Event date:
Mar 29 2023 3:30 pm

Zooming MCB: Gene Therapy to Prolong Vision

Prof. Constance Cepko
Online on Zoom
There are >200 human disease genes leading to blindness. Although gene therapy in which each disease gene is augmented or edited is possible, this approach would be extremely expensive and logistically challenging. To provide an alternative, more general approach, our laboratory has been analyzing mouse models of blindness, looking for problems that are common across genotypes. We were particularly interested in mouse models for retinitis pigmentosa (RP), as it is well modeled in mice, relative to humans. In RP, the disease starts with the expression of mutant genes in rod photoreceptors, the cell type that initiates dim light vision, leading to poor night vision. However, color vision, which originates with cone photoreceptors, is normal at birth. Over time, cones become affected due to bystander effects from rod loss. This causes color blindness and can lead to total blindness. Other cells also are affected by the loss of rods: the retinal pigmented epithelial cells (RPE), which provide various types of support to rods and cones. Studies of these mouse models led to the hypothesis that the bystander effects include: oxidative damage, metabolic shortcomings, and inflammation. To combat these problems, many different types of genes were delivered using adeno-associated viruses (AAV). Genes that fight inflammation, a transcription factor that regulates genes that fight oxidative damage, and genes that provide metabolic support were found to prolong cone and RPE survival as well as vision across 3 strains of RP mice.

Dr Constance Cepko is Bullard Professor of Genetics and Neuroscience at Harvard Medical School and a Howard Hughes Medical Institute Investigator. She trained in virology with Phil Sharp at MIT for a Ph.D. and later with Richard Mulligan at the MIT Whitehead Institute. She helped develop retroviral vectors for transduction into the nervous system for lineage analysis and for studies of gene function in vivo. Her laboratory has focused on the topic of cell fate determination in the retina through the analysis of the behavior of progenitor and stem cells. More recently, they have been studying the mechanisms of photoreceptor death in diseases that cause blindness, such as retinitus pigmentosa and macular degeneration. Furthermore, her lab develops new tools for genetic perturbations using nanobodies, and is developing VSV as a transsynaptic virus for mapping synaptic connections among neurons. (https://hsci.harvard.edu/people/constance-cepko-phd)