Photopharmacological control of neuronal activity using synthetic photochromic ligands, or photoswitches, is a promising approach for restoring visual function in patients suffering from degenerative retinal diseases. Azobenzene photoswitches, such as AAQ and DENAQ, have been shown to restore the responses of retinal ganglion cells to light in mouse models of retinal degeneration but do not recapitulate native retinal signal processing. Here, we describe diethylamino-azo-diethylamino (DAD), a third-generation photoswitch that is capable of restoring retinal ganglion cell light responses to blue or white light. In acute brain slices of murine layer 2/3 cortical neurons, we determined that the photoswitch quickly relaxes to its inactive form in the dark. DAD is not permanently charged, and the uncharged form enables the photoswitch to rapidly and effectively cross biological barriers and thereby access and photosensitize retinal neurons. Intravitreal injection of DAD restored retinal light responses and light-driven behavior to blind mice. Unlike DENAQ, DAD acts upstream of retinal ganglion cells, primarily conferring light sensitivity to bipolar cells. Moreover, DAD was capable of generating ON and OFF visual responses in the blind retina by utilizing intrinsic retinal circuitry, which may be advantageous for restoring visual function.
Laura Laprell, Ivan Tochitsky, Kuldeep Kaur, Michael B. Manookin, Marco Stein, David M. Barber, Christian Schön, Stylianos Michalakis, Martin Biel, Richard H. Kramer, Martin P. Sumser, Dirk Trauner, Russell N. Van Gelder
Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (
Alicia A. Nugent, Jong G. Park, Yan Wei, Alan P. Tenney, Nicole M. Gilette, Michelle M. DeLisle, Wai-Man Chan, Long Cheng, Elizabeth C. Engle
Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-α/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists.
Lindsay S. Keir, Rachel Firth, Lyndsey Aponik, Daniel Feitelberg, Susumu Sakimoto, Edith Aguilar, Gavin I. Welsh, Anna Richards, Yoshihiko Usui, Simon C. Satchell, Valeryia Kuzmuk, Richard J. Coward, Jonathan Goult, Katherine R. Bull, Ruchi Sharma, Kapil Bharti, Peter D. Westenskow, Iacovos P. Michael, Moin A. Saleem, Martin Friedlander
Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare
Tomokazu Souma, Stuart W. Tompson, Benjamin R. Thomson, Owen M. Siggs, Krishnakumar Kizhatil, Shinji Yamaguchi, Liang Feng, Vachiranee Limviphuvadh, Kristina N. Whisenhunt, Sebastian Maurer-Stroh, Tammy L. Yanovitch, Luba Kalaydjieva, Dimitar N. Azmanov, Simone Finzi, Lucia Mauri, Shahrbanou Javadiyan, Emmanuelle Souzeau, Tiger Zhou, Alex W. Hewitt, Bethany Kloss, Kathryn P. Burdon, David A. Mackey, Keri F. Allen, Jonathan B. Ruddle, Sing-Hui Lim, Steve Rozen, Khanh-Nhat Tran-Viet, Xiaorong Liu, Simon John, Janey L. Wiggs, Francesca Pasutto, Jamie E. Craig, Jing Jin, Susan E. Quaggin, Terri L. Young
Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8-
Jingxing Ou, Camasamudram Vijayasarathy, Lucia Ziccardi, Shan Chen, Yong Zeng, Dario Marangoni, Jodie G. Pope, Ronald A. Bush, Zhijian Wu, Wei Li, Paul A. Sieving
Emixustat is a visual cycle modulator that has entered clinical trials as a treatment for age-related macular degeneration (AMD). This molecule has been proposed to inhibit the visual cycle isomerase RPE65, thereby slowing regeneration of 11-
Jianye Zhang, Philip D. Kiser, Mohsen Badiee, Grazyna Palczewska, Zhiqian Dong, Marcin Golczak, Gregory P. Tochtrop, Krzysztof Palczewski
Oxidative stress contributes to the loss of neurons in many disease conditions as well as during normal aging; however, small-molecule agents that reduce oxidation have not been successful in preventing neurodegeneration. Moreover, even if an efficacious systemic reduction of reactive oxygen and/or nitrogen species (ROS/NOS) could be achieved, detrimental side effects are likely, as these molecules regulate normal physiological processes. A more effective and targeted approach might be to augment the endogenous antioxidant defense mechanism only in the cells that suffer from oxidation. Here, we created several adeno-associated virus (AAV) vectors to deliver genes that combat oxidation. These vectors encode the transcription factors NRF2 and/or PGC1a, which regulate hundreds of genes that combat oxidation and other forms of stress, or enzymes such as superoxide dismutase 2 (SOD2) and catalase, which directly detoxify ROS. We tested the effectiveness of this approach in 3 models of photoreceptor degeneration and in a nerve crush model. AAV-mediated delivery of NRF2 was more effective than SOD2 and catalase, while expression of PGC1a accelerated photoreceptor death. Since the NRF2-mediated neuroprotective effects extended to photoreceptors and retinal ganglion cells, which are 2 very different types of neurons, these results suggest that this targeted approach may be broadly applicable to many diseases in which cells suffer from oxidative damage.
Wenjun Xiong, Alexandra E. MacColl Garfinkel, Yiqing Li, Larry I. Benowitz, Constance L. Cepko
Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP.
Aditya Venkatesh, Shan Ma, Yun Z. Le, Michael N. Hall, Markus A. Rüegg, Claudio Punzo
Mutations in the cellular retinaldehyde–binding protein (CRALBP, encoded by
Yunlu Xue, Susan Q. Shen, Jonathan Jui, Alan C. Rupp, Leah C. Byrne, Samer Hattar, John G. Flannery, Joseph C. Corbo, Vladimir J. Kefalov
Alternative splicing of nucleoredoxin-like 1 (
Leah C. Byrne, Deniz Dalkara, Gabriel Luna, Steven K. Fisher, Emmanuelle Clérin, Jose-Alain Sahel, Thierry Léveillard, John G. Flannery