Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of Tuberous Sclerosis Complex.

摘要

Tuberous Sclerosis Complex (TSC) is a genetic disorder resulting from mutations in either the TSC1 or TSC2 genes. TSC is characterized by abnormal skin pigmentation and tumor formation in multiple organ systems. The TSC1 and TSC2 gene products are involved in cell signaling; in particular they are involved in the mammalian target of rapamycin (mTOR) signaling pathway. In TSC, the epidermal basal cells contain a mutant copy of either the TSC1 or TSC2 gene. A loss of heteroszygosity results in constitutive activation of mTOR leading to production of epidermal cells at a faster rate than the ability to slough the dead cells. This overproduction of skin cells, in conjunction with angiogenesis, results in the formation of visible facial angiofibromas over time. The lesions appear as red or pink papules distributed over the central face, especially on the nasolabial folds, cheeks, and chin. Lesions appear in early childhood and are present in up to 80% of TSC patients. Facial angiofibromas create considerable cosmetic morbidity for patients with TSC and currently there is no effective method for preventing or permanently removing them. Rapamycin is a naturally occurring antifungal macrolide that binds with high specificity to mTOR resulting in inhibition of mTOR activity and ultimately in downregulation of cell growth. Systematically administered rapamycin has an unfavorable side effect profile, limiting its potential use. Commonly reported side effects include oral ulcers, hyperlipidemia, thrombocytopenia, acneiform rash, immunosuppression, and impaired wound healing. Rapamycin has a molecular weight of 914.2 grams, allowing for its absorption through the superficial layers of the epidermis.