) to inactivate ABCA12 (Enjalbert et al, 2020;Smits et al, 2017). Successful editing of ABCA12 was measured by a lack of protein expression.…”

Section: Cationic Vectorsmentioning

confidence: 99%

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Research Techniques Made Simple: Delivery of the CRISPR/Cas9 Components into Epidermal Cells

Shi

Smits

Bogaard

et al. 2021

Journal of Investigative Dermatology

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CRISPR/Cas9 technology is a powerful tool used to alter the genetic landscape of various hosts. This has been exemplified by its success in the transgenic animal world where it has been utilized to develop novel mouse lines modeling numerous disease states. The technology has helped to develop both in vitro and in vivo systems that simulate diseases within the fields of epithelial biology, skin cancer biology, dermatology, and beyond. Importantly, the delivery of the single-guide RNA/Cas9 editing complex to the host cell is key for its success. In this paper, we discuss the various methods that have been utilized as delivery techniques for CRISPR/Cas9 components, the benefits and pitfalls of each, and how successful they have been at genetically modifying epidermal cells. In addition, we acknowledge recent advances in the field of dermatology that have harnessed these methods to better understand epidermal biology, identify potential therapeutic targets, or serve as novel methods to treat disease states.

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“…miR-211 is known to be downregulated in vitiligo melanocytes, 5 where it regulates cellular metabolism. 6 The findings of Brahmbhatt et al shift the focus to NSV keratinocytes and DNA…”

mentioning

confidence: 99%