UCSD-led team is trying to reprogram Muller glia cells into photoreceptors.

A research team led by principal investigator Kang Zhang, M.D., Ph.D., professor of ophthalmology at the University of California, San Diego (UCSD) has been awarded a five-year, $4.66 million NIH grant to investigate the regenerative potential of retinal cells. The long-term goal is to restore visual function lost through diseases such as macular degeneration and retinitis pigmentosa.

Dr. Zhang is a professor at UCSD’s Shiley Eye Center and director of UCSD’s Institute of Genomic Medicine. Co-principal investigators are Sheng Ding, Ph.D., from The Scripps Research Institute, and Thomas Reh, Ph.D., from the University of Washington.

Some vertebrates, such as goldfish and newts, have a remarkable ability to regenerate a lost limb or eye—something it was thought no mammal can do. However, Dr. Zhang’s group recently showed proof of principle at a small-scale level in mice by turning Muller cells into a type of retinal neuron.

“The human genome is quite similar to that of a newt, but we humans seem to have lost the potential to regenerate our own cells, possibly due to some inhibitory mechanisms,” Dr. Zhang says. “We are seeking small molecule chemicals that can block these inhibitions and consequently unlock humans’ regenerative potential.”

Muller cells are abundant and have the ability to regenerate nerve cells after retinal injury in fish. They usually play a supporting role in the central nervous system neurons of humans, such as those present in the eye or brain.

Dr. Zhang’s group will develop and apply high-throughput screening to more than 100,000 small molecules to identify those that will enhance Muller glia cells’ ability to reprogram and differentiate into retinal neurons in mammals. Identification, optimization, and characterization of chemical tools will provide new avenues for development of cell-based therapy as well as conventional small molecule therapeutics for regenerative medicine.

“Our ultimate goal is to use a chemical approach to turn on the regenerative potential of hibernating stem cells such as Muller cells by introducing a small molecule directly into the eye, perhaps even by eye drop or pill,” Dr. Zhang explains. He added that there is no need to transplant cells, but instead the body’s own cells would be used.

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