The trial results announced here represent a promising step forward in efforts to regenerate an age-damaged retina, particularly because the patients were in an advanced stage of their degenerative condition and nonetheless achieved a meaningful degree of restored sight. Macular degeneration has a number of different manifestations, and here the wet form was treated, which involves excessive growth of blood vessels in the retina and consequent death of the retinal cells necessary for vision. Researchers have established an approach involving the generation of a patch of engineered retinal cells that can be implanted to restore some of the lost retinal function. Given the details, it is interesting to speculate on the degree to which the transplanted cells are helping by integrating into the retina versus helping by issuing signals that spur local regeneration. In most cell therapies it is the latter, but here the transplanted cells are more organized into a tissue-like structure.
Human embryonic stem cells (ESCs) represent a promising source for cellular replacement therapies owing to their availability, pluripotency, and unlimited self-renewal capacity. However, they also carry risks of neoplastic change, uncontrolled proliferation, and differentiation to inappropriate cell types. The eye is advantageous in investigating hESC-based cell therapy as it is accessible and confined, and the transplanted cells can be monitored directly in vivo, with the possibility of being removed or destroyed if there is evidence of neoplastic change. Furthermore, long-term immunosuppression can be delivered locally.
Late age-related macular degeneration (AMD) is characterized by irreversible cell loss, initially of retinal pigment epithelium (RPE) cells and subsequently of neuroretinal and choroidal cells, and thus may be amenable to hESC-based cell therapy. Suspensions of hESC-derived RPE (hESC-RPE) cells have been transplanted in human subjects with dry AMD and Stargardt's disease, but the extent of cell survival and restoration of vision remains ambiguous.
We developed a therapeutic, biocompatible hESC-RPE monolayer on a coated synthetic membrane, herein termed a 'patch', for transplantation in wet and early-stage dry AMD. The choice of membrane material and its preparation, including the human vitronectin coating, has not been described previously to our knowledge. In contrast to RPE suspensions, cells on the patch are delivered fully differentiated, polarized, and with the tight junction barrier formed, that is, in a form close to their native configuration. The synthetic membrane allows the patch to be handled easily and robustly. The main disadvantage of the patch is that it requires a purpose-built delivery tool and a more complicated surgery compared to cell suspensions, and the use of hESCs may require immunosuppression, unlike an autologous cell source.
The clinical trial was designed as a phase 1, open-label, safety and feasibility study of implantation of an hESC-RPE patch in two subjects with acute wet AMD and recent rapid vision decline. For safety reasons and to obtain an early efficacy signal, the trial involved patients with severe wet AMD only, although we aim to study the RPE patch in early dry AMD in the future. We reported three serious adverse events to the regulator. These were exposure of the suture of the fluocinolone implant used for immunosuppression, a retinal detachment, and worsening of diabetes following oral prednisolone. All three incidents required readmission to the hospital, with the first two incidents requiring further surgery and the third being treated medically. The three incidents were treated successfully. Both patients achieved an improvement in best-corrected visual acuity of more than 15 letters at 12 months after transplantation.
Although 12 months is sufficient to begin to describe cell survival and clinical outcomes, it is early in terms of safety monitoring, especially for late teratoma formation. The patients will be followed for five years after surgery. These two early cases are also instructive as they show an encouraging outcome despite very advanced disease, which increases the complexity of surgery and involves more damaged neuroretina.