Stem cells reprogrammed to fight corneal diseases and restore sight

To date, only four patients have been involved, but the results of a new therapy using pluripotent stem cells, reprogrammed thanks to genetic engineering to treat a corneal disease called LSCD (which can lead to blindness), are so encouraging that we may rightfully hope that this marks the start of a turning point, perhaps for other diseases as well.

The technique was trialled at Osaka University Hospital in Japan, with the results appearing on 16 November in the Lancet, one of the most highly-respected medical journals in the world.

LSCD stands for “limbal stem-cell deficiency”, a problem that occurs when the stem cells in the corneal limbus (the border between the cornea and the sclera—in other words, the white part of the eye) either do not function properly or are insufficient in number. These cells play a fundamental role in maintaining corneal transparency and corneal regeneration. When LSCD appears (due to autoimmune or genetic issues or trauma), scars form on the cornea, compromising eyesight and, in the most severe cases, resulting in blindness.

For years, researchers have tried to use “other” stem cells to restore limbal stem cells, but the attempts carried out to date were generally based on a transplant of corneal cells (derived from stem cells from a patient’s own healthy eye), and did not have much success, because the procedure is invasive and the outcome uncertain. What’s more, if both eyes are affected, it is impossible to use cells from a healthy eye; attempts have therefore been made with transplants from deceased donors, but in such circumstances there is always the risk of rejection.

That is why the ophthalmologists at Osaka University decided to use induced pluripotent stem cells (known by their acronym, iPS cells), which earned their “inventor”, the Japanese researcher Shinya Yamanaka, the Nobel Prize for Medicine in 2012.

Using this system, which has revolutionised stem-cell based treatments, any type of adult stem cell can be genetically reprogrammed to return to a state similar to that of embryonic stem cells.
The researchers in Osaka used adult cells from the blood of a healthy donor; once they reprogrammed them, they transformed them into a transparent corneal epithelial cell sheet. Then, between June 2019 and November 2020, they “enrolled” two women and two men between 39 and 72 years of age, all with LSCD in both eyes, and performed surgery on them. First, the ophthalmologists scraped away the layer of scar tissue that covered their corneas, then they “sutured” on the epithelial cell sheets derived from the iPS cells. Lastly, a protective soft contact lens was applied over the graft to protect it.

After two years, none of the patients had experienced serious adverse effects. Importantly, none developed tumours—one of the most well-known and feared risks when using iPS cells—and none showed signs of rejection (not even the two patients who had been administered an immunosuppressant treatment). Moreover, all began very quickly to recover their eyesight, although one later experienced regression in one eye, for reasons as yet unclear.

Admittedly, there are many other details still to be understood about how iPS cells work, and the researchers will have to carefully assess the extent of the impact that the removal of the scar tissue, performed before the sheet of new cells was introduced, had on the positive outcomes achieved. The ophthalmologists conjecture that the transplant could have triggered a sort of migration of stem cells from other regions of the eye, with a resulting “rejuvenation” of the cornea; future tests will clarify exactly what did happen.