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Decoding genetic skin disorders: lessons and new technologies

Wednesday, April 15, 2015

Speaker

Amy S. Paller, M.D., M.S.
Walter J. Hamlin Professor and Chair
Northwestern University

Summary

The underlying molecular basis has been determined for more than 2,000 inherited monogenic disorders, of which at least 20 percent have cutaneous manifestations. The explosion of knowledge about genetics and genetic disease during the past 20 years has helped us to understand how gene changes translate into clinical manifestations. The current availability of whole exome sequencing (WES) is rapidly decoding rare genetic skin disorders, uncovering new causes, facilitating genotype-based diagnosis at a fraction of pre-next generation sequencing costs, and enabling new individualized therapies based on knowledge of the underlying gene mutation. Emerging therapeutic options include the use of topical gentamycin for “readthrough” of null mutations, replacement with recombinant protein, topical pathogenesis-based therapy for lipid biosynthesis defects, and cell-based therapies through grafting or stem cell transplantation. An exciting result of WES is the ability to decode somatic mosaic genetic disorders through the comparative analysis of DNA from a lesional skin biopsy and genomic DNA. Many of these mutations in mosaic disorders result from activation of the RAS or PI3K/AKT signaling pathways, allowing targeted topical therapy with small-molecule inhibitors or gene suppression. New technology, such as microneedles and topically applied nanoconjugate creams, promise to deliver antisense DNA or siRNA through the epidermal barrier to skin targets. Clinically normal skin in generalized recessive skin disorders may represent sites of revertant mosaicism, allowing expansion of the patient’s own phenotypically normal cells as replacement of abnormal cells with the risk of immune rejection. These therapeutic options, together with the plummeting cost of technology, will revolutionize our ability to provide personalized therapy for patients with genetic skin disorders.


The page was last updated on Thursday, June 18, 2015 - 9:44am