Transglutaminase 1 Replacement Therapy Successfully Mitigates the Autosomal Recessive Congenital Ichthyosis Phenotype in Full-Thickness Skin Disease Equivalents

Plank, Roswitha; Yealland, Guy; Miceli, Enrico; Cunha, Dulce Lima; Graff, Patrick; Thomforde, Sari; Gruber, Robert; Moosbrugger‐Martinz, Verena; Eckl, Katja Martina; Hennies, Hans Christian; Hedtrich, Sarah

doi:10.1016/j.jid.2018.11.002

Cited by 26 publications

(22 citation statements)

References 15 publications

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“…This proof-of-principle study demonstrates the feasibility of RF heating induced release of bovine serum albumin labeled with fluorescein (BSA-FITC) from thermoresponsive nanogels using an integrated ThermalMR setup for anatomic reference imaging, temperature monitoring, and thermal intervention. The release profile from the thermoresponsive nanogels obtained for the reference data using a water bath as temperature stimulus is in accordance with the release kinetics deduced from the ThermalMR setup and from previous studies [ 35 , 36 , 37 , 38 ]. The nanogels were initially designed to deliver proteins into the skin thus the slower release rate in comparison to thermoresponsive carriers tailored for drug delivery at the tumor site [ 39 , 40 ].…”

Section: Discussionsupporting

confidence: 88%

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Winter

Navarro

et al. 2020

Cancers

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Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care.

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Section: Discussionsupporting

confidence: 88%

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Winter

Navarro

et al. 2020

Cancers

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“…Currently, management of autosomal recessive ichthyosis is largely supportive. However, new treatments specific to the inherent skin pathology are in clinical development, such as topical transglutaminase 1 protein replacement therapy, which emphasize the likely future importance of stratification by genotype in delivering tailored treatments. Our study findings in this English cohort add new phenotypic data that will sharpen clinical skills, as well as creating a database for future translational research.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis

et al. 2019

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Summary Background Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype–phenotype correlation in some populations. Objectives We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype–phenotype correlation. Methods Deep phenotyping was undertaken by history‐taking and clinical examination. DNA was screened for mutations using a next‐generation sequencing ichthyosis gene panel and Sanger sequencing. Results Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self‐improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. Conclusions These data refine genotype–phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype–phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

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“…In HSEs with knocked down ALOX12B , ALOXE3, or NIPAL4 , they observed reduced amounts of FLG as well as increased permeability to LY [99], suggesting major impairment of the SC barrier. Recently, in a follow-up study, the same group utilized TGM1 knocked down HSEs to test the effectiveness of TGM1 replacement therapy [100]. This is of great importance because no cure exists for patients with monogenetic ichthyoses.…”

Section: 3d Cultures To Study Cellular and Molecular Abnormalitiesmentioning

confidence: 99%

“…In their work, Plank et al topically applied TGM1 loaded in a thermoresponsive nanogel (dPG-pNIPAM tNGs) which allows effective delivery through the SC [101]. They observed not only TGM1 in the granular layer of TGM1 knocked down epidermis but also its activity [100]. A similar strategy was successfully deployed by Stout at al.…”

Section: 3d Cultures To Study Cellular and Molecular Abnormalitiesmentioning

confidence: 99%

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris

Leman

Moosbrugger‐Martinz

Blunder

et al. 2019

Cells

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Atopic dermatitis (AD) is characterized by dry and itchy skin evolving into disseminated skin lesions. AD is believed to result from a primary acquired or a genetically-induced epidermal barrier defect leading to immune hyper-responsiveness. Filaggrin (FLG) is a protein found in the cornified envelope of fully differentiated keratinocytes, referred to as corneocytes. Although FLG null mutations are strongly associated with AD, they are not sufficient to induce the disease. Moreover, most patients with ichthyosis vulgaris (IV), a monogenetic skin disease characterized by FLG homozygous, heterozygous, or compound heterozygous null mutations, display non-inflamed dry and scaly skin. Thus, all causes of epidermal barrier impairment in AD have not yet been identified, including those leading to the Th2-predominant inflammation observed in AD. Three dimensional organotypic cultures have emerged as valuable tools in skin research, replacing animal experimentation in many cases and precluding the need for repeated patient biopsies. Here, we review the results on IV and AD obtained with epidermal or skin equivalents and consider these findings in the context of human in vivo data. Further research utilizing complex models including immune cells and cutaneous innervation will enable finer dissection of the pathogenesis of AD and deepen our knowledge of epidermal biology.

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Transglutaminase 1 Replacement Therapy Successfully Mitigates the Autosomal Recessive Congenital Ichthyosis Phenotype in Full-Thickness Skin Disease Equivalents

Cited by 26 publications

References 15 publications

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Genotype–phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis

3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris

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