Topical delivery of keratin 10 mutation-specific siRNA-gold nanoparticles for epidermolytic ichthyosis (2012)

Amy Paller, MD
Walter J. Hamlin Professor and Chair of Dermatology and Professor of Pediatrics at Northwestern University’s Feinberg School of Medicine

Amy Paller, MD

The blistering and thickening of skin seen in EI usually results from a change in a single letter of the DNA code (a mutation) in one copy of the gene that provides the codes for manufacture of a keratin protein in the upper layers of skin. Small interfering RNAs (siRNAs) are small pieces of genetic material that can identify DNA pieces and bind to them, preventing the gene from being translated into protein. siRNAs are able to distinguish the mutated DNA from the normal DNA, and thus are able to prevent only the abnormal keratin protein from being formed. The problem with siRNA has been getting it through the skin barrier to where it needs to go. Dr. Paller and her team have found a way to get the siRNAs through the skin, through nanotechnology. By putting about 30 copies of the siRNA all around a central gold nanoparticle (leading to what her group calls “spherical nucleic acids”), the siRNAs are able to be rubbed into skin in a simple moisturizer, Aquaphor ointment. In the grant proposal, Dr. Paller’s team will deliver an siRNA that specifically recognizes the common mutation of EI, R156H, with the intent to turn down production of the abnormal protein, while maintaining production of the normal protein. Dr. Paller has grown skin cells from several patients with EI and is using these to test if this technique will work for EI using both the cells in culture and a mouse model in which the human cells are grafted to the back of a mouse.


How is this work relevant to the Foundation for Ichthyosis & Related Skin Types?
The results of the project have many potential benefits for individuals with EI, as well as other ichthyotic conditions in which there is a localized mutation that can be targeted and the gene product reduced (another example is the most common form of palmoplantar keratoderma). While the project has very exciting potential, Dr. Paller notes that the proposed studies are just the first step in moving the technology towards human trials. In addition, since the siRNA that is developed in this proposal is precisely geared towards decreasing the manufacture of a very specific, mutation-based keratin protein, additional siRNAs would have to be developed to match the needs of each person with EI.

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