Preclinical validation of a tissue engineered product consisting in RPE derived from human embryonic stem cells disposed on human amniotic membrane in non-human primates.

Abstract

Purpose : In developed countries, retinal degenerative diseases affecting Retinal Pigmented Epithelium (RPE), including Age-related Macular Dystrophy and inherited retinal diseases such as Retinitis Pigmentosa (RP), are the predominant causes of human blindness worldwide. Despite the scientific advances achieved in the last years, there is no cure for such diseases. In this context, we have developed a cell therapy medicinal product based on our expertise in tissue engineering and in the manipulation of pluripotent stem cells. This novel tissue engineered product (TEP) consists in RPE cells derived from clinical grade human embryonic stem cells disposed on a biocompatible substrate allowing the formation of a 3D functional sheet, suitable for transplantation. After functional validation in a rodent model of RP (Ben M'Barek et al., 2017), our purpose was to test the safety of the surgery and local tolerance in non-human primates (NHP).

Methods : A specific device was developed in order to (i) embed the TEP in gelatin, (ii) allow its transport in a specific medium and (iii) cut the transplant at the right format. Non-human primates (NHP, n=6) were transplanted in one eye (right eye) with the TEP in the macular region. Left eye was left untreated. Retinal integrity and functionality were assessed at different time points (week 1, 2, 4, 6 and 7) through Eye fundus, Optical-coherence tomography (OCT) and electroretinography (ERG). Inflammation was also assessed using slit lamp. At the end of the experimental period, histological analysis was performed to evaluate the correct location and integration of the TEP within the host retina.

Results : We successfully developed a device allowing us to prepare and implant the TEP in the subretinal space of six NHP. We showed that ERG responses were not modified by the surgery and that it did not cause any long lasting inflammation. Moreover, transplanted cells were integrated in the retina and were able to phagocyte photoreceptor debris.

Conclusions : We have shown in NHP that our surgical method of implantation was safe and did not provoke any local inflammation or retinal deterioration. Morphologic and histologic studies indicated that RPE cells were integrated into the host retina and were able to interact with photoreceptors. Our results lay the foundations for clinical studies early 2019.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.