Constance Cepko, PhD
Professor
Department of Genetics, Harvard Medical School
Howard Hughes Medical InstituteRetina development and pathophysiology
Investigate the mechanisms of the development of different retinal cell types derived from multipotent retinal progenitor cells with a focus on photoreceptor cells; study the pathological loss of photoreceptors, and devise genetic procedures for restoring retinal function
Commercial Opportunities
Apply fundamental knowledge of retinal cell development pathways, gene expression signatures of different retinal cells, and retroviral gene transfer in retinal cell models, to prevent and restore vision loss
Dr. Cepko’s pioneering work on retinal developmental biology is now being applied to retinal degenerative diseases, with the goal of making diseases such as macular degeneration and Retinitis Pigmentosa tractable disorders that can be prevented or managed. The catastrophic consequences for vision resulting from the loss of photoreceptor cone cells is a non-autonomous process that is dictated by the prior loss of rod cells, suggesting that contextual and environmental factors are involved. An important consequence of this sequential process is that a window of time exists for genetic or pharmacologic intervention before the eventual decline in cone cell function is consummated.
Dr. Cepko is exploring a variety of approaches to uncover the molecular mechanisms that support normal retinal cell function, and consequently has honed in on critical genes and metabolic processes that appear to go awry in particular eye diseases. Dr. Cepko is exploiting these findings for different therapeutic approaches, including gene therapy and pharmacological interventions. Her work on cell type specific expression of specific genes in different retinal cell types is fundamental to some of these approaches. Dr. Cepko is capitalizing on this expertise and versatility with viral transduction vectors (e.g., retroviral and adeno-associated virus) that can target mitotic or post-mitotic cells. These studies are elucidating the etiology of eye-related diseases, as well as laying the groundwork for therapeutic approaches that will herald a new era in treatments for blindness caused by retinal degeneration.
Retinal cone cell death and mTOR:
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3-Dimensional rendering of a cone photoreceptor showing the cellular localization of phosphorylated mTOR in the dorsal retina of wild-type mice. Magenta: cone cell body marked with anti beta-galactosidase. The transgene is expressed in all cones. Green: cone outer segment marked with PNA; Red: phosphorylated mTOR. See Punzo et al., Nature Neuroscience, 2009 for more details.
Current Research Interests
Dr. Cepko’s work on retinal biology is centered on the numerous cell types that comprise the retina, their developmental pathways and functions within the unique environment of the eye, and pathophysiology of photoreceptor loss in mouse models of retinal diseases.
Dr. Cepko’s efforts on promoting survival and restoring function to degenerating retinal cells is focused on pharmacologic and gene therapy approaches that reconstitute defective signaling pathways, employing viral transduction vectors. This approach is supported by findings that link particular genetic defects with retinal diseases such as Retinitis Pigmentosa. Some of the genes that will be introduced into photoreceptor cells are based upon their studies of the non-autonomous demise of cone cells in various retinal degenerative diseases. In addition, their attempts to understand the biochemical signals that interconnect rod and cone cell metabolism may suggest critical pharmacological interventions in this process. An additional approach is to provide cells other than photoreceptor cells with the ability to sense light, making them into surrogates for rod and cone cells. Dr. Cepko’s extensive knowledge and insights into retinal cell gene expression, cell-type specific promoter elements, and viral gene therapy are instrumental in facilitating these studies.
Research Expertise
Dr. Cepko has a longstanding interest in the cellular and genetic mechanisms that define the developmental programming of the vertebrate retina, and her landmark scientific studies have led to prestigious professional accolades, including election to the National Academy of Science and selection as a Howard Hughes Investigator. The diverse cell types that constitute the retina are generated from multipotent progenitor cells along a complex route, and Dr. Cepko has employed a variety of methodologies to unravel the molecular signals that determine cell fate. Dr. Cepko has pioneered the use of retroviral techniques for identifying the lineal relationships among neuronal and glial cell types within the retina and identified genes that modulate retinal cell development. Her recent work has studied the cell type specific properties of various retinal cell types, including the multipotent retinal progenitor cells, bipolar cells, ganglion cells, amacrine cells, and Müller glial cells. These studies have yielded important insights into the underlying gene expression networks that characterize these unique cell types. Interestingly, when individual retinal progenitor cells were analyzed at the transcriptome level, there was a significant degree of heterogeneity, particularly with respect to transcription factor gene expression. These data suggest a complex picture for developmental pathways derived from these progenitor cells. They also revealed the Muller glial cells are molecularly very similar to multipotent progenitor cells, suggesting that they might be able to play a role in regeneration.
More recently, her work has included an analysis of the mechanisms that lead to the death of photoreceptors in genetic forms of blindness. They have discovered that cone photoreceptor cells, which provide vision in the daylight, show signs of nutritional deficiencies before they die in diseases such as Retinitis Pigmentosa. They also have discovered that introduction of a gene, histone deacetylase 4, can prolong photoreceptor survival in animal models where the cells are doomed to die. They are currently investigating whether these observations can be translated into therapies for individuals who inherit disease genes causing photoreceptors to die.