Russell N Van Gelder, MD, PhD
Outer retinal degenerative diseases including age related macular degeneration and retinitis pigmen- tosa are among the leading causes of blindness world-wide. Blindness results from loss of photore- ceptive cells. However, the inner retina is left largely intact. Several strategies have been explored for restoring vision to these eyes, including opto-elec- tronics, stem cell replacement, and photopigment gene therapy. Photopharmacology is a newer approach utilizing photoswitch organic compounds, in which a photoisomerizable moiety such as azo- benzene is covalently coupled to a pharmacologic agent. In some cases, this will confer light-activation to these agents. When coupled to blockers of voltage-gated potassium channels, such agents have the ability to confer light-dependent action potential generation to neurons.
Our laboratory has studied a number of these photo- switch compounds for restoration of vision in ani- mal models of outer retinal degeneration. First generation compounds such as AAQ demonstrated light-dependent retinal ganglion cell ﬁring and res- toration of behavioural light responses in blind ani- mals. Second generation compounds including DENAQ and BENAQ featured broader spectral sen- sitivity, better kinetics, and long durations of action. Finally, third generation compounds such as DAD demonstrate ‘upstream’ retinal speciﬁcity, high solu- bility, and very rapid kinetics.
To understand the effect of pharmacologically repro- gramming the retina, we have engineered an in vitro method for assessing visual function from explanted retina. In this system, high-resolution movie images are projected onto the retina and gan- glion cell responses are recorded by multi-electrode array. Using a machine-learning paradigm, a com- puter program attempts to discriminate and predict images, permitting determination of outcomes such as visual acuity and contrast sensitivity. Using this technique, we demonstrate that pharmacologic photoswitches are capable of restoring high- resolution vision to blind retinas. The implications of these ﬁndings for clinical translation will be discussed.
Brief Curriculum Vitae:
Dr Van Gelder was born and raised in and around New York City. He earned his BS, MD, and PhD degrees from Stanford University. Dr Van Gelder completed his ophthalmology residency and uveitis and medical retina fellowship at Washington Uni- versity in St. Louis. He remained on faculty at Washington University from 1999 until 2007, serv- ing as Residency Program Director and Director of the Uveitis Service.
Dr Van Gelder is an active clinician-scientist and teacher. His research has been continuously funded by the NIH since 1999. His laboratory has been at the forefront of two ﬁelds, non-visual photorecep- tion and pathogen detection in uveitis. As a gradu- ate student, he developed the ampliﬁed RNA technique used in almost all gene expression proﬁl- ing experiments. In the ﬁeld of non-visual photore- ception, his laboratory has made a number of seminal discoveries. The Van Gelder laboratory developed assays allowing characterization of the photoreceptive properties of cryptochrome proteins; helped establish the importance of melanopsin in non-visual photoreception; was ﬁrst to demonstrate multiple physiologic subtypes of intrinsically photosensitive retinal ganglion cells; established that that the melanopsin photocycle is distinct from that of rods and cones; and most recently demon- strated the presence of a novel photoreceptive path- way in the retina utilizing the orphan opsin neuropsin. His laboratory has also been at the fore- front of optochemical approaches to vision restora- tion. In the area of uveitis, his laboratory pioneered application of multiplex and real-time PCR to ocular pathogen detection; developed the Biome Represen- tational in Silico Karyotyping (BRiSK) methodology for representational deep DNA sequencing; per- formed the deﬁnitive characterization of the ocular surface microbiome; and discovered that torque teno virus is a highly prevalent on the ocular surface and found in the vitreous in culture-negative endophthalmitis.
He has published over 150 papers and book chap- ters. Dr Van Gelder has won numerous awards for his research, including the Research to Prevent Blindness Career Development Award, the Transla- tional Scientist Award of the Burroughs-Wellcome Foundation, the Heed-Gutman award of the Heed Foundation, and an ‘Audacious Goals’ award of the National Eye Institute. He is the 2017 recipient of the Bressler Prize of the Lighthouse Guild. He has given over 20 named lectures and over 100 invited talks.
Dr Van Gelder is Associate Editor of IOVS and serves on the editorial board of Ophthalmology. Nationally, he served in 2015 as President of the American Academy of Ophthalmology, having previously served as chair of the AAO Council. He currently serves on the National Advisory Eye Council of the NEI. He is also past president of the American Uve- itis Society and President Elect of the Association of University Professors of Ophthalmology.
Prior to moving to University of Washington, he held the Bernard Becker Professorship at Washington University. Since 2008, Dr Van Gelder has been the Boyd K. Bucey Memorial Chair, profes- sor and chairman of the Department of Ophthalmol- ogy at University of Washington in Seattle, where he also serves as founding director of both the UW Medicine Eye Institute and the University of Washington Vision Science Center. He lives near Seattle Washington with his wife Suzy, a professor of pathology at UW. They have two children, a daughter in college and son in high school.