1. Functional Availability of ON-Bipolar Cells in the Degenerated Retina: Timing and Longevity of an Optogenetic Gene Therapy
- Author
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Sonja Kleinlogel and Jakub Kralik
- Subjects
Retinal degeneration ,mGluR6 ,genetic structures ,Genetic enhancement ,Cell ,multi-electrode array recordings ,Blindness ,Receptors, Metabotropic Glutamate ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Biology (General) ,610 Medicine & health ,Spectroscopy ,Mice, Inbred C3H ,0303 health sciences ,micro ERGs ,Metabotropic glutamate receptor 6 ,rd1 mouse line ,General Medicine ,Computer Science Applications ,Chemistry ,medicine.anatomical_structure ,ON-bipolar cells ,615 Pharmacology & therapeutics, prescription drugs ,Signal Transduction ,Melanopsin ,Retinal Bipolar Cells ,QH301-705.5 ,Optogenetics ,Biology ,Article ,ganglion cells ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Electroretinography ,medicine ,Animals ,Opto-GPCRs ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Vision, Ocular ,030304 developmental biology ,Cyclic Nucleotide Phosphodiesterases, Type 6 ,Retina ,Organic Chemistry ,optogenetic gene therapy ,Retinal ,Genetic Therapy ,medicine.disease ,Mice, Mutant Strains ,eye diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,chemistry ,retinal degeneration ,vision restoration ,570 Life sciences ,biology ,sense organs ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Degenerative diseases of the retina are responsible for the death of photoreceptors and subsequent loss of vision in patients. Nevertheless, the inner retinal layers remain intact over an extended period of time, enabling the restoration of light sensitivity in blind retinas via the expression of optogenetic tools in the remaining retinal cells. The chimeric Opto-mGluR6 protein represents such a tool. With exclusive ON-bipolar cell expression, it combines the light-sensitive domains of melanopsin and the intracellular domains of the metabotropic glutamate receptor 6 (mGluR6), which naturally mediates light responses in these cells. Albeit vision restoration in blind mice by Opto-mGluR6 delivery was previously shown, much is left to be explored in regard to the effects of the timing of the treatment in the degenerated retina. We performed a functional evaluation of Opto-mGluR6-treated murine blind retinas using multi-electrode arrays (MEAs) and observed long-term functional preservation in the treated retinas, as well as successful therapeutical intervention in later stages of degeneration. Moreover, the treatment decreased the inherent retinal hyperactivity of the degenerated retinas to levels undistinguishable from healthy controls. Finally, we observed for the first time micro electroretinograms (mERGs) in optogenetically treated animals, corroborating the origin of Opto-mGluR6 signalling at the level of mGluR6 of ON-bipolar cells.
- Published
- 2021
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