The impact of network remodelling on outcomes for regenerative medicine in the retina - defining the therapeutic window

Inherited retinal diseases are a leading cause of blindness, affecting millions of people worldwide. These conditions typically lead to a loss of the specialised light sensing cells of the eye progressing to a loss of vision and ultimately blindness. There are a number of promising regenerative approaches to treating these conditions currently in human clinical trials, raising the possibility of restoring vision to many human patients.

Visual loss in these conditions is generally a slow, progressive process, yet the current clinical trials are confined to those patients in which all vision has been lost. The diseases involve complex slow changes to the visual tissues and there is reason to believe that the timing of regenerative interventions may be critical in determining the ultimate success of therapy. Here we have devised a program of experiments that determine the impact of the time of intervention upon the level of visual restoration using an established animal model of the human condition.

We will use one of the promising current optogenetic approaches to regenerative therapy delivered to a mouse model of hereditary human blindness. The treatment will be delivered at different stages of the disease and its ability to restore vision will be assessed. In order to understand the process at the cellular level we will measure the detailed responses of the visual system in neurons in the retina and brain using state of the art approaches.

These findings will influence the development of new improved treatment options for patients suffering from retinal disease and loss of vision.

Some of the most encouraging data in regenerative medicine have come from attempts to restore photosensitivity in retinal degeneration. Introduction of stem cell-derived photoreceptors, optogenetic actuators, or electronic prosthetics to the degenerate retina have all been shown to restore light responses in human patients or animal models of the disease. Clinical development of these therapies currently concentrates on subjects with end stage degeneration and profound visual loss. However, retinal degeneration is accompanied by profound neuroanatomical reorganisation of the surviving visual circuits, raising the possibility that early therapeutic intervention could be advantageous. Here we have devised a program that determines the impact of the time of intervention upon the level of visual restoration using the rd1 mouse. We will first define the impact of remodelling on the capacity of retinal/central circuits to transmit and process visual signals. We will then determine the extent to which therapy at early or late stages of degeneration alters the progress of remodelling to improve the functional capacity of visual circuits, before finally asking whether time of intervention impacts on the quality of restored vision. We propose an innovative 'double-optogenetic' approach, using expression of a red-shifted channelrhodopsin in ON bipolar or ganglion cells as a circuit interrogator in combination with electrophysiological recordings to probe the transfer of information through visual circuits. Our candidate therapeutic will be an optogenetic intervention (ectopic expression of rhodopsin in ON bipolar cells) shown previously to restore vision in rd1 mice. By defining the impact of remodelling on circuit function and its interaction with therapy our study addresses issues of substantial concern to regenerative medicine, while answering the specific practical question of whether intervention at the early stages of retinal degeneration improves efficacy.

This programme will provide significant advances to our knowledge of the dynamics of regenerative restoration of vision. These findings will be directly applicable to the treatment of human retinal degenerative disease and will help determine the future potential of therapies to restore functional vision in human patients. Ultimately the findings of this research will aid in the development of much needed clinical treatments for retinal disease, and will pave the way for optimized therapeutic trials to help realize the full potential for effective therapy in humans. This will have significant impact on the fields of retinal biology, treatment of retinal disease and modern regenerative medicine in general. We therefore expect our findings to be of wide interest to healthcare providers, sufferers of inherited retinal diseases, as well as members of the general public not only in the UK, but Worldwide. This research will push UK science further to the forefront of the rapidly emerging field of applied optogenetics, helping maintain the Universities of Oxford, Manchester and the MRC's reputation as world leaders in basic biology and translational medicine.

Hereditary retinal degenerations are a common cause of blindness representing 5.5% of registrations for severe sight loss in the UK. There are several potentially life changing regenerative approaches to the restoration of vision in current clinical trials. However, the current recruitment and trials target late stage disease following loss of vision and regenerative therapies are applied after profound remodelling of the visual circuits has occurred. Our study will challenge this therapy design and explore the potential advantages of early treatment. We know that late stage intervention can restore low level vision in mice and this has been shown in several independent studies, however early intervention may lead to a transformation in our ability to restore functional vision.

We expect this study to lead to a range of new academic collaborations in the UK and beyond. Through the established interaction between the Nuffield Laboratory of Ophthalmology (NLO) and the Oxford Eye Hospital (OEH) and Manchester Royal Eye Hospital, this project will also lead to an improved understanding of regenerative medicine, and specifically the potential of emerging gene therapy based treatments in front line health care providers. These interactions will drive new future clinical research collaborations. Furthermore, given the relevance of this project to the treatment of retinal disease we would also expect this project to lead to new industrial collaborations with biotech companies and private healthcare providers, as well as increased interactions with health care policy makers.

The impact of this proposal is expected to extend well beyond the scientific and clinical research communities. Improved treatments for impaired vision will lead to clear socioeconomic benefits, improving quality of life and increasing integration of the visually impaired into everyday society and employment. This study also has the potential to influence public understanding and appreciation of science. Optogenetic research and particularly that pertaining to the treatment of retinal disease typically attract a significant public and media attention. The obvious translational applications of this research offer a clear example of 'bench to bedside' research, in a context that is easily appreciated and widely valued - the restoration of vision. This offers a valuable opportunity to engage with the public over issues of biological research, ethical considerations including the use of animals in research, and the scientific process in general. Thus the outputs of this programme of work have the potential to improve understanding and drive public interest in scientific research.