Current therapy of the ichthyoses, including the lipid synthetic, autosomal recessive congenital ichthyoses (ARCI), is largely 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 proposed new approach has been first, to identify pathogenic mechanisms in ARCI patients, using biopsies from patients and animal models, as well as organotypic models (HEEs) of the ARCI, prepared from either patient fibroblast or keratinocyte cell lines, or from normal fibroblasts by CRISPR/Cas 9 technology. Using ultrastructural, lipid biochemical, and RNA-seq technology, we will assess both the cellular and genetic basis for these disorders, and identify compensatory mechanisms that account for patient survival. We then will assess whether this new information can translate into readily-deployable, topical therapies for patients after their initial optimization in ARCI HEEs, and in disease-appropriate animal models. Following identification and optimization of effective therapy in the animal models, we will initiate clinical studies for these patients, supported by 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 syndromic disorders with extracutaneous disease manifestations, successful pathogenesis-based therapy for these ARCI could also identify comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.
Current treatment of the ichthyoses is based largely upon improving appearance by removal of excess scale, with a distant dream of gene therapy. Our prior studies illuminated cellular mechanisms that lead to the skin features of several of the inherited ichthyoses, including disorders of lipid (fat) metabolism, genetic mutations result in both a deficiency of the pathway end-product (e.g., cholesterol) and excessive accumulation of toxic precursors. Accordingly, we were able to treat the ichthyotic skin in one group of these patients with a combination of topical cholesterol (end-product) along with a statin (preventing accumulation of toxic metabolites, and here we will assess whether this concept applies to additional inherited, lipid-based metabolic disorders, the autosomal recessive congenital ichthyoses (ARCI), as well as the efficacy of therapies that correct one or both of these mechanistic abnormalities in animal models, ultimately leading to new types of treatment for these patients.
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