Three AGI-funded projects are developing models to gauge survival and integration of regenerated cells, including light-sensing photoreceptors and retinal ganglion cells (RGCs), which carry visual signals from the retina to the brain.
The three teams will share data and technology with each other and with the AGI Translational Models Consortium. An external scientific oversight committee will closely monitor progress, provide technical recommendations, and assist evaluation of project milestones.
Total funding for the projects is about $3.7 million per year for five years.
Accelerating photoreceptor replacement therapy with in-vivo cellular imaging of retinal function (1U24EY033275)
Principal inevestigators: Juliette McGregor, Ph.D., University of Rochester; David Gamm, M.D., Ph.D., University of Wisconsin; and Teresa Puthussery, O.D., Ph.D., University of California Berkeley
Juliette McGregor has assembled a multidisciplinary team of researchers to evaluate the survival and functional integration of transplanted photoreceptors. Her team will leverage imaging technology developed with prior AGI funding to locally ablate photoreceptors and evaluate restored retinal activity in vivo. In collaboration with David Gamm and colleagues at the University of Wisconsin, they will transplant replacement photoreceptors into damaged retina as microaggregates and in scaffolds designed to promote integration. Teresa Puthussery will examine the impact of photoreceptor loss and restoration of photoreceptor signaling on existing retinal circuitry.
A two-pronged approach to generating novel models of photoreceptor degeneration for regenerative cell therapy (1U24EY033272)
Principal investigators: Yingbin Fu, Ph.D., Baylor College of Medicine; Michiko Mandai, M.D., Ph.D., RIKEN Center for Biosystems Dynamics Research; Takeshi Iwata, Ph.D., National Hospital Organization, Tokyo Medical Center; and Takashi Yamamoto, Ph.D., Hiroshima University
Yingbin Fu and collaborators will compare two potential strategies for evaluating regeneration of the retina. In the first strategy, they will use lasers to specifically ablate photoreceptors in an advanced animal model. The second strategy will use a gene editing technology called Platinum Talen to selectively prune photoreceptors from the retina through gene disruption. The latter approach more accurately depicts the gradual loss of photoreceptors observed in inherited retinal diseases such as retinitis pigmentosa. After characterizing the anatomical changes in both ablation models, they will evaluate their ability to incorporate stem cell-derived replacement retina in host animals. The project will combine leading expertise in Platinum Talen gene editing from a team led by Takashi Yamamoto, inherited retinal degeneration and advanced animal disease models from teams led by Fu and Takeshi Iwata, and regenerative cell therapy from a team led by Michiko Mandai.
Overcoming barriers to retinal ganglion cell replacement in experimental glaucoma (1U24EY033269)
Principal investigators: Jason Meyer, Ph.D., Indiana University; Brad Fortune, O.D., Ph.D., Legacy Research Institute; Benjamin Sivyer, Ph.D., Oregon Health and Science University; Yvonne Ou, M.D., University of California San Francisco; and Gareth Howell, Ph.D., The Jackson Laboratory
Jason Meyer and colleagues are using an established glaucoma model from the laboratory of Brad Fortune for testing manipulations to improve the long-term survival of transplanted RGCs derived from human induced pluripotent stem cells from the Meyer lab. Glaucoma causes permanent damage to the optic nerve—the bundle of data cable-like RGC axons that travel between the retina and brain. To enhance RGC transplant survival and integration, they will modify the immune interactions of donor and host tissue, modify the cellular age of host retina, and enhance neural connectivity of donor ganglion cells into host retinal circuitry. Ben Sivyer and Yvonne Ou will help the team assess the functional and anatomical integration of donor ganglion cells in the glaucoma model. Gareth Howell will provide expertise in immune-like responses in glaucoma.