Eyeworld

EW RETINA 68 by Michelle Dalton EyeWorld Contributing Writer loss at a stage when the cones are still healthy." Dr. Lipinski said CNTF "was able to slow down the degeneration of rod photoreceptors—a novel finding—and as a consequence, cone photoreceptors also were preserved. Furthermore, those cones retained a relatively normal morphology and produced outer segments. So the key to maintaining cone-medi- ated vision would appear to be the preservation of rod photoreceptors. The problem clinically is that this is unlikely to be feasible in all RP patients, where many suffer from advanced rod photoreceptor degen- eration at the time of presentation." For researchers, this raises a "complex question" of whether visu- al function suppression during early stages of a degenerative disease out- weigh the possibility of extending vision beyond where it would have naturally been lost without therapy, Dr. Lipinski said. "Our work demonstrates for the first time the ability of a neurotroph- ic compound to provide lifelong protection in a mouse model of degenerative disease. Yet one of the current challenges is whether the protective effects of CNTF can be teased apart from the negative impact it has on electrophysiological activity. In essence, can we preserve photoreceptors without suppressing their function?" Their findings may have more broad-based applications, expanding to other neurodegener- ative diseases such as amyotrophic lateral sclerosis. EW Reference 1. Lipinski DM, Barnard AR, Singh MS, et al. CNTF gene therapy confers lifelong neuropro- tection in a mouse model of human retinitis pigmentosa. Mol. Ther. 2015 Aug;23(8):1308– 19. Editors' note: Drs. Lipinksi and MacLaren are listed as inventors on a patent on CNTF gene therapy owned and filed by the University of Oxford. Contact information Lipinski: dlipinski@ufl.edu over the time course of the experi- ment in low-dose and control eyes, reaching 0 by week 24. "The mouse model used in this study never develops rod-mediated vision, due to a total absence of rhodopsin protein. Cone-mediated vision is relatively normal at week 4–6, but declines steadily and is absent by around week 15–18," Dr. Lipinski said. Next-generation sequencing at 30 weeks showed upregulation of several gene families, notably ser- ine-type endopeptidase inhibitors, which were up to 89 times more highly-expressed in high-dose eyes than in controls. A university press release noted the preserved cells were able to drive visually guided behavior, even in the later stages of the condition and despite becoming less sensitive to light. "The sensitivity of photorecep- tors to light and the ability of an experimental animal to see are very separate outcome measures," Dr. Lipinski said. "In line with many other studies, it was very clear from the electroretinography recordings that cone function was suppressed by CNTF treatment. Yet in spite of this functional suppression, animals were able to track a high contrast visual stimulus much more reliably with their CNTF-treated eyes than their control eye," he said. "This indicates that treated eyes still retain the ability to relay useful visual information." Clinical relevance CNTF remains an enigma—it can be "extremely protective" against photoreceptor loss, but also can sup- press retinal function, noted Robert MacLaren, DPhil, FRCS, professor of ophthalmology, University of Oxford, U.K., who supervised the research. "The recent trials on late-stage RP have shown some possible bene- fit in preserving photoreceptors, but there are also signs of reduced reti- nal sensitivity at higher doses," he said. "The important inference from our study is that it may be necessary to intervene earlier and prevent rod Several compounds have demonstrated "some efficacy in the preservation of retinal neurons," including ciliary neurotrophic factor (CNTF), which has been shown to be "highly protective against retinal cell death." 1 There has, however, been a hesitancy to embrace the pro- tein completely because of concerns about side effects. Study details The researchers looked at a mouse model of RP in which the mice lack rhodopsin. At age 4 weeks—before cone loss had begun—the mice were dosed with a virus vector designed to secrete human CNTF protein from the inner retina following intravitreal administration. The unique approach in this study was to use a mouse that had fluorescent green cone photoreceptors that could be count- ed by examining the living retina with a standard laser ophthalmo- scope at various time points during the course of the degeneration, allowing cell survival to be assessed in vivo in response to a vector dose. Eyes were randomized to treatment or saline, and at 8 weeks, non-invasive imaging showed sim- ilar numbers of cones in all treated and untreated eyes. However, the number of cones decreased rapidly An early stage study is showing promise in retinitis pigmentosa G ene therapy can give lifelong protection to the light-sensitive photore- ceptor cells responsible for color vision in a mouse model of retinitis pigmentosa (RP), researchers in the U.S. and the U.K. have found. The surviving photore- ceptors were able to confer some de- gree of vision, even in later stages of the condition and despite becoming less sensitive to light. 1 One of the issues for researchers and clinicians is that the long-term outcome of any neuroprotective agent or therapy for preventing cell death in these types of neurodegen- erative disorders remains unknown since these diseases are typically slow to progress. "For reasons that are incom- pletely understood, cone photore- ceptor survival is intrinsically linked to the presence of surrounding rods—so once rod degeneration has advanced to a certain stage, cone photoreceptor degeneration inevi- tably follows," said Daniel Lipinski, MSc, DPhil, lead author of the study and assistant professor, University of Florida, Gainesville. October 2015 Novel gene therapy approach may protect against photoreceptor loss In vivo imaging of fluorescent cone photoreceptors (white dots) in sham treated (left panel) and AAV.CNTF treated (right panel) eyes over several months. Note the absence of cone photoreceptors in the sham treated eye by week 30 and the appearance of pigmentary changes consistent with retinitis pigmentosa. By contrast, CNTF treated eyes retain more than 50% of cone photoreceptors over the same period. Source: Daniel Lipinski, MSc, DPhil

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