Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases: Part 2


Amy Paller, MD, MS

Biologics as Targeted Therapy

Genetic advances are teaching us more about psoriasis as a disease state. The discovery of pathways that influence psoriasis have led to treatments such as TNF alpha inhibitors, interleukin-23 inhibitors, and IL-17 and its receptors. We have also learned that CARD14 mutations are a cause of familial psoriasis/PRP. One of the ways that CARD14 works is through the activation of IL-23 signaling and Th-17 expression, leading to the use of ustekinumab, a commercially available agent that targets IL-12/-23 with success.

Through exome sequencing, we have learned more about generalized pustular psoriasis. There is a deficiency of the interleukin-36 receptor antagonist, DITRA, in hereditary pustular psoriasis (and some cases of “sporadic” generalized pustular psoriasis show mutations in the IL-36R antagonist). This discovery suggests that activated IL-36 (or its related compound, IL-1) may be an important target in pustular psoriasis.

What about alopecia areata? We have learned from some excellent genome-wide association studies (GWAS) that there are several loci that are increased in this disease, one is which is CTLA4. There are ongoing trials of abatacept (CTLA4-Ig initiated) and rixolitinib (JAK 1/2 inhibitor to suppress IL-15 activity), but an early report of JAK1/2 inhibition showed great promise.

Targeting Functional Pathways

We can use systemic administration of small molecule inhibitors to suppress signaling activation. This can be seen with the use of vismodegib in basal cell carcinoma and basal cell carcinoma syndrome (BCNS) (activation of hedgehog signaling) and oral rapamycin in tuberous sclerosis (activation of mTOR signaling). GNAQ mutations cause the majority of blue nevi and 90 percent of cases of Sturge-Weber syndrome and nonsyndromatic portwine stains. GNAQ mutations have now been shown to activate PKC and MAPK but not AKT or mTOR. This observation suggests that an inhibitor of PKC or MAPK signaling might be effective if applied topically. With epidermal nevi, activating mutations have been detected in the genes encoding RAS family members or affecting FGFR3/PI3K/AKT signaling. Differentiating the activated pathway could influence decision-making about the most appropriate inhibitor to apply topically in the future. G13R and Q61R or Q61L Hras mutations in melanocytes cause Spitz nevi and speckled lentiginous nevi, yet another situation in which a targeted inhibitor which blocks Ras signaling might be considered as therapy.

Protein Replacement Therapy

Intradermal or intravenous introduction of recombinant collagen VII into RDEB (recessive dystrophic epidermolysis bullosa) mice leads to the deposition of collagen VII at wound BMZ and decreased skin fragility. Recently, FDA approved a trial of injected collagen VII in patients with RDEB. Future investigations might involve topically applied recombinant collagen VII to wounds or even intravenous delivery to reach mucosal sites as well. Interestingly, studies in mice without epidermolysis bullosa suggest that even normal wounds heal more readily if collagen VII is administered, broadening the potential value of topically delivered collagen VII.

Replacement; however, may not be sufficient. In CHILD syndrome, the cholesterol biosynthetic pathway is blocked, leading to deficiency of cholesterol but also accumulation of toxic metabolites. Application of topical cholesterol to skin is not sufficient, but use of a statin to block both the accumulation of toxic metabolites, as well as replacement of cholesterol leads to dramatic improvement in affected skin using this “pathogenesis-based” therapy.


New technology has facilitated the advancement in our knowledge about gene function and the effects of gene alteration, including for some of the mosaic disorders. These discoveries have translated into new therapies for patients with genetic disorders and will help with innovative treatment in the future, whether personalized gene-based or pharmacologic therapy. While there are new discoveries to be made, one of the exciting new frontiers involves epigenetics—unraveling how and why genes are turned off with cell and tissue specificity – and then translation this information towards treating human disease.