Spark Therapeutics’ Luxturna made history as the first FDA-approved therapy that directly delivers a normal gene to take the place of a nonfunctional version to restore vision. Scientists are now using gene transfer in a different way to treat blinding diseases—by activating a type of dormant stem cells in the retina.
A team of researchers led by Mount Sinai have their eyes on a type of retinal cells called Müller glial (MG). As the team reported in a study published in Nature, they helped blind mice regain some visual function after reprogramming MGs in two steps of gene transfer.
In zebrafish, MGs act as a source of stem cells that are part of a retinal self-repair system: They can proliferate on their own to replenish damaged retinal neurons. In mammals, however, MGs lack that self-regenerative capability. Scientists can activate mammalian MG to divide, but it requires injuring the tissue.
“From a practical standpoint, if you're trying to regenerate the retina to restore a person's vision, it is counterproductive to injure it first to activate the Müller glia,” said Bo Chen, Ph.D., an associate professor of ophthalmology at the Icahn School of Medicine at Mount Sinai and lead investigator of the study, in a statement. Using gene transfers, Chen’s team made MG to divide in mice without having to injure the retina.
They first stimulated the dormant MG cells in mice to re-enter the cell cycle by injecting their eyes with a gene to turn on a protein called beta-catenin. To ensure these newly divided cells developed into rod photoreceptors, they injected the mice’s eyes with three transcription factors.
Rod photoreceptor cells, which allow us to see in dim light, are affected in early stages of retinitis pigmentosa, a genetic eye disease that causes blindness. As the disease progress, the loss of rods can result in the loss of cone photoreceptor cells, the other photoreceptor that is responsible for sensing color and visual acuity.
“If rods can be regenerated from inside the eye, this might be a strategy for treating diseases of the eye that affect photoreceptors,” said Thomas Greenwell, Ph.D., retinal neuroscience program director at the NIH’s National Eye Institute, which funded the study.
Investigators found that new rod photoreceptors were indeed generated in blind mice. They looked structurally the same as real rods and communicated with other retinal neurons. What’s more important, the team found the rods integrated into the visual pathway, as evidence showed that light response signals were being sent from the retina to the brain. Four to six weeks after the reprogramming, the blind mice were able to sense light and regained their vision, the team reported.
“This study opens a new pathway for potentially treating blinding diseases by manipulating our own regenerative capability to self-repair,” said Chen in a statement. “This is the first step to finding promising cures for patients that involve self-repair as opposed to medicine or invasive procedures.”
Other techniques that try to address vision loss either inherited or age-related are being developed. The Salk Institute, for example, developed a gene editing technique that can insert DNA to a specific location in non-dividing cells. Scientists there used the technology to deliver a functional copy of a gene behind retinitis pigmentosa to rats and helped the animals regain sight. Another team led by the University of Southern California made a stem cell-based retinal implant, which showed promise in four people with dry from of age-related macular degeneration.
Next up, Chen’s team plans to conduct behavioral studies to determine whether the mice have regained the ability to perform visual tasks and will test the technique on cultured human retinal tissue. As the team sees it, the findings can help develop regenerative therapies for blinding diseases such as age-related macular degeneration and retinitis pigmentosa, and perhaps other eye diseases like glaucoma as well.