Stem Cell Therapy for Vision Loss: iPSC-Derived Corneal Grafts Show Safety and Efficacy in New Study

In a recent groundbreaking study published in The Lancet, a team of international researchers evaluated the safety and preliminary effectiveness of human induced pluripotent stem cell (iPSC)-derived corneal epithelial cell sheets (iCEPS) for treating limbal stem cell deficiency (LSCD). This debilitating eye condition is marked by the depletion of corneal stem cells, resulting in severe vision impairment. The study was conducted at the Department of Ophthalmology at Osaka University Hospital, following Japan’s stringent regulatory standards for regenerative medicine.

Background

The corneal epithelium, vital for clear vision, depends on limbal stem cells located at the corneal edge for continuous renewal. When these limbal stem cells are damaged or lost due to trauma, immune conditions, or genetic factors, LSCD occurs, leading to corneal surface damage, conjunctival scarring, and substantial vision loss. Traditional treatment methods, which involve reconstructing the corneal surface and grafting healthy tissue, have limitations. Autologous and allogeneic grafts often carry risks such as immune rejection, biopsy challenges, and variability in tissue quality. In this context, iPSC-derived corneal grafts have emerged as a promising alternative, though their long-term efficacy and safety require further exploration.

Study Overview

The recent study was conducted on four adult participants diagnosed with LSCD, monitored over a period of 52 weeks, with an additional one-year safety follow-up. Ethical approval was obtained from relevant committees, and participants were thoroughly briefed with accessible materials before providing informed consent. LSCD stages ranged from moderate vision loss due to partial stem cell depletion (stage IIB) to severe loss with significant corneal damage (stage III).

The participants were carefully selected based on strict inclusion criteria, excluding those with allergies, recent cancers, uncontrolled diabetes, or ongoing infections. Women who were pregnant or breastfeeding were also excluded. Recruitment was facilitated through institutional networks, ensuring compliance with safety guidelines.

In this study, a unique approach was taken to generate and purify corneal epithelial cells from iPSCs, leading to the production of transparent iCEPS with a cobblestone-like structure. These cells exhibited key markers of healthy corneal epithelium, such as tumor protein 63 (p63), keratin-12, keratin-3, and mucin-16. Each iCEPS sheet underwent rigorous quality control before being transplanted. Tumorigenicity was ruled out through extensive assessments, including testing in immunodeficient mice and karyotype analyses.

Procedure and Follow-Up

The transplantation process involved a specialized keratectomy to remove damaged tissue, followed by the placement of the iCEPS on the patients’ eyes, secured with therapeutic contact lenses. Postoperative care included antibiotics, corticosteroids, and regular monitoring to prevent complications. Safety was the primary concern, with adverse events closely monitored throughout the study. Metrics for efficacy included visual acuity, LSCD stage, and overall corneal health, which were evaluated at multiple intervals before and after surgery.

Of the four patients, the first two received iCEPS transplants mismatched for Human Leukocyte Antigen (HLA). After six months of follow-up, these initial transplants showed no signs of immunological rejection, leading to the decision to forgo additional immunosuppression in the subsequent two patients. Clinical improvements were noted in all participants, with stages of LSCD reduced in most cases. Patients 1 and 2 showed significant recovery from stage III to stage IA, while patient 3 improved from stage IIB to IA, with these improvements maintained throughout the follow-up. Patient 4 initially improved from stage III to IA but experienced a regression to stage IIB after one year, possibly due to subclinical immune responses.

Results and Safety Profile

The study reported no cases of tumor formation or immunological rejection. In total, 26 minor adverse events were observed across all patients during the 52-week observation, all of which were mild and manageable. An additional nine minor events were recorded during the extended safety monitoring, with no serious adverse effects. Improvement in visual acuity was most pronounced in patients 1 and 2, with stabilized or improved symptoms reported by all patients. Corneal opacification was reduced, and a decrease in corneal neovascularization was noted for patients 1 and 2, while the remaining patients showed stable or slightly increased neovascularization. Quality of life metrics improved for patients 1, 2, and 3, though patient 4 experienced some decline.

Conclusions and Future Directions

This pioneering first-in-human study demonstrated that iPSC-derived corneal epithelial cell sheets are well-tolerated, with no evidence of tumorigenicity or immune rejection. The results indicate a promising therapeutic option for LSCD patients, especially those who do not match HLA criteria for traditional transplants. While significant improvements were observed in LSCD staging and visual outcomes, further multicenter clinical trials are essential to confirm these findings on a broader scale.

These positive results underscore the potential of iPSC-derived therapies to overcome the limitations of current treatments for LSCD, providing a new avenue for patients who suffer from this debilitating condition.

Reference:

1. Kumar Malesu, Vijay. "Stem-cell implants restore vision in patients with corneal stem cell deficiency". News-Medical. https://www.news-medical.net/news/20241112/Stem-cell-implants-restore-vision-in-patients-with-corneal-stem-cell-deficiency.aspx. (accessed December 07, 2024).

(Input from various sources)

(Rehash/Ankur Deka/MSM)