Reagents and methods for modulating cone photoreceptor activity
Inventors
Neitz, Jay • Neitz, Maureen • Kuchenbecker, James A. • Hauswirth, William W.
Assignees
University of Washington • University of Florida Research Foundation Inc
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Publication Number
US-11160488-B2
Publication Date
2021-11-02
Expiration Date
Abstract
The present invention provides reagents and methods for modulating cone photoreceptor activity, and devices for assessment of cone photoreceptor activity.
Core Innovation
The invention relates to cone-photoreceptor gene therapy in a primate using a recombinant adeno-associated virus (AAV) gene delivery vector. The vector includes a promoter region comprising an M opsin promoter sequence comprising the nucleic acid sequence of SEQ ID NO:2 and a gene encoding a therapeutic protein comprising the amino acid sequence of SEQ ID NO:11.
In vivo expression of the therapeutic protein in cone cells of the primate serves to restore visual capacity in the primate, specifically in the context of blue cone monochromacy. The vector architecture further includes an upstream cone-specific enhancer element, including an L/M minimal opsin enhancer SEQ ID NO:51, operatively linked to the gene, and an intron with splice donor/acceptor region positioned between the promoter and the therapeutic gene.
The disclosure also emphasizes unexpected efficacy in adult primates, supported by a described adult primate example using rAAV2/5 delivering an L-opsin gene under L/M enhancer/promoter control with expression in a subset of M cones. Functioning opsin/transgene expression is mapped and monitored using a wide-field color multifocal electroretinogram (mf-ERG) system with matched red/green/blue/UV stimuli and processing to form a topographical map of retinal responses.
Claims Coverage
The independent claim is clm-00001, covering an AAV-vector-based method for treating blue cone monochromacy in a primate by in vivo expression of a therapeutic protein in cone cells. The independent claim includes 2 principal inventive elements: an M opsin promoter comprising SEQ ID NO:2 and a therapeutic protein gene comprising SEQ ID NO:11, with restoration of visual capacity as the functional outcome.
A recombinant AAV vector with an M opsin promoter sequence (SEQ ID NO:2)
A recombinant adeno-associated virus (AAV) gene delivery vector having a promoter region comprising an M opsin promoter sequence including the nucleic acid sequence of SEQ ID NO:2.
A therapeutic protein gene encoding an amino acid sequence (SEQ ID NO:11)
A gene encoding a therapeutic protein comprising the amino acid sequence of SEQ ID NO:11, expressed in cone cells of the primate.
Restoration of visual capacity by in vivo cone-cell expression
Wherein in vivo expression of the therapeutic protein in cone cells of the primate serves to restore visual capacity in the primate.
Selecting a specific visual-capacity improvement category
The treatment further specifies selecting a visual capacity from the group consisting of reduced or slowed vision loss, improved visual acuity, or decreased abnormal sensitivity to bright lights.
Monitoring the primate’s response to the treatment
The method includes monitoring the primate’s response to the treatment.
Adding an upstream enhancer element (SEQ ID NO:51) operatively linked to the gene
The gene delivery vector further includes an upstream enhancer element containing the nucleic acid sequence SEQ ID NO:51, with the gene operatively linked to that enhancer element.
Including an intron with a splice donor/acceptor region between promoter and gene
The gene delivery vector further includes an intron with a splice donor/acceptor region placed downstream of the promoter and upstream of the gene.
Overall claim coverage centers on treating blue cone monochromacy in a primate by administering an AAV gene delivery vector with an M opsin promoter (SEQ ID NO:2) driving a therapeutic protein gene (SEQ ID NO:11) such that in vivo cone-cell expression restores visual capacity. Dependent refinements narrow the type of visual-capacity restoration, require monitoring the response, and specify optional vector elements including an upstream enhancer (SEQ ID NO:51) and an intron with splice donor/acceptor regions placed between the promoter and the gene.
Stated Advantages
Restore visual capacity in the primate following in vivo expression of the therapeutic protein in cone cells.
Documented Applications
Treating blue cone monochromacy in a primate by administering to the eye a recombinant AAV gene delivery vector with an M opsin promoter (SEQ ID NO:2) and a gene encoding a therapeutic protein (SEQ ID NO:11) for cone-cell expression and visual-capacity restoration.
Monitoring opsin/transgene expression and retinal functioning responses using a wide-field color multifocal electroretinogram (mf-ERG) system with matched red/green/blue/UV stimuli to generate topographical maps of retinal responses.
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