Five research teams will develop new models for eye disease research

NEI Audacious Goals Initiative funds projects to accelerate the development of regenerative treatments for blindness
The National Eye Institute (NEI), part of the National Institutes of Health, has awarded grants to five multi-disciplinary teams to develop new disease models for a range of eye conditions. The program, which will award $30 million over 5 years, is part of the NEI Audacious Goals Initiative (AGI) for Regenerative Medicine. The AGI seeks to catalyze new treatments for blinding conditions like glaucoma, age-related macular degeneration, retinitis pigmentosa, and other degenerative eye diseases. New models will enable researchers to test novel regenerative therapies, including gene- and cell-based therapies, and help transition them to the clinic.
“Models that recapitulate human disease are essential to predicting the success of new therapies in humans. These audacious projects will be pivotal in our efforts to translate the latest science advances into new treatments for vision loss and blindness,” said NEI Director Paul A. Sieving, M.D., Ph.D.
Scientists use disease models throughout the process of developing new treatments. From cell or animal models of eye diseases, researchers can learn the root cause of disease, study the changes that occur to eye tissues as disease progresses, and test potential therapies. New and emerging treatments, like gene therapy or stem cell-based tissue-replacement, also require novel surgical techniques and ways to understand how well therapy is working, all of which must be tested before being tried in humans. Having models that closely match human biology and disease will help vision scientists create and test new methods to preserve and restore sight. Key are models that mimic important aspects of human physiology, including similar light-sensing cells, pathways for connecting the eye to the brain, and brain regions.

Retinal Disease Models for Translational Photoreceptor Replacement (EY029890)
Principal investigators: John H. Wolfe, Children’s Hospital of Philadelphia; William A. Beltran, University of Pennsylvania; David M. Gamm, University of Wisconsin
Wolfe, Beltran, Gamm and their colleagues have been using animal models to develop gene therapies for degenerative eye diseases, including retinitis pigmentosa. However, because gene therapies currently can only save regions of the retina that retain living cells, these treatments cannot restore function to damaged areas of the retina. In this new project, the team will be developing models to study how to implant replacement adult stem cell-derived light-sensing photoreceptor cells into these damaged retinal regions. The models will enable them to test surgical techniques, evaluate how well the replacement cells are working, and determine whether the treatment restores vision.

Retinal Ganglion Cell Replacement in Optic Neuropathies (EY029903)
Principal investigators: Jeffrey L. Goldberg, Stanford University; David J. Calkins, Vanderbilt University; Thomas A. Reh, University of Washington; Donald J. Zack, Johns Hopkins University
Goldberg and colleagues study glaucoma, a condition where progressive degeneration of the optic nerve threatens vision. The optic nerve, made up of retinal ganglion cell nerve fibers, conducts visual information from the retina to the brain. This team is generating a new animal model system to study how to place new retinal ganglion cells into the eye and guide the cells’ nerve fibers to appropriate regions of the brain. Success would constitute overcoming a major hurdle in the development of treatments for vision loss due to glaucoma and other optic neuropathies.

Models of Cone Disorders and Other Heritable Retinal Diseases (EY029904)
Principal investigators: Jeffrey A. Rogers, Rui Chen, and John T. Stout, Baylor College of Medicine; Sara M. Thomasy and Ala Moshiri, University of California Davis, California National Primate Research Center (CNPRC)
Rogers and colleagues are exploring cases where animals have naturally occurring ocular diseases. The team will use these animal models to help develop therapies for diseases that cause the loss of cone photoreceptors—cells in the retina that detect color. In humans, cones are concentrated in an area of the retina responsible for central vision called the macula. Few models of cone disorders exist because many of the animals most commonly used in research have primarily rod photoreceptors, which cannot detect color, and few cone photoreceptors. The investigators at the CNPRC have discovered several animals with naturally occurring visual impairment and cone dysfunction. The Baylor team has identified specific mutations in those impaired animals in genes like PDE6C that in humans cause cone photoreceptor degeneration. The project will characterize retinal degeneration in these animals, explore ways to replace cone photoreceptors and restore visual function, and survey additional animals to identify other valuable naturally occurring disease models.

Developing Cone-Dominant Retinal Disease Models as a Resource for Translational Vision Research (EY029891)
Principal investigators: Joseph Carroll, Medical College of Wisconsin; Jacque Duncan, University of California San Francisco
Carroll and colleagues are pursuing new small animal models that will enable translational research into diseases that affect cone photoreceptors. Their team is working with two small mammals with high cone density: the 13-lined ground squirrel and the tree shrew. Key aims of the project are to use molecular and chemical tools to generate models of cone diseases that mimic those seen in humans and to evaluate stem cell-based treatments of these disease models. Further, the team seeks to develop imaging and functional assays to assess cone structure and function, both to validate the disease models and assess the treatment efficacy.

Retinal Ganglion Cell Replacement in Clinically Relevant Models of Optic Neuropathy (EY029893)
Principal investigators: Tonia Rex, Vanderbilt University Medical Center; Brian Samuels, University of Alabama at Birmingham; Petr Baranov, Massachusetts Eye and Ear, Harvard Medical School
Rex and colleagues are developing optic cup organoids – lab-grown tissues with the potential to regrow retinal ganglion cells. Using tree shrews, the team will first characterize what happens after optic nerve trauma or glaucoma in these animals. They will then test how to transplant retinal ganglion cells, isolated from stem cell-derived organoids. The team hopes the model will yield a better understanding of how transplant-type therapies may help preserve and restore vision lost due to optic nerve damage.

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NEI leads the federal government’s research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit
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