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Comparing optogenetic approaches to visual restoration in a model of retinal degeneration

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  • معلومة اضافية
    • Contributors:
      Hankins, MW; Downes, S
    • الموضوع:
      2021
    • Collection:
      Oxford University Research Archive (ORA)
    • نبذة مختصرة :
      The inherited retinal degenerations (IRDs) are the most common cause of irreversible visual loss in the young - but therapeutic options have traditionally been limited. While genetically heterogeneous, the IRDs are linked by a final common pathway of visual loss secondary to photoreceptor death, with cells of the neural retina surviving relatively intact. The technique of optogenetics (inducing light sensitivity by exogenous expression of light sensitive proteins within cells) is developing as a therapeutic method to stimulate these surviving cells: returning light signals to the degenerate retina and ultimately restoring lost vision. The aim of this thesis was to compare different optogenetic tools and cellular targets for optogenetic visual restoration in a model of inherited retinal degeneration in order to inform future translational work. Three novel mouse models of retinal degeneration, additionally devoid of native melanopsin and incorporating cell specific Cre recombinase expression were devolved and validated to allow cell population specific targeting of genetic constructs both delivered transgenically and by using intravitreal injections of adenoassociated viral vectors (AAVs). These models were used to isolate ON-bipolar cells from dissociated degenerate retina in the first comparison of gene expression profiles in such cells to their wildtype counterparts. This demonstrated a lack of changes likely to preclude these attractive cellular targets for therapeutic optogenetics. Cell targeted delivery of a candidate optogenetic tool (melanopsin) using these models was compared to conventional (non-specific) AAV delivery. This showed restoration of retinal electrophysiological light responses on ex vivo multiple electrode array recordings with kinetics differing between delivery approaches. Targeted delivery of three candidate tools (melanopsin, rhodopsin and ReaChR- channelrhodopsin) were similarly compared with markedly differing response characteristics demonstrated between tools Finally, translatable, ...
    • Relation:
      https://ora.ox.ac.uk/objects/uuid:5c08e746-5981-4d77-b6a2-54ac5a3a7719
    • الدخول الالكتروني :
      https://ora.ox.ac.uk/objects/uuid:5c08e746-5981-4d77-b6a2-54ac5a3a7719
    • Rights:
      info:eu-repo/semantics/openAccess
    • الرقم المعرف:
      edsbas.938AC79C