Thesis
Developing gene therapy for inherited retinal degenerations
- Abstract:
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The aim of this thesis was to evaluate the efficacy and safety of retinal gene therapy in a pre-clinical model of CDHR1-associated retinal degeneration – a hitherto untreatable, blinding disorder.
Deep phenotyping of the Cdhr1-/- murine model demonstrated severe early deficits in cone and rod photoreceptor function followed by progressive photoreceptor cell death – recapitulating CDHR1 cone-rod dystrophy. Two AAV8 vectors expressing the full-length human CDHR1 coding sequence were designed, manufactured, validated and titrated in vivo.
Sub-retinal injection of AAV8.GRK1.CDHR1.pA (1.5 x 108 vg) in Cdhr1-/- mice at 3-4 weeks of age resulted in functional rescue of cone and rod photoreceptors with improved response amplitudes and decreased implicit times to 12-months post-injection; a slowing of photoreceptor cell death with regeneration of full-length photoreceptor outer segments confirmed on ultrastructural analysis to 21-months post-injection; and a behavioural rescue effect on photopic and scotopic optomotor testing, sustained to 21-months post-injection. AAV8.GRK1.CDHR1.pA at 1.5 x 108 vg appeared safe in C57BL/6J mice by the same outcome measures to 22-months post-injection.
Genetic prevalence estimates presented herein suggest more than 200,000 affected individuals worldwide. We characterised 146 individuals with biallelic variants in CDHR1, describing the retinal phenotype, natural history, genotype-phenotype associations, with 25 novel pathological sequence variants.
This is the first therapy shown to improve retinal structure and function in a pre-clinical model of CDHR1-associated retinal degeneration. A patent to protect the vectors described herein has been filed on behalf of the University of Oxford, with commercial agreements obtained in preparation for an onward phase 1 clinical trial.
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- Files:
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(Preview, Dissemination version, pdf, 69.9MB, Terms of use)
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Authors
Contributors
- Role:
- Supervisor
- ORCID:
- 0000-0002-3096-4682
- Role:
- Supervisor
- ORCID:
- 0000-0002-0351-6673
- Role:
- Examiner
- ORCID:
- 0000-0003-3653-834X
- Role:
- Examiner
- Funder identifier:
- http://dx.doi.org/10.13039/501100000265
- Funding agency for:
- Yusuf, IH
- Grant:
- MR/R000735/1
- Programme:
- Development of AAV gene therapy for blindness caused by cone-rod dystrophy
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
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English
- Keywords:
- Subjects:
- Pubs id:
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2043073
- Local pid:
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pubs:2043073
- Deposit date:
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2022-04-05
- ARK identifier:
Terms of use
- Copyright holder:
- Yusuf, IH
- Copyright date:
- 2022
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