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-10314924-B2
Publication Date
2019-06-11
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 provides methods for treating human subjects who have X-linked Retinitis Pigmentosa (XLRP) or other clinically-defined ophthalmological conditions caused by loss-of-function mutations in the gene encoding the retinitis pigmentosa GTPase regulator (RPGR) protein. The method involves administering to the subject a nucleic acid containing an adeno-associated viral vector with an abbreviated human RPGR cDNA, which encodes a protein that is at least 80% identical to the full-length RPGR protein sequence (SEQ ID NO:2), optionally deleting up to 200 amino acids surrounding a specific deleted region in SEQ ID NO:2.
The background highlights that Retinitis Pigmentosa (RP) is a leading cause of inherited blindness, with X-linked RP (XLRP) representing a severe form affecting both rod and cone photoreceptors. Mutations in RPGR account for over 70% of XLRP cases and 10%-20% of all RP cases. Despite many known causative genes, RPGR is a critical target due to the severity and prevalence of its mutations in XLRP.
The summary emphasizes the discovery of an abbreviated form of human RPGR that restores functional RPGR activity. Methods include using an abbreviated human RPGR cDNA under the control of a human rhodopsin kinase (hRK) promoter packaged in AAV-2/8 or AAV-8 viral vectors, administered into the subretinal space at varying dosages. This abbreviated RPGR variant is capable of localizing properly to photoreceptor connecting cilia and rescuing photoreceptor degeneration and function in RPGR-deficient models, suggesting a viable therapeutic approach for treating XLRP caused by RPGR mutations.
Claims Coverage
The patent includes nine main inventive features based on independent claims relating to methods, nucleic acids, viral vectors, and cells for treating XLRP and other ophthalmological conditions caused by RPGR mutations.
Method of treating XLRP or ophthalmological conditions using an abbreviated human RPGR cDNA viral vector
Administering to a human eye a nucleic acid comprising a viral vector with an abbreviated human RPGR cDNA encoding a protein comprising SEQ ID NO:2.
Use of human rhodopsin kinase promoter to control RPGR cDNA expression
The RPGR cDNA is under the control of a human rhodopsin kinase (hRK) promoter, optionally comprising SEQ ID NO:5.
Administration of nucleic acid at defined viral genome doses
Administering the nucleic acid at low (~2×10¹⁰ vg/mL), middle (~2×10¹¹ vg/mL), or high (~2×10¹² vg/mL) doses.
Subretinal delivery technique with targeted fluid flow
Administering the nucleic acid into the subretinal space using a micro injection cannula inserted temporal to the optic nerve and above major arcade vessels directing flow toward the macula.
Provision of nucleic acid encoding abbreviated human RPGR
Nucleic acid encoding an abbreviated human RPGR at least 80% identical to full-length SEQ ID NO:2, optionally under an hRK promoter.
Adeno-associated viral vector comprising abbreviated human RPGR nucleic acid
A viral vector, particularly adeno-associated virus such as AAV2/8 or AAV-8, comprising nucleic acid encoding abbreviated human RPGR.
Isolated host cells harboring viral vectors expressing abbreviated RPGR
Isolated host cells containing the viral vector that express abbreviated human RPGR protein.
Method of treating ocular disease using abbreviated human RPGR nucleic acid
Administering nucleic acid encoding abbreviated human RPGR protein (SEQ ID NO:2) to treat XLRP or other RPGR-related ophthalmological conditions.
Use of adeno-associated viral vectors for RPGR gene delivery
Utilizing AAV, specifically serotype 2/8 or 8, to deliver abbreviated human RPGR cDNA for therapeutic purposes.
The claims cover therapeutic methods administering abbreviated human RPGR cDNA via AAV vectors, nucleic acids and vectors encoding this cDNA under a rhodopsin kinase promoter, and host cells expressing the protein, with particular focus on subretinal administration, dosages, and viral serotypes.
Stated Advantages
The abbreviated human RPGR cDNA retains functional activity sufficient to correct photoreceptor degeneration caused by RPGR mutations.
Use of an abbreviated RPGR gene circumvents difficulties associated with the full-length RPGR, including cloning instability.
Gene therapy using the abbreviated RPGR effectively rescues rod and cone photoreceptor structure and function in an RPGR knockout mouse model.
The method enables targeted and efficient gene delivery to photoreceptors via AAV vectors and a promoter that drives expression in rods and cones.
Subretinal delivery allows localized administration, improving treatment precision and efficacy.
Documented Applications
Treatment of human subjects with X-linked Retinitis Pigmentosa caused by loss-of-function RPGR mutations.
Treatment of other clinically-defined ophthalmological conditions due to RPGR loss-of-function mutations, including X-linked cone-rod dystrophy.
Use in subjects who retain some photoreceptor cells and residual visual function, as determined by electroretinographic testing and optical coherence tomography.
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