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!
Infants later diagnosed with autism follow adults’ gaze, but seldom initiate joint attention
24.05.2019 | Schwedischer Forschungsrat - The Swedish Research Council
When wheels and heads are spinning - DFG research project on motion sickness in automated driving
22.05.2019 | Technische Universität Berlin
A new assessment of NASA's record of global temperatures revealed that the agency's estimate of Earth's long-term temperature rise in recent decades is accurate to within less than a tenth of a degree Fahrenheit, providing confidence that past and future research is correctly capturing rising surface temperatures.
The most complete assessment ever of statistical uncertainty within the GISS Surface Temperature Analysis (GISTEMP) data product shows that the annual values...
Physicists at the University of Basel are able to show for the first time how a single electron looks in an artificial atom. A newly developed method enables them to show the probability of an electron being present in a space. This allows improved control of electron spins, which could serve as the smallest information unit in a future quantum computer. The experiments were published in Physical Review Letters and the related theory in Physical Review B.
The spin of an electron is a promising candidate for use as the smallest information unit (qubit) of a quantum computer. Controlling and switching this spin or...
Engineers at the University of Tokyo continually pioneer new ways to improve battery technology. Professor Atsuo Yamada and his team recently developed a...
With a quantum coprocessor in the cloud, physicists from Innsbruck, Austria, open the door to the simulation of previously unsolvable problems in chemistry, materials research or high-energy physics. The research groups led by Rainer Blatt and Peter Zoller report in the journal Nature how they simulated particle physics phenomena on 20 quantum bits and how the quantum simulator self-verified the result for the first time.
Many scientists are currently working on investigating how quantum advantage can be exploited on hardware already available today. Three years ago, physicists...
'Quantum technologies' utilise the unique phenomena of quantum superposition and entanglement to encode and process information, with potentially profound benefits to a wide range of information technologies from communications to sensing and computing.
However a major challenge in developing these technologies is that the quantum phenomena are very fragile, and only a handful of physical systems have been...
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
24.05.2019 | Physics and Astronomy
24.05.2019 | Medical Engineering
24.05.2019 | Life Sciences