Abstract for laypersons

Degenerative retinal disorders are a common cause of blindness and lead to loss of photoreceptor cells. These cells are the only cells in the eye that translate light signals into neural code. Once photoreceptors are lost, the body has no mechanism to regenerate these cells, making vision loss irreversible. It has been proposed that light sensitive proteins (so-called opsins) could be brought into surviving cells of the retina by the means of gene therapy to allow these surviving cells to substitute the function of the lost photoreceptors. Proof-of-principle laboratory and clinical trail data has been published. There are different classes of opsins available. One of them, the group of mammalian opsins, initiates intracellular signalling cascades possibly offering an efficient and somewhat naturalistic way of stimulating the host cells. However, their suitability critically depends on how precisely these opsins interact with the cellular environment encountered in the host cell. Therefore, careful optimization of the opsin’s properties is required to obtain an optimal tool for vision restoration. In this project we will follow a systematic approach to efficiently optimize mammalian opsins as tools for vision restoration by examining and tweaking the way how these opsins interact with intracellular signalling cascades of surviving retinal neurons.

Scientific abstract

Background: Degenerative retinal disorders are a common cause of blindness and lead to irreversible photoreceptor death. In optogenetic gene therapy exogenous light sensitive proteins (opsins) are expressed in surviving cells of the retina to allow them to substitute the function of the lost photoreceptors. Research thus far has mostly focused on the use of opsins of microbial origin. However, these represent only one of the two main classes of optogenetic tools: the other being G-protein coupled receptor opsins of mammalian origin, which might bear certain advantages as for their more physiological way of stimulating their host cells. There is no consensus on which mammalian opsin could serve best for that purpose. Probably each of the opsins has certain advantages and disadvantages and systematic re-engineering of available mammalian opsins is needed to make a “perfect” tool for vision restoration.

Purpose: In this project we will systematically re-engineer mammalian opsins to make an optogenetic tool that is ideal for the purpose of vision restoration when expressed in defined classes of retinal neurons that are retained throughout retinal degeneration.

Methods: We will establish cutting-edge techniques to specifically monitor opsin signalling in real time. Using these tools as a readout, we will optimize the compatibility of mammalian opsins to the signal transduction cascades available in surviving retinal neurons. The resulting “optimized” opsin will be tested as a tool for vision restoration side-by-side against microbial opsins in electrophysiological ex-vivo and in-vivo recordings from retina and visual cortex.



Impact: This program will, for the first time, provide a systematically optimized mammalian opsin for use in vision restoration and will offer the potential to overcome the limitations observed in alternative tools. Tests in an established murine disease model will quantify its added value and pave the way towards clinical translation.