Towards in vivo genome editing of post-mitotic mammalian photoreceptors for treatment of Inherited Retinal Dystrophies (360G-Wellcome-215343_Z_19_Z)

£98,979

Retinitis Pigmentosa (RP) causes untreatable visual loss. Gene augmentation trials for genetic eye disease have disappointed, partly due to difficulties in optimising correct, persistent exogenous gene expression. The possibility of precise, efficient gene correction using genome editing technology for highly genetically heterogenous diseases like RP would overcome these dosage issues. To determine the feasibility of genome editing, we have developed powerful fluorescent reporter mouse models, allowing sensitive readouts of editing events in time and space. Using these, we demonstrated post-natal murine photoreceptors are amenable to genome editing in retinal explants. However, several obstacles exist to making editing a reality in the disease setting. This project aims to: optimise targeted editing machinery delivery to photoreceptors in vivo; improve photoreceptor repair efficiency; explore novel, homology-independent strategies for photoreceptor gene correction; assess potential for editing technology to rescue vision. To expedite solutions, we propose using our reporter models to develop in vivo photoreceptor editing. We have prepared retinotrophic AAV serotypes containing machinery necessary to edit our models. Following optimisation in reporter models, we will assess repair of disease-causing mutations in our humanised mouse RP models. These experiments will provide vital pilot data towards securing industrial partnerships to translate this technology into clinic.

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Grant Details

Amount Awarded 98979
Applicant Surname Megaw
Approval Committee Science Seeds Advisory Panel
Award Date 2018-11-02T00:00:00+00:00
Financial Year 2018/19
Grant Programme: Title Seed Award in Science
Internal ID 215343/Z/19/Z
Lead Applicant Dr Roly Megaw
Partnership Value 98979
Planned Dates: End Date 2021-10-01T00:00:00+00:00
Planned Dates: Start Date 2019-04-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland