Scientist and dermatologist Amy S. Paller and chemist Chad A. Mirkin are the first to develop a topical gene regulation technology that speeds the healing of ulcers in diabetic animals. They combined spherical nucleic acids (SNAs, which are nanoscale globular forms of RNA) with a common commercial moisturizer to create a way to topically knock down a gene known to interfere with wound healing.
Type 2 diabetes and its enormous associated costs are on the rise in the United States. More than one-fifth of the 27 million type 2 diabetics in the country have chronic, non-healing skin wounds, and many undergo amputation. The Northwestern discovery offers a possible solution to this serious problem.
* Six million diabetic Americans have chronic, non-healing skin wounds
* Spherical nucleic acids naturally penetrate skin and can be applied topically
* Moisturizer treatment ‘worked beautifully’ in an animal study
* Opens door to treatment of other debilitating health conditions with genetic basis
PNAS - siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown
“Finding a new way to effectively heal these resistant diabetic wounds is very exciting,” said Dr. Paller, director of Northwestern’s Skin Disease Research Center. “But, in addition, this study further proved that SNAs -- in nothing but common moisturizer -- can penetrate the skin barrier, a challenge that other therapies have been unable to conquer.”
In earlier work, Paller’s lab had discovered that depleting an enzyme called GM3 synthase made cells particularly sensitive to growth factors and led to normal wound healing despite diabetic conditions. She teamed up with Mirkin, who designed SNAs targeting the gene that produces this troublesome enzyme.
The SNAs were put in the moisturizer Aquaphor and simply applied to the edges of the wounds in diet-induced diabetic mice. The research team noted improved healing in the mice treated with SNAs as compared to the control groups after only four days. The wounds in the treated animals were healed by 12 days; the control group’s wounds took 18 days to heal -- 50 percent longer. Blood circulation at the wound site in the treated animals also improved.
“This work illustrates the scope and potential impact of the SNA platform for treating conditions of the skin with a known genetic basis,” said Mirkin, who invented SNAs at Northwestern in 1996. “It is the only known nucleic acid platform for treating such ailments and constitutes a new pipeline of therapeutics to address a broad swath of debilitating health conditions.”
Diabetic patients often suffer from impaired wound healing, which can develop into nonhealing diabetic ulcers, facilitate bacterial infections, and necessitate amputation. Current strategies for treatment have failed to achieve the anticipated efficacy and do not address the fundamental molecular abnormalities that prevent efficient wound closure. In this work, we introduce a previously unidentified approach to treating diabetic wound healing by using topically delivered spherical nucleic acids to effect the knockdown of ganglioside-monosialic acid 3 (GM3) synthase, a mediator of impaired wound healing, in type 2 diabetic mice. In addition to laying the groundwork for developing a therapy for a debilitating condition, this work also validates the critical role of GM3 in diabetic wound healing.
Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nm-diameter gold cores functionalized with densely packed and highly oriented nucleic acids) dispersed in Aquaphor have been shown to penetrate the epidermal barrier of both intact mouse and human skin, enter keratinocytes, and efficiently down-regulate gene targets. ganglioside-monosialic acid 3 synthase (GM3S) is a known target that is overexpressed in diabetic mice and responsible for causing insulin resistance and impeding wound healing. GM3S SNAs increase keratinocyte migration and proliferation as well as insulin and insulin-like growth factor-1 (IGF1) receptor activation under both normo- and hyperglycemic conditions. The topical application of GM3S SNAs (50 nM) to splinted 6-mm-diameter full-thickness wounds in diet-induced obese diabetic mice decreases local GM3S expression by >80% at the wound edge through an siRNA pathway and fully heals wounds clinically and histologically within 12 d, whereas control-treated wounds are only 50% closed. Granulation tissue area, vascularity, and IGF1 and EGF receptor phosphorylation are increased in GM3S SNA-treated wounds. These data capitalize on the unique ability of SNAs to naturally penetrate the skin and enter keratinocytes without the need for transfection agents. Moreover, the data further validate GM3 as a mediator of the delayed wound healing in type 2 diabetes and support regional GM3 depletion as a promising therapeutic direction.
SOURCE - PNAS, Northwestern University