Though retinal researchers have been working with induced pluripotent stem cells (iPSC) for little more than five years, I still find it amazing what they’re doing with them. Scientists are able to take small samples of skin or blood cells from a patient, genetically turn back the clock on those cells, so that they revert back to a stem-cell state, and then coax them forward to become retinal cells. From there, the resulting cells might be used as a transplantation therapy, as a platform for testing potential treatments in a dish and as a resource for learning why retinal diseases cause vision loss and how to prevent it.
I am particularly excited about Foundation-funded iPSC research at the University of Iowa recently published in the journal eLife. A team led by Ed Stone, M.D., Ph.D., and Budd Tucker, Ph.D., has gained valuable insights into retinitis pigmentosa (RP) caused by defects in the gene USH2A, which, depending on how it’s mutated, can cause vision loss from RP or combined vision and hearing loss from Usher syndrome type 2A.
The Iowa researchers created retinal tissue from the skin of a 62-year-old patient with vision loss from USH2A-associated RP. The knowledge they’re gaining from studying these cells — which, in essence, are human models of disease — is guiding the research community toward developing effective therapies for saving and restoring vision.
In its experiment, the Iowa team developed an eyecup from the skin cells of the USH2A patient. You can think of an eyecup as being like a retina during the early-development stage. Creating the eyecup was in itself a remarkable achievement, given the many types of cells that make up the retina and their complex organization. The ability to do this validates that viable retinal cells can be derived from iPSC.
Next, the investigators observed the activity of the USH2A gene, which is defective in these partially developed cells. By studying the effects of the mutations on retinal cells, they are determining which therapeutic strategies — such as corrective gene therapy or cell replacement — might have the best chance of working.
But perhaps the most noteworthy part of the investigation was the transplantation of the eyecup into mice with a retinal degeneration. After transplantation, the eyecups’ photoreceptor precursors integrated into the mice retinas and further developed into what the researchers call “recognizable” photoreceptors.
This is good news on two fronts. First, it indicates that USH2A defects don’t have a significant effect on photoreceptor development, which occurs before birth in humans. This is consistent with the fact that many USH2A patients maintain relatively useful vision into young adulthood. Second, it shows that cells from an older adult are viable for producing and transplanting iPSC-derived retinal cells.
Because photoreceptors affected by USH2A mutations degenerate slowly, we might be able to replace them in adult patients without using gene therapy to correct the defect. The newly transplanted photoreceptors — derived from the patient’s skin or blood — would have the USH2A defect, but would likely provide useful vision for a few decades.
That doesn’t mean that gene therapy should not also be pursued. Genetically corrected transplanted retinal cells would be the optimal solution. However, because the USH2A gene is relatively large, it has thus far been difficult to design a gene therapy that can deliver the large USH2A cargo to affected retinal cells. But Foundation-funded researchers such as Luk Vandenberghe, Ph.D., of Massachusetts Eye and Ear Infirmary, are working on the gene therapy cargo challenge, as well. So, down the road, we may have multiple options for USH2A treatments — with and without gene therapy.
While this particular project is basic research — it isn’t preparing a specific therapy for a human study — it provides critical information for developing future treatments. It gives us clear targets for what our best therapeutic strategies might be. That’s why the Foundation funds a balance of both clinical and basic scientific studies. Both are essential for getting vision-saving cures out to the people who need them.
By the way, the first-ever clinical trial for an iPSC-derived, retinal-disease treatment (for wet age-related macular degeneration) just moved into a clinical trial in Japan.
Pictured, above: Dr. Budd Tucker isolates induced pluripotent stem cells from a patient with a retinal disease.