Post Doctoral Researcher University of Modena and Reggio Emilia - Centre for Regenerative Medicine Stefano Ferrari Modena, Italy
Abstract: The autologous cultivated human stem-cell based limbo-corneal epithelium is the first regenerative advanced therapy medicinal product in ophthalmology globally, and it is now a therapy with proven safety and efficacy across various regulatory frameworks available worldwide for limbal stem cell deficiency patients. In Europe is Holoclar, applied in 4 studies compliant with current regulatory rules. These include two pan-European prospective studies (HOLOCORE and HOLOCORE FOLLOWUP) on 60 patients, monitored for 1 and 6 years, respectively; a real-world evidence PASS “registry like” 5-year follow up study on commercially-treated patients (HOLOSIGHT); and a 20-year study on patients treated previously (HOLOUP). The critical and integrate analysis of these study results has provided valuable biological insights. First, the expanded clinical experience has allowed for identification of the optimal biopsy to achieve an effective therapy. Then, optimization of biological and clinical procedures has enabled the reduction of the minimum required p63 bright stem cells within the cultivated autologous limbal graft (previously set at 3% based on statistical correlations with clinical efficacy found in real-world evidence) to 2%. Furthermore, despite the previously observed correlation between patient age and stem cell count, the positive treatment outcomes in elderly individuals (6 people treated aged 65 to 84 years) have shown that these residual stem cells were still capable of effectively regenerating tissue and maintaining it in the long term. Together with restoring tissue architecture and proper cellular localization, the transplanted cultivated epithelium produced multiple paracrine effects, steadily influencing the surrounding microenvironment with various outcomes. These included, among others, partial reabsorption of stromal opacities (suggesting an effect on keratocytes), promotion of physiological wound healing, as evidenced by full success following stromal substitution (perforating keratoplasty), regression of neovascularization, maintenance of lacrimal secretion, and improved visual acuity. In conclusion, this evidenced-based acquired knowledge is key for a deeper understanding of the system’s biology and for the advancement of future cell therapy applications.
