Research
The primary focus of the Horsager Lab is to develop novel gene therapies for the treatment of blindness due to photoreceptor disease. Our research is motivated by the need for therapies that are both broadly applicable and allow for precise neuromodulation, thus restoring naturalistic visual processing independent of the underlying cause of retinal disease. In addition, we have two supporting lines of research that are more basic in nature: 1) understanding how gene regulatory networks are modulated in normal, diseased, and treated states, and using these data to develop synthetic molecular tools to target transgene expression to specific tissue types, and 2) understanding how circuit-specific neuromodulation is integrated within the retina and its subsequent impact on visual perception.
Optogenetic Approach to Restoring Sight
We are using a combination of gene therapy and optogenetic techniques to restore sight to mouse models of blindness, specifically the rd10 model. This involves the development of adeno-associated viral vectors that deliver promoters + genes that encode light-sensitive protein expression to specific subsets of retinal cells, thus enabling circuit-specific activation of the retina. We are currently working on a method that targets expression of channelrhodopsin-2, a gene encoding a light-sensitive cation channel obtained from the green algae Chlamydomonas reinhardtii, to the ON bipolar cells. Our recent paper, published in Molecular Therapy, describes how this approach could be used to treat retinitis pigmentosa and age-related macular degeneration in human patients.
Understanding regulatory networks within individual retinal cell types
The retina consists of dozens of different cell types, each performing a highly specific task. Ganglion cells, the cells that transmit the retinal signal to cortex, consist of more than 20 different subtypes, suggesting that over 20 different discrete types of information are being processed in the retina and sent, in parallel, to higher visual centers. Understanding the molecular profile, or transcriptome, is fundamental to understanding their function. Combined with computational analyses, this provides information about how best to genetically target transgene expression to these different subtypes of cells so that each individual subtype can be studied independently.
Computational modeling and physiological characterization of specific retinal circuits
Each retinal microcircuit parses and modulates the visual signal from photon capture in the photoreceptors (or other light-sensitive cell) through the ganglion cells. Looking at this from a biophysical perspective and incorporating the use of different light-sensitive proteins with cell specific expression targeting, is is possible to interrogate and understand how these different cell types integrate and modulate the signal? We are combining physiological and compuational approaches to study these questions.