According to new research by University of Kentucky investigators, an emerging pharmaceutical platform used in treating a variety of diseases may produce unintended and undesirable effects on eye function. The paper, "Short-interfering RNAs Induce Retinal Degeneration via TLR3 and IRF3", appears in the current online edition of the journal Molecular Therapy, a publication of the Nature Publishing Group and the American Society of Gene and Cell Therapy.
"Short-interfering RNA (siRNA) technology has been regarded as one of the most exciting emerging platforms for new pharmaceuticals, said Dr. Jayakrishna Ambati, professor of physiology, and professor and vice chair of ophthalmology and visual sciences at UK.
To this point, siRNA drugs have been the subject of clinical trials past and present for a variety of disorders including: cancers, viral respiratory infections, hypercholesterolemia, macular degeneration, diabetic retinopathy and glaucoma. Major obstacles to realizing the therapeutic potential of siRNAs include delivery of the drug into cells and a generic suppression of blood vessel growth through immune activation, as shown by a 2008 paper from the Ambati group in the journal Nature.
"We now show a new undesirable effect of siRNAs that are 21 nucleotides or longer in length: these siRNAs, regardless of their sequence or target, can cause retinal toxicity. By activating a new immune pathway consisting of the molecules TLR3 and IRF3, these siRNAs damage a critical layer of the retina called the retinal pigmented epithelium (RPE). Damage to the RPE cells by siRNAs can also lead to secondary damage to the rods and cones, which are light-sensing cells in the retina," said Ambati.
The scientists' findings indicate that caution should be applied when designing or using siRNAs intended for either direct application to the eye, or intended for use in a way that may allow the drug to access the eye.
"Another novel aspect of this research is that the RPE degeneration caused by siRNAs resembles the pathology seen in the advanced form of age-related macular degeneration called geographic atrophy, said Ambati. "As there are few models of geographic atrophy, which affects millions of people worldwide, this paper provides an important advance for research in developing new treatments for this disease."
Because the research shows that siRNAs shorter than 21 nucleotides in length can evade the TLR3-IRF3 off-target immune response, it may be possible to achieve therapeutic effects without retinal damage by designing shorter siRNAs.
The lead authors on this paper are Mark E. Kleinman, Assistant Professor of Ophthalmology & Visual Sciences, and Hiroki Kaneko and Won Gil Cho, also of UK. Other members of the UK research team in the Department of Ophthalmology & Visual Sciences include: Sami Dridi, Benjamin J. Fowler, Alexander D. Blandford, Yoshio Hirano, Valeria Tarallo, Bradley D. Gelfand, Sasha Bogdanovich and Judit Z. Baffi, Assistant Professor of Ophthalmology. Ambati is also the Dr. E. Vernon & Eloise C. Smith Endowed Chair in Macular Degeneration Research.
This research was supported by the National Eye Institute, the Doris Duke Charitable Foundation, the Burroughs Wellcome Fund, and Research to Prevent Blindness, and was a collaboration with Yonsei University in Korea, Nagoya University, Mie University, Kyoto University in Japan and the University of Utah.
Allison Elliott | EurekAlert!
Purdue cancer identity technology makes it easier to find a tumor's 'address'
16.11.2018 | Purdue University
Microgel powder fights infection and helps wounds heal
14.11.2018 | Michigan Technological University
Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.
Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...
Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.
Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...
Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.
In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...
On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.
When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure
Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...
19.11.2018 | Event News
09.11.2018 | Event News
06.11.2018 | Event News
19.11.2018 | Materials Sciences
19.11.2018 | Information Technology
19.11.2018 | Life Sciences