Clinical trial of cone photoreceptor transplantation for the treatment of retinal degeneration

The human eye makes use of two types of light-sensing cells, rods and cones. Of the two, the cones, which are active in daylight and which confer detailed (reading) vision, are by far the most important for day-to-day life. In conditions like cone dystrophy or Stargardt disease, the cone cells die over time, and as the human body is unable to replace these cells, this results in severe vision impairment. In this project we aim to create a source of transplantable cone cells and test whether the transplantation of these cells into the human eye can restore the vision that is lost in patients with advanced cone dystrophy.
In a previous project, we have shown that we can grow up human cones in the laboratory using methods that make them suitable for subsequent transplantation into patients. When we transplanted these cells into mice that lack all light-sensing cells, we could prove that the human cells survived and made connections with the nerve cells of the mouse. As a result, light-sensation was restored in the mouse eye and the animal's behaviour changed in response to light, indication that some vision was restored. The aim of this project is to (1) scale-up the cone production method to be able to make enough cells for treating the human eye, (2) produce a large batch of cones that passes the quality regulations for human use, and (3) transplant these cone cells into the eyes of up to 12 patients with advanced cone dystrophy. As this is the first time that we test these cells the primary objective of the patient study will be to establish whether the transplantation of cones is safe. The secondary objective is to determine whether the transplanted cone cells can survive and restore vision, using a range of vision tests. If the study is successful, we will develop the transplantation method further to be able to treat a increasing range of blinding diseases.

Loss of cone photoreceptors is a common feature of a range of inherited retinal dystrophies, including cone and cone-rod dystrophies (CD), where only the photoreceptors are affected, as well as Stargardt disease and age-related macular degeneration (AMD), in which both the photoreceptors and the RPE are compromised. The prevalence of these conditions varies from 1:30,000 for CD to 1:150 for advanced AMD. Endstage disease for all these conditions is characterised by a lack of central vision, due to the absence of surviving cones in the macula. We hypothesise that replacement of the photoreceptors, either in isolation or with RPE, can restore vision in all these conditions, despite the different disease aetiologies. In a previous MRC-funded study (MR/M007871/1) we developed a GMP-compatible protocol that allows the differentiation of human embryonic stem (ES) cells to cone precursors. We have recently shown that transplantation of these cells into mouse models of endstage retinal dystrophy allows them to form functional connections with the underlying retina and restore vision. The objective of this study is to scale-up the developed GMP protocol, produce clinical grade ES-derived cone photoreceptor precursors and conduct a combined phase I/II clinical trial of cell therapy for the treatment of cone dystrophies. The objectives of the clinical trial will be to establish the safety and efficacy of ES-derived cone photoreceptor transplantation in patients with a cone dystrophy in whom there is a central scotoma due to cone photoreceptor loss without overt damage to the underlying retinal pigment epithelium (RPE). Following transplantation, we will characterise retinal structure using retinal imaging and will determine whether there is an improvement in visual function using electrophysiology and psychophysics.This study will pave the way for the development of therapies for Stargardt disease and AMD which require co-transplantation of cone photoreceptors and RPE.