RPGR gene therapy for retinitis pigmentosa
Inventors
Sandberg, Michael A. • Pawlyk, Basil • Wright, Alan Finlay • Shu, Xinhua • Li, Tiansen • ALI, Robin
Assignees
UCL Business Ltd • Massachusetts Eye and Ear • US Department of Health and Human Services
Publication Number
US-11045558-B2
Publication Date
2021-06-29
Expiration Date
2035-07-17
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Abstract
Methods for treating a human subject who has X-linked Retinitis Pigmentosa (XLRP) or another clinically-defined ophthalmological condition due to a loss-of-function mutation in the gene encoding the retinitis pigmentosa GTPase regulator (RPGR) protein, the method comprising administering to the subject a nucleic acid comprising an adeno-associated viral vector comprising an abbreviated human RPGR cDNA.
Core Innovation
The invention relates to methods for treating a human subject who has X-linked Retinitis Pigmentosa (XLRP) or another ophthalmological condition caused by a loss-of-function mutation in the gene encoding the retinitis pigmentosa GTPase regulator (RPGR) protein, by administering to the subject a nucleic acid comprising an adeno-associated viral vector containing an abbreviated human RPGR cDNA. This abbreviated human RPGR cDNA encodes a protein that is at least 80% identical to the full length of SEQ ID NO:2, optionally with a deletion of up to 200 amino acids in the region surrounding the deleted region in SEQ ID NO:2.
Retinitis pigmentosa (RP) is a leading form of inherited blindness in humans, with X-linked RP (XLRP) being a severe form affecting both rod and cone photoreceptors. Mutations in the RPGR gene cause over 70% of XLRP and 10%-20% of all RP cases, making RPGR one of the most important disease genes for retinitis pigmentosa. The invention addresses the challenge by providing an abbreviated form of human RPGR that successfully recreates functional RPGR activity, enabling treatment of subjects who retain some photoreceptor cells.
The invention includes using viral vectors, particularly adeno-associated viral vectors such as AAV2/8 or AAV-8, to deliver the abbreviated human RPGR cDNA under control of a human rhodopsin kinase (hRK) promoter. The method can involve subretinal administration with controlled dosing. The approach is based on the discovery that shortening the purine-rich repetitive region of ORF15 exon by up to one-third does not compromise function, thus overcoming difficulties in cloning and stability encountered with the full-length RPGR.
Claims Coverage
The patent contains multiple independent claims covering compositions and methods related to abbreviated human RPGR nucleic acids and their use in gene therapy for X-linked Retinitis Pigmentosa.
Method of treating XLRP with abbreviated human RPGR protein
Administering to an eye of a human subject a nucleic acid encoding an abbreviated human RPGR protein comprising SEQ ID NO:2.
Method of treating XLRP using viral vectors encoding abbreviated human RPGR
Administering to an eye of a human subject a viral vector comprising a nucleic acid encoding an abbreviated human RPGR protein comprising SEQ ID NO:2.
Use of a human rhodopsin kinase promoter in gene therapy
Using a nucleic acid under the control of a human rhodopsin kinase (hRK) promoter, optionally comprising SEQ ID NO:5, in the viral vector for expression of abbreviated human RPGR.
Use of adeno-associated viral vectors for delivery
Utilizing adeno-associated viral vectors, including AAV-2, AAV-8, or pseudotyped AAV2/8, as delivery vehicles for the abbreviated human RPGR nucleic acids.
Subretinal administration and dosing
Administering the nucleic acid into the subretinal space with specified doses including about 2×10^10 vg/mL, 2×10^11 vg/mL, and 2×10^12 vg/mL, optionally using a micro injection cannula inserted temporal to the optic nerve and above major arcade vessels.
Nucleic acids and isolated host cells expressing abbreviated human RPGR
Isolated nucleic acids encoding the abbreviated human RPGR protein comprising SEQ ID NO:2, and isolated host cells comprising the viral vectors and expressing the abbreviated human RPGR protein.
The claims cover methods of treating XLRP by delivering abbreviated human RPGR proteins encoded by nucleic acids under hRK promoter control via adeno-associated viral vectors administered subretinally, as well as the nucleic acids and vectors themselves.
Stated Advantages
The abbreviated human RPGR gene retains functional activity despite deletions in the purine-rich repetitive region, overcoming prior cloning and stability challenges.
The AAV-mediated gene delivery method enables effective expression and localization of RPGR protein in photoreceptors.
Treatment leads to preservation and rescue of rod and cone photoreceptors, improving visual function as shown by morphological and electrophysiological measures.
Use of the hRK promoter ensures rod and cone cell-specific expression of RPGR.
Documented Applications
Treatment of human subjects with X-linked Retinitis Pigmentosa (XLRP) caused by loss-of-function mutations in the RPGR gene.
Treatment of other clinically-defined ophthalmological conditions due to RPGR mutations, such as X-linked cone-rod dystrophy.
Use in gene therapy protocols involving subretinal administration of adeno-associated viral vectors encoding abbreviated human RPGR to restore or preserve photoreceptor function.
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