Age-related macular degeneration (AMD) is a highly prevalent blinding disease of the elderly that affects both photoreceptors and the retinal pigment epithelium (RPE). Currently, a treatment option exists only for the less prevalent neovascular form of the disease.
AMD is a multifactorial disease, with both modifiable risk factors such as diet and smoking, and non-modifiable risk factors such as age. As age causes several alterations in ocular tissues that lead to reduced oxygen delivery and hypoxic conditions in the retina, we use several mouse models of pseudo and true hypoxia to understand the pathology of the disease.
Using histology, immunofluorescence, multi-omics as well as fluorescence lifetime imaging of genetically encoded biosensors we focus on the role of the hypoxia-inducible transcription factor HIF1 in the disease process.
We show that the chronic activation of HIF1 downregulates oxidative phosphorylation and the Krebs cycle, which severely affects not only energy metabolism but also anabolism in photoreceptors leading to cell death and retinal degeneration.
Since we have recognized HIF1 as the pathological HIF isoform in photoreceptors while others have defined overactivation of HIF2 as being causative for the degeneration of the RPE, we developed an AAV-based dual-acting RNA interference gene therapy strategy to simultaneously downregulate HIF1 in photoreceptors and HIF2 in the RPE.
The application of the therapeutic virus significantly protected photoreceptors and retinal morphology in two models for more than one year post treatment. Our work suggests that targeting HIF transcription factors may be a promising strategy to preserve vision in patients affected by AMD.
About the speaker
Christian Grimm, PhD, is Professor for Experimental Ophthalmology at the University of Zurich, Switzerland. He received his Ph.D. degree in molecular genetics at the University of Berne in 1990. After an initial postdoc position in the field of snRNP maturation, Dr. Grimm conducted research at the University of Wisconsin in Madison, WI, where he studied nucleo-cytoplasmic transport of small RNAs.
In 1997 Dr. Grimm moved back to Switzerland where he joined the Lab for Retinal Cell Biology in the department of Ophthalmology at the University of Zurich. Dr. Grimm has led the Lab for Retinal Cell Biology since 2006 and was appointed Professor for Experimental Ophthalmology and joined the medical faculty in 2008.
Dr. Grimm has published more than 160 original research and review articles and edited six books. His research focuses on molecular mechanisms of photoreceptor cell death, hypoxic signaling, photoreceptor metabolism and gene therapy. Dr. Grimm has secured research grants from the Swiss National Science Foundation, the European Union, the University of Zurich, Innosuisse and several private funding organizations. Dr. Grimm has received the Alfred Vogt Award (2000 and 2020), the Retinitis Pigmentosa Award of Pro Retina Germany (2003) and the Pfizer Research Award in Neuroscience (2004). He serves on the board of two journals and is a member of the scientific advisory boards of Pro Retina Germany and Retina Suisse.
