Inherited retinal dystrophies: How regeneration may help restore vision

Studying zebrafish helps unravel mysteries of photoreceptor regeneration

This article was reviewed by Brian Perkins, PhD.

Inherited retinal dystrophies (IRDs) are char­acterized by degeneration of rods and cones; generally, the rods initially degenerate in the peripheral retina, progressing to the central retina, which leads to minimal vision in the fovea and, ultimately, blindness.

The speed of progression varies with the dis­ease. IRDs are not uncommon, and an estimated 1 in 4000 individuals worldwide may be affected, with more gene mutations being identi­fied. Treatments are limited.

Personalizing medicine for patients with IRDs can be challenging.

Brian Perkins, PhD

“Personalized medicine requires targeting and correcting possibly thousands of unique mutations, considering the wide heterogeneity,” said Brian Perkins, PhD, an associate staff member at the Cleveland Clinic’s Cole Eye Institute in Cleve­land, Ohio.

To address this, the National Eye Institute estab­lished the Audacious Goals Initiative, which is work­ing toward regeneration of neurons and neural con­nections in the eye and vision system with the targets being photoreceptors and ganglion cells.

“This goal in humans emerged from the recog­nition that some species already have the ability to repair damaged photoreceptors,” Perkins said.

Goldfish and zebrafish are noteworthy exam­ples. Fish have similar anatomy and physiology to humans in addition to the ability to regenerate reti­nal, brain, spinal cord, cardiac, and pancreatic tis­sues and appendages.

Perkins demonstrated that when a zebrafish’s pho­toreceptors are damaged, they release molecules that trigger Müller glial cells in the retina to transform into stem cells that divide, mature, and regener­ate, restoring the lost rods and cones. Much of this knowledge came from examining acute damage to the retina, such as from light damage or mechanical injury, and not from genetic disorders, he explained.

Perkins and his colleagues are investigating zebrafish that have genetic mutations in genes that are known to cause retinal degenerations in humans. The CEP290 gene has been linked to Leber congen­ital amaurosis and retinitis pigmentosa. Zebrafish with this mutated gene have scoliosis, fertility issues, photoreceptor degeneration, and other pathologies.

zebrafish vision regeneration

Importantly, the few remaining cones in the affected fish are more disorganized and do not regenerate, which raises the question of whether mutant zebrafish have lost the ability to regenerate.

In siblings of the affected zebrafish and the mutant zebrafish themselves, the investigators damaged the retinas with high-intensity light. The photoreceptors were seen to degenerate, and after approximately 2 weeks they began to regenerate. With cone degen­eration, the investigators questioned if the disease environment would limit full regeneration.

Investigation led to the finding that zebrafish with progressive degeneration do not fully regenerate the photoreceptors after damage, Perkins explained.

“This is critical because it indicates that the dis­ease environment somehow limits the overall capac­ity for regeneration,” he said.

Many questions remain, including why the retina responds differently to acute damage than to disease, whether full restoration of the cone density is lim­ited by the diseased retina, whether immune cells promote or inhibit regeneration, and whether regen­eration can be stimulated without causing additional damage. Future investigation involves translating these findings to mammalian models of blindness to develop better therapies.

Brian Perkins, PhD
e: perkinb2@ccf.org
Perkins has no financial interest in this subject matter.

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