Current therapy of the Ichthyoses is purely symptomatic, and often irrational;e.g., when removal of excess scale interferes with homeostatic responses that allow patients to survive in a harsh, terrestrial environment. At the other extreme, corrective gene therapy, though seductive in concept, remains a distant dream, with many potential pitfalls. Our approach will be first, to identify pathogenic mechanisms in patients, and then to assess whether this new information can be translated into readily-deployable, topical therapy in disease-appropriate animal models. Initially, we will study Ichthyosis pathogenesis (in patients and relevant animal models) with inherited, syndromic disorders of distal cholesterol metabolism (Group I disorders) where the cutaneous phenotype can range from severe (as in CHILD syndrome, lathosterolosis, and SC4MOL deficiency), to moderately-severe (as in CHH), or mild-to-inapparent (as in SLOS and desmosterolosis). Then, we will translate mechanistic insights into potentially-effective therapies in relevant animal models. This pathogenesis-based approach then will be extended to patients (and animal models) of other syndromic disorders of lipid metabolism (Group II). Following identification and optimization of effective therapy in the animal models, we will launch clinical studies for these patients, as part of a parallel grant proposal. If successful, this approach should initiate a paradigm shift in how many of the Ichthyoses will be treated in the future. Finally, since the cutaneous phenotype reflects pathogenic mechanisms that also are on-going in extracutaneous tissues, successful pathogenesis-based therapy for the Ichthyoses could point to comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.
Current treatment of the Ichthyosis based upon improving appearance by removal of excess scale, with a distant dream of gene therapy. Our recent work has been illuminated cellular mechanisms that lead to the skin features of the Ichthyoses. In the case of disorders of lipid (fat) metabolism, genetic mutations result in both a deficiency of the pathway end-product (e.g., cholesterol) and accumulation of toxic precursors. We will assess whether this concept applies to additional lipid metabolic disorders, and assess the efficacy of therapies that correct both of these abnormalities, leading to clinical improvement.
|Huang, Li-Ning; Zhong, Yi-Ping; Liu, Dan et al. (2018) Adverse cutaneous reactions to skin care products on the face vary with age, but not with sex. Contact Dermatitis 79:365-369|
|Elias, Peter M; Sugarman, Jeffrey (2018) Does moisturizing the skin equate with barrier repair therapy? Ann Allergy Asthma Immunol 121:653-656.e2|
|Grond, Susanne; Radner, Franz P W; Eichmann, Thomas O et al. (2017) Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation. J Invest Dermatol 137:403-413|
|Blunder, Stefan; Rühl, Ralph; Moosbrugger-Martinz, Verena et al. (2017) Alterations in Epidermal Eicosanoid Metabolism Contribute to Inflammation and Impaired Late Differentiation in FLG-Mutated Atopic Dermatitis. J Invest Dermatol 137:706-715|
|Grond, Susanne; Eichmann, Thomas O; Dubrac, Sandrine et al. (2017) PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides. J Invest Dermatol 137:394-402|
|Young, Christina A; Eckert, Richard L; Adhikary, Gautam et al. (2017) Embryonic AP1 Transcription Factor Deficiency Causes a Collodion Baby-Like Phenotype. J Invest Dermatol 137:1868-1877|
|Zhang, Lei; Ferreyros, Michael; Feng, Weiguo et al. (2016) Defects in Stratum Corneum Desquamation Are the Predominant Effect of Impaired ABCA12 Function in a Novel Mouse Model of Harlequin Ichthyosis. PLoS One 11:e0161465|
|Choate, Keith A; Lu, Yin; Zhou, Jing et al. (2015) Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti. J Clin Invest 125:1703-7|
|Tiganescu, Ana; Hupe, Melanie; Jiang, Yan J et al. (2015) UVB induces epidermal 11?-hydroxysteroid dehydrogenase type 1 activity in vivo. Exp Dermatol 24:370-6|
|Rorke, E A; Adhikary, G; Young, C A et al. (2015) Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function. Cell Death Dis 6:e1647|
Showing the most recent 10 out of 28 publications