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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR061106-01A1
Application #
8232543
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (05))
Program Officer
Baker, Carl
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$333,450
Indirect Cost
$108,450
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Menon, G K; Orsó, E; Aslanidis, Charalampos et al. (2014) Ultrastructure of skin from Refsum disease with emphasis on epidermal lamellar bodies and stratum corneum barrier lipid organization. Arch Dermatol Res 306:731-7
Elias, Peter M; Williams, Mary L; Choi, Eung-Ho et al. (2014) Role of cholesterol sulfate in epidermal structure and function: lessons from X-linked ichthyosis. Biochim Biophys Acta 1841:353-61