A New Model for Studying Retinal Degeneration

Led by Magdalene Seiler, PhD, UC Irvine researchers have created a new rat strain for studying retinal degeneration and the feasibility of retinal transplantation as a novel therapeutic approach to vision loss.

It typically starts with night blindness and, in many cases, can lead to complete vision loss. That is the trajectory for people suffering from retinitis pigmentosa, a condition caused by inherited mutations that lead to the degeneration of photoreceptors — the light-sensitive cells in the back of the eye.

This is exactly the type of condition Magdalene Seiler, PhD, a professor in residence in the UC Irvine Department of Physical Medicine & Rehabilitation, is working to address.

“Our ultimate goal is to develop stem-cell-derived retinal organoid transplants as a treatment for patients with advanced retinal degeneration — that is, when most photoreceptors have been lost,” says Seiler, also a member of the Sue & Bill Stem Cell Research Center and the Brunson Center for Translational Vision Research.

Retinal degeneration affects millions of people in the United States, yet effective treatments remain limited. The Seiler lab hopes to one day use retinal transplants to restore vision.

To that end, researchers in the Seiler lab have created a new rat strain useful for cell therapy and retinal degeneration studies.

A New Retinal Degeneration Rat Model

“Transgenic rat models have proven their unparalleled contribution to vision research in humans,” says Seiler. “We created a unique retinal degeneration rat model for studying retinal transplant connectivity, which can also be used to generate retinal degeneration rats with other cell-specific labels.”

They outline their experimental study in a paper published in Translational Vision Science & Technology: “Generation of a New Immunodeficient Rat Model of Retinal Degeneration with LSL TdTomato Reporter and TdTomato-Pcp2 Expression.”

“We have previously shown that retinal sheet transplants can improve vision in the RhoS334ter-3 rat model of retinitis pigmentosa, but we could not directly demonstrate connections between transplant and host cells,” explains Seiler.

So, they generated a new transgenic rat strain with photoreceptor degeneration and a defective immune system that expresses a “floxed” TdTomato reporter gene. “This means that the tissue itself is not fluorescent, but specific cells become red fluorescent in combination with Cre-recombinase,” says Seiler. “Retinas exposed to a virus expressing ‘Cre,’ in combination with the promoter for a neuron-specific protein (Synapsin), developed TdTomato labeling after eight to nine days.”

A retinal degenerate transplant recipient expressing TdTomato in specific cells enables more cell therapy studies in rats. “All our previous transplantation studies only had a label of the donor cells, not of the host cells,” says Seiler. “Having a combination of host and donor cell labels makes it possible to study interactions between transplant and host cells.”

Next Steps

Retinal degenerate rats with fluorescent-labeled cells can be used as recipients for human stem cell-derived retinal and photoreceptor transplants at a stage of blindness, when most photoreceptors have been lost.

“We would like to use TdTomato-labeled retinal degenerate rats to compare the transplant of retinal organoid sheets with transplants of photoreceptor-only sheets,” says Seiler. “A retinal degenerate recipient with specifically labeled retinal neurons will make it possible to quantify transplant-host connectivity. It will also make it possible to compare different cell sources.”

Seiler views this work as offering a promising path to vision restoration. “This new model is a valuable tool for evaluating the efficiency and feasibility of retinal transplantation as a novel therapeutic approach.”

This work was supported in part by grant funding from the National Institutes of Health and by bridge funding from the UC Irvine Department of Ophthalmology.

— Shani Murray