Constance Cepko, Ph.D.

Constance Cepko, Ph.D.

Harvard Medical School
Connie Cepko, HMS

The Cepko lab investigates why photoreceptor cells die in the many forms of retinal degeneration, and seeks to develop a gene therapy that prevents their death and the subsequent loss of vision.

The mechanisms that cells use when they choose their fate during development of the central nervous system is the main problem under study in the Cepko lab. They have focussed their studies on the retina, a tractable model for the rest of the central nervous system. The group also enjoys developing new technologies that enable these studies as well as others.

The Cepko lab develops new tools for genetic perturbations using nanobodies, and is developing VSV as a transsynaptic virus for mapping synaptic connections among neurons.

The lab uses genomic approaches to examine gene expression over time and identifies candidate genes for regulating cell cycle exit and cell fate choices. These studies have revealed that the retina has distinct types of progenitor cells that are biased, or committed, to produce distinct types of daughter cells in terminal divisions. The gene regulatory networks that underlie these cell fate choices are being studied by analysis of both gene function and cis-regulatory networks. Cell fate determination events are also being studied in the context of patterning in the chick retina, which exhibits a high acuity area, similar to the fovea in humans. The events that localize this zone to the center of the retina, and that direct the formation of specific cell types within this area, are under study.

To augment existing techniques that allow the analysis of gene function in specific cell types, they have derivatized nanobodies, which are small high affinity binding reagents derived from camelid antibodies. By making fusions of such nanobodies with transcription factors or recombinases, and by making the activity of these fusions dependent upon the nanobody's epitope, they have created reagents that allow functional perturbations or labeling only of cells that express the epitope. As some of these reagents are based upon GFP nanobodies, they have greatly expanded the utility of the many transgenic strains of animals that express GFP in specific patterns.

The lab has an interest in developing gene therapy for blindness. Some of the genes required for photoreceptor development lead to human blindness when mutated, as do many other genes required for phototransduction and other aspects of photoreceptor physiology. The lab is developing gene therapy using AAV to prolong survival of photoreceptor cells, regardless of which of the many photoreceptor disease genes is mutated. They have produced vectors that prolong vision in mouse models, targeting generic problems, such as inflammation, metabolic insufficiency, and oxidative damage.


Connie 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.

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