Retinal gene therapy in X-linked retinitis pigmentosa caused by mutations in RPGR: results at 6 months in a first in human clinical trial
Retinal gene therapy in X-linked retinitis pigmentosa caused by mutations in RPGR: results at 6 months in a first in human clinical trial
X-linked retinitis pigmentosa (RP), caused by mutations in the RP GTPase regulator (RPGR) gene, is the most common form of recessive RP. It is characterised by a primary degeneration of rod and cone photoreceptors in childhood, leading to visual field constriction and early, severe sight loss. Currently, there is no treatment for RPGR related RP. The inherent instability of the RPGR coding sequence, which has a repetitive purine rich region, presents challenges to translate this therapy into human trials. Codon optimisation of the sequence has increased RPGR stability and fidelity, providing the basis for this Phase I/II dose escalation retinal gene therapy clinical trial.
In total, 18 patients with genetically confirmed variants in RPGR were recruited in the trial and received increasing subretinal doses of adeno-associated viral vector serotype 8 encoding codon-optimized human RPGR driven by the photoreceptor specific rhodopsin kinase promoter (AAV8.RK.coRPGR). The vector uses codon optimisation to disable the alternate splice donor site and stabilise the open reading frame (ORF) 15 region of RPGR. As a result, the ORF15 domain of the retinal isoform of the RPGR protein is preserved and fully functional, as evidenced by glutamylation levels which are indistinguishable from the wildtype protein. The primary outcome of the study was safety and secondary outcomes included visual acuity, microperimetry and central retinal thickness.
Apart from steroid-responsive subretinal inflammation in patients at the higher doses, a gene therapy trial with AAV8.RK.coRPGR vector did not have any dose limiting toxicities, meeting the pre-specified primary endpoint. Visual field improvements beginning at one month and maintained to the last point of follow-up were observed in six patients. One patient with an exceptional visual improvement had evidence of possible outer segment regeneration seen on retinal imaging.
In conclusion, this first in human gene therapy trial with AAV8.RK.coRPGR vector had no significant safety concerns. The observed reversal of visual field loss may relate to regeneration of outer retinal structures following successful gene transfer.
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
2020
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Lotery, Andrew
(2020)
Retinal gene therapy in X-linked retinitis pigmentosa caused by mutations in RPGR: results at 6 months in a first in human clinical trial.
23rd ASGCT Annual Meeting, Hynes Convention Center, Boston, United States.
12 - 15 May 2020.
1 pp
.
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Abstract
X-linked retinitis pigmentosa (RP), caused by mutations in the RP GTPase regulator (RPGR) gene, is the most common form of recessive RP. It is characterised by a primary degeneration of rod and cone photoreceptors in childhood, leading to visual field constriction and early, severe sight loss. Currently, there is no treatment for RPGR related RP. The inherent instability of the RPGR coding sequence, which has a repetitive purine rich region, presents challenges to translate this therapy into human trials. Codon optimisation of the sequence has increased RPGR stability and fidelity, providing the basis for this Phase I/II dose escalation retinal gene therapy clinical trial.
In total, 18 patients with genetically confirmed variants in RPGR were recruited in the trial and received increasing subretinal doses of adeno-associated viral vector serotype 8 encoding codon-optimized human RPGR driven by the photoreceptor specific rhodopsin kinase promoter (AAV8.RK.coRPGR). The vector uses codon optimisation to disable the alternate splice donor site and stabilise the open reading frame (ORF) 15 region of RPGR. As a result, the ORF15 domain of the retinal isoform of the RPGR protein is preserved and fully functional, as evidenced by glutamylation levels which are indistinguishable from the wildtype protein. The primary outcome of the study was safety and secondary outcomes included visual acuity, microperimetry and central retinal thickness.
Apart from steroid-responsive subretinal inflammation in patients at the higher doses, a gene therapy trial with AAV8.RK.coRPGR vector did not have any dose limiting toxicities, meeting the pre-specified primary endpoint. Visual field improvements beginning at one month and maintained to the last point of follow-up were observed in six patients. One patient with an exceptional visual improvement had evidence of possible outer segment regeneration seen on retinal imaging.
In conclusion, this first in human gene therapy trial with AAV8.RK.coRPGR vector had no significant safety concerns. The observed reversal of visual field loss may relate to regeneration of outer retinal structures following successful gene transfer.
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Published date: 2020
Venue - Dates:
23rd ASGCT Annual Meeting, Hynes Convention Center, Boston, United States, 2020-05-12 - 2020-05-15
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Local EPrints ID: 452435
URI: http://eprints.soton.ac.uk/id/eprint/452435
PURE UUID: ffa43fbd-467c-4f57-b028-ac94e7274110
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Date deposited: 11 Dec 2021 03:29
Last modified: 17 Mar 2024 02:57
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