Organizational model for characterization and treatment of orphan bilateral blindness due to different forms of ocular surface stem cell deficiency: the bioengineered oral mucosa from bench to bedside.

Corneal opacity affects 4.5 million people worldwide and is the fifth leading cause of blindness globally. Complete bilateral corneal stem cell deficiency is associated with blindness due to a total absence of corneal stem cells affecting both eyes. Autologous approaches such as SLET or CLET are not applicable as no residual limbus is available to extract stem cells. The standard of care is generally the allogeneic transplant of conjunctival-limbal or kerato- limbal graft, with significant issues: disease transmission and most transplants fail within five years, and the associated graft rejection requires immunosuppressants with associated risks. The patients' illness has high costs for repeated treatments and procedures and impacts quality of life and productivity. The autologous bioengineered oral mucosa has the potential to avoid these issues and has shown clinical efficacy in previous proof of concept applications on heterogeneous cases. However, increasing numbers of advanced-therapy medicinal products (ATMPs), comprising cell therapies and tissue-engineered products, are regulated by Regulation (EC) 1394/2007 through EMA. Very few ATMPs achieved this authorization due to hurdles on the pathway to regulatory approval, including quality, safety, and efficacy. Moreover, there are also hurdles in the requirements that support the product's clinical use, including instructions for use supplemented with detailed training materials, product information for patients, organized safety reporting and any obligations for further clinical studies to increase the safety and efficacy data set. The health system's resources are decreasing, and a tailored organizational model and the patient's active role in the management of his/her health become critical. The project aims to create an organizational model with a network of ophthalmologists, a patients' supporting organization and a centralized cell therapy laboratory producing bioengineered oral mucosa as an alternative source of stem cells. This network will implement a total Limbal Stem Cell Deficiency (LSCD) blind patient database and a platform for online medical consulting. The group will promote the project for analysis and classification of the related pathologies with grading on blind-specific websites and in scientific societies to characterize and prepare the treatment for bilateral blindness due to ocular LSCD. A specific patient journey will be defined, including online consulting and medical service on bioengineering applications. The patient characterization will be obtained at clinical, molecular, and transcriptome levels by the different UOs to identify subgroups of pathologies to include/exclude from the selection of patients. The clinical protocol for the specific etiologies and grading will be designed from the results of the studies for a personalized approach. Finally, the clinical centres will implement the phase I quality path preparatory for a clinical trial (not included here).