Reprogrammed Fibroblasts Partially Restore Vision in Mice

By Marilynn Larkin

April 21, 2020

NEW YORK (Reuters Health) - A set of five chemical compounds drove the conversion of fibroblasts into photoreceptor-like cells in mice with retinal degeneration, thereby restoring some aspects of vision, researchers say. Clinical trials could take place in two to three years, they believe.

"Stem cell-based strategies... offer a cell candidate to replace damaged or lost photoreceptors in the hope of restoring vision," Dr. Sai Chavala of CIRC Therapeutics and the Center for Retina Innovation in Dallas, Texas, told Reuters Health by email. By contrast, he said, "Our technique goes directly from skin cell to photoreceptor without the need for stem cells in between."

"We have a patented method of reprogramming dermal fibroblasts into retinal-like photoreceptor cells, he said. "These cells, when transplanted in blind mice, partially restored some aspects of vision and visual behavior."

"The small-molecule technology enables scientists to generate retinal replacement cells in less than two weeks, which is faster and less expensive than using stem cells," he noted.

As reported in Nature, Dr. Chavala and colleagues identified a set of five small-molecule compounds that together can drive the conversion of dermal fibroblasts into rod photoreceptor-like cells.

Gene expression profiling showed that these chemically induced photoreceptor cells (CiPCs) derived from mouse embryonic fibroblasts were similar to native rods in appearance and function.

Specifically, the authors explain, treatment with these five compounds led to the translocation of AXIN2 to the mitochondria, resulting in the production of reactive oxygen species, activation of NF-kappaB and upregulation of Ascl1.

The researchers transplanted the cells into 14 mice with retinal degeneration and tested their pupillary reflexes, a measure of photoreceptor function after transplantation. After three to four weeks, six (43%) showed an improved pupillary response under low light. These mice then underwent a light aversion test (mice that can see prefer dark spaces). The mice with pupil constriction were significantly more likely to seek out and spend time in dark spaces compared with treated mice with no pupil response and untreated controls

Summing up, the authors state, "A combination of five small molecules can convert fibroblasts into functional CiPCs that are capable of partially restoring pupil reflex and visual function in a mouse model of retinal degeneration."

"We anticipate that CiPCs could have therapeutic potential for restoring vision," they conclude.

Dr. David Calkins, Director, Vanderbilt Vision Research Center and Vice-Chairman and Director for Research, The Vanderbilt Eye Institute in Nashville, commented in an email to Reuters Health, "The use of chemicals to transform a set of non-neuronal cells into neurons - in this case, retinal photoreceptors - is indeed promising, since it bypasses many of the difficulties intrinsic to using stem cells."

"One can imagine a large effort to identify unique sets of such transformational compounds for custom-made neurons, depending on the need," he said. "This research is particularly important for diseases that affect the central nervous system, including the retina and optic nerve, since damaged neurons do not regenerate or turn over the way that non-neural cells do in other tissues."

Nonetheless, he noted, "For this research to truly translate to human diseases - like macular degeneration and glaucoma or even Alzheimer's and Parkinson's - requires some major steps. The survival of newly transplanted neurons must be long-term and not susceptible to immune-rejection by the host tissue. Transformed neurons, once transplanted, must also form appropriate connections to restore function."

"To establish these milestones requires testing in larger animal models, preferably non-human primates, since often therapies that work in mice do not translate to human use," he said. "Even so, this kind of research offers much promise for the many of millions of people worldwide suffering from blindness due to retinal or optic nerve disease."

The University of North Texas has a patent pending on the chemical reprogramming method reported in this paper. CIRC Therapeutics is a start-up company that plans to commercialize treatments using the technology.

SOURCE: Nature, online April 15, 2020.