A brief recap
Macro photograph of a human eye. Source: Unsplash.
You might recall Johanne Provost’s story, which I covered in the September edition of RMNU🔬. New details have since emerged regarding the specifics of her disease: Ms. Provost had been suffering from a rare autoimmune disease – lichen planus – that destroyed the limbal stem cells maintaining the transparent layer of tissue over each corneal surface.
As mentioned in my previous highlight, the destruction resulted in an aberrant fibrosis obscuring her vision and causing her significant pain. To address this deficiency, her health care team at Toronto’s University Health Network (UHN) ultimately decided she was a suitable candidate for a limbal stem cell transplant from a deceased donor. The usual route would have been to graft healthy stem cells from her other eye but, unfortunately, both corneal limbi were affected.
Though this procedure successfully restored Ms. Provost’s sight, she will have to remain on immunosuppressive medications. The cornea surgeon on her UHN team, Dr. Clara Chan, commented on this for The Globe and Mail:
“Not every patient is able to tolerate these strong drugs and even if they can, there are many patients who remain at high risk for rejection. […] My hope is that there will be ways that we can modify the limbal stem cells to avoid triggering the recipient’s immune system, which would lessen the medication regimen for these patients.”
The latest on a world-first
Research published in The Lancet late last year (November 2024) appears to have brought us closer to realizing this goal, though there’s still some distance to go. There’s been plenty of media coverage on this story, but I believe there are important details that require expanded discussion.
Dr. Kohji Nishida’s team at Osaka University published the results of a small trial to ascertain the safety of an induced pluripotent stem cell (iPSC)-based treatment for limbal stem cell deficiencies. Generally, this type of deficiency can be caused by conditions including autoimmune disorders, thermal and chemical burns, or Stevens-Johnson syndrome.
A critical factor in the Osaka study, however, was that the iPSCs were not generated from the patients themselves. The intention was to develop an allogeneic therapy, where donor blood cells were reprogrammed and differentiated into a sheet of corneal epithelium that would ultimately replace the patients’ scarred ocular tissue. The reason why – along with the trade-off – matters greatly in this context.
Pros and cons
A key advantage of autologous rather than allogeneic iPSC therapies is that they have the potential to eliminate the need for immunosuppressive medications. Since the treatment uses the patient’s own cells, the risk of immune rejection is significantly reduced. However, similarly to other groups discussing “off-the-shelf” iPSC therapies, the authors argue that an approach involving patient-derived iPSCs also poses disadvantages, including matters of cost and time efficiency.
Despite being more immunogenic, allogeneic stem cells are proposed to be more readily available if produced ahead of time in bulk, which could additionally reduce overall treatment costs. Of course, an off-the-shelf approach would not be without its own set of logistical and quality-assurance challenges, including manufacturing consistency, genomic instability, storage, and the potential for disease transmission. Go to Madrid et al.’s November 2024 white paper if you’re interested in more information on this topic.
While there are efforts ongoing to reduce or eliminate the immunogenic properties of off-the-shelf iPSC therapies, the authors further argue that their specific disease case offers unique advantages in this regard. Previous experiments have shown lab-grown corneal epithelial cell sheets to have limited immunogenicity as assayed in cynomolgus monkeys. The lowered threat profile of this tissue comes down to two features:
1) The cells’ immune-related gene expression profile is advantageous, as HLA I and II are present at much lower levels. HLA proteins are cell surface molecules that present antigens to the immune system, and downregulation of HLA I and II would reduce the likelihood of the recipient’s immune system recognizing and rejecting transplanted tissue.
2) Lab-grown corneal epithelial cell sheets have an ideal cellular composition. The tissue does not contain immunocompetent cells and is fabricated exclusively from induced corneal epithelial progenitors, unlike certain cadaver-sourced materials.
Originally, these qualities led the authors to hypothesize that the use of immunosuppressive agents beyond corticosteroids would not be necessary for their treatment (although preclinically, mild immunosuppression was deployed). However, they still tested this requirement in their experiments, and it’s a good thing they did. The trial was designed such that two of the four patients were on corticosteroids, and the other two were administered corticosteroids plus low-dose cyclosporine.
Two years post-treatment, none of the four patients presented with severe side effects such as tumour formation. Critically, while the immune response was not sufficient for the tissue to be rejected in the classical sense, patients did not appear to be completely immunotolerant of the cells; indeed, the immunosuppressed group exhibited more pronounced visual improvements, suggesting that subclinical immune rejection may have been a factor in the corticosteroid-only group.
The bottom line
It is important to bear in mind that we only have data on four subjects. Given the (understandably) limited nature of the study, a much larger trial is being organized to determine efficacy.  This was slated for March 2025, though there is no news yet. For now, the data do afford a preview of the treatment’s potential: All four patients experienced immediate vision improvements. It should be mentioned that these effects were durable in only three subjects; one individual’s particularly severe underlying condition is thought to have caused their regression to baseline.
Once again, the ultimate goal will be to leave immunosuppressive regimes behind completely, an important element that will require protocol optimization. If the next trial is successful, it may pave the way for autologous or engineered, virtually non-immunogenic allogeneic iPSC treatments in future. For now, the Osaka strategy may still mark an improvement as compared to the current benchmark, since rejection rates are quite high (40 per cent, according to the authors) following standard corneal limbal transplants, such as those from cadavers.
I’ll continue to monitor the latest on this line of investigation in upcoming editions of Regenerative Medicine News Under the Microscope, so make sure to check back for updates.
Lyla El-Fayomi
This was a really informative and well-written update! I appreciate how clearly you explained the science behind the treatment and the pros and cons of different approaches. Looking forward to more updates in the next edition!
Thanks! I’ll be sure to let Lyla know you are enjoying her posts.