A radical stem cell transplant has significantly improved the blurry vision of three people with severe damage to their corneas, the clinical trial in Japan signalling a huge advancement for stem cell research.
Two years after the operation, the first of its kind in the world, no serious safety concerns have come to light, and from the outside looking in, all three corneas look much more transparent than they once did.
Four participants were involved in the study, all of whom suffer from a disorder that causes scar tissue build-up on the cornea, called limbal stem cell deficiency (LSCD).
If the cornea is imagined as the “transparent window” at the front of the eye, then the limbus is similar to its frame, holding the glass to the white ball.
This crucial framework also contains a hearty supply of stem cells, which are ready to replenish any worn-out units in the cornea, like little windshield wipers, keeping the glass clear of fogginess as we age.
Without the vigilance of the limbal stem cell community, gradual vision loss is inevitable.
Today, people with LSCD in one eye can have their scar tissue surgically removed and replaced by a slice of healthy cornea from the other eye. But if the loss of limbal stem cells extends to both eyes, there needs to be a donor transplant.
Of the 12.7m people worldwide who experience cornea-related vision loss, transplants are available for just one in 70. Even for those who do receive a transplant, graft survival is often a problem: there is always a risk of rejection.
That’s where the potential of induced pluripotent stem cells (iPSCs) comes into play.
These all-powerful units are converted from the cells of any human’s body. Once reprogrammed back into an embryonic-like state, they propagate indefinitely, with the ability to shape-shift into any type of adult human cell, including those of the cornea.
In 2023, researchers in the US announced they had used limbic stem cells to restore vision in two patients with corneal damage up to a year later.
Now, reports Science Alert, scientists at Osaka University Hospital in Japan have gone a step further and used iPSCs, derived from healthy human blood cells, to restore vision.
In the lab, the resulting iPSCs were coaxed into corneal epithelial cell sheets (iCEPS). These sheets were then transplanted over the patients’ cornea after scar tissue was removed, and a protective contact lens topped it off.
Some seven months after the transplant, all four patients showed improvements to their vision. A year after, however, the vision of patient four, a 39-year-old woman with the most severe vision loss of the cohort, had once again regressed.
The best improvements to vision were seen among patients one and two, a 44-year-old woman and a 66-year-old man, respectively.
Researchers suspect patients three and four may have not shown the same improvement because of an insidious immunological response to the transplant. None of the patients was given immunosuppressive drugs, apart from steroids.
Researchers have previously used iPSCs from a patient’s own skin to restore vision in those with degeneration of the macula – at the centre of the retina – but this is the first time scientists have achieved a similar feat for this other form of vision loss, and without using materials derived from the patients’ own cells.
While these small trials are extremely hopeful, such procedures remain highly experimental and potentially dangerous. Far more research needs to be done to assess their safety and efficacy.
“To our knowledge, this study provides the first description of iPSC-derived cell constructs being transplanted into or on to patients’ corneas, and represents a promising future treatment option for individuals with an LSCD,” the team from Osaka University Hospital said.
They are now planning a multi-centre clinical trial to “build on the encouraging results”.
The study was published in The Lancet.
Study details
Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan
Takeshi Soma, Yoshinori Oie, Hiroshi Takayanagi et al.
Summary
Background
The loss of corneal epithelial stem cells from the limbus at the edge of the cornea has severe consequences for vision, with the pathological manifestations of a limbal stem-cell deficiency (LSCD) difficult to treat. Here, to the best of our knowledge, we report the world’s first use of corneal epithelial cell sheets derived from human induced pluripotent stem cells (iPSCs) to treat LSCD.
Methods
This non-randomised, single-arm, clinical study involved four eyes of four patients with LSCD at the Department of Ophthalmology, Osaka University Hospital. They comprised a woman aged 44 years with idiopathic LSCD (patient 1), a man aged 66 years with ocular mucous membrane pemphigoid (patient 2), a man aged 72 years with idiopathic LSCD (patient 3), and a woman aged 39 years with toxic epidermal necrosis (patient 4). Allogeneic human iPSC-derived corneal epithelial cell sheets (iCEPSs) were transplanted onto affected eyes. This was done sequentially in two sets of HLA-mismatched surgeries, with patients 1 and 2 receiving low-dose cyclosporin and patients 3 and 4 not. The primary outcome measure was safety, ascertained by adverse events. These were monitored continuously throughout the 52-week follow-up period, and during an additional 1-year safety monitoring period. Secondary outcomes, reflective of efficacy, were also recorded. This study is registered with UMIN, UMIN000036539 and is complete.
Findings
Patients were enrolled between June 17, 2019 and Nov 16, 2020. We had 26 adverse events during the 52-week follow-up period (consisting of 18 mild and one moderate event in treated eyes, and seven mild non-ocular events), with nine recorded in the additional 1-year safety monitoring period. No serious adverse events, such as tumourigenesis or clinical rejection, occurred during the whole 2-year observational period. At 52 weeks, secondary measures of efficacy showed that the disease stage had improved, corrected distance visual acuity was enhanced, and corneal opacification had diminished in all treated eyes. Corneal epithelial defects, subjective symptoms, quality-of-life questionnaire scores and corneal neovascularisation mostly improved or were unchanged. Overall, the beneficial efficacy outcomes achieved for patients 1 and 2 were better than those achieved for patients 3 and 4.
Interpretation
iCEPS transplantation for LSCD was found to be safe throughout the study period. A larger clinical trial is planned to further investigate the efficacy of the procedure.
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