Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases

Amy Paller, MS, MD

Our great progress in understanding the underlying basis for immune-mediated and genetic diseases has led to breakthroughs in therapy beyond prenatal and preimplantation diagnosis. Newer technology, ranging from next-generation sequencing to microarrays to proteomics, has facilitated these breakthroughs. Gene replacement through skin grafts has been initiated for treating recessive dystrophic epidermolysis bullosa based on early mouse studies and our knowledge of the deficiency of collagen VII and stem cell therapy to replenish cells with collagen VII- or laminin 332-producing skin cells at wounds has been modified to decrease risk and increase efficiency.

The availability of technology to create induced pluripotent stem cells and direct their differentiation into skin cells means designable sources of both stem cells and skin cells for grafts. New technology, such as use of microneedles or topically applied interfering RNA, is being studied as well to suppress the abnormal protein product and correct dominant-negative skin disorders, such as epidermolysis bullosa simplex and dominant dystrophic epidermolysis bullosa. Laboratory-based technology has also delineated the alterations in RNA and protein expression that define cutaneous immune-mediated disorders and tumors.

By understanding pathways that are activated, new therapy has been developed to target specifically these pathways and suppress the overactive immune system or growth and survival pathways. Recognition of the key roles of TNF, IL-23, and IL-17 in psoriasis has revolutionized our intervention through the development of targeted biologics.  The promising ongoing trials of IL-4 receptor antagonist and other blockers of Th2/Th22 pathways suggest that severe atopic dermatitis will similarly be treated with effective biologics. Already small molecules that target the activated signaling pathways in basal cell carcinomas (vismodegib), neurofibromatosis (imatinib for mast cells), and tuberous sclerosis (rapamycin) have suppressed tumor growth. Rapamycin is currently being applied to other disorders in which Akt/mTOR signaling is activated, such as venous malformations and could be considered for the subset of epidermal nevi with Akt pathway activation.

The other pathway leading to growth is the MAP kinase pathway, including through Ras and Raf activation. While a classic example of successful pathway suppression includes vemurafenib for Braf activation/ the Braf V600E mutation in melanoma, this MAP kinase pathway also plays a role in pediatric skin disorders of keratinocytes  (e.g., epidermal nevi), melanocytes (e.g., several forms of pigmented nevi), and endothelial cells (e.g., portwine stains). Finally, protein or lipid replacement therapy is an option used for several noncutaneous genetic disorders and is finding its way to dermatology. Injected recombinant collagen VII protein is now in trials for adults with recessive dystrophic EB and the combination of a statin to suppress the accumulation of cholesterol pathway precursors and cholesterol to replete the deficiency from pathway blockade has been used topically to reverse the skin changes of CHILD syndrome (Congenital Hemidysplasia with Ichthyosis and Limb Defects), which results from an enzyme deficiency in cholesterol biosynthesis.

These examples are just the beginning of what laboratory breakthroughs can yield for our patients. The next frontier is epigenetics and scientists are now unraveling the mechanisms that control cell- and tissue-specific gene expression. We can only imagine what scientists will discover in the future to transform medicine through personalized mutation-based gene and pharmacologic therapy.