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Publication Number
US-11865148-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Provided herein are methods of delivering transgenes to an eye of a subject comprising the use of pharmaceutical compositions having one or more polynucleotides suitable for enhancing, increasing, augmenting, and/or supplementing the levels of the transgene in the eye. Also provided herein are methods of correcting vision loss in a subject in need thereof comprising the use of the pharmaceutical compositions described herein.
Core Innovation
The invention relates to delivery of a human transgene to an eye of a subject using a replication-defective herpes simplex virus type-1 (HSV-1). The recombinant HSV-1 genome comprises one or more polynucleotides comprising the human transgene, and the transgene polynucleotides are operably linked to a promoter suitable for transcription in a mammalian cell. The pharmaceutical composition includes a pharmaceutically acceptable carrier and is administered topically or via injection to the eye of the subject.
A central aspect is engineering the recombinant HSV-1 to reduce or eliminate toxic HSV gene expression by providing inactivating mutations in immediate early genes. The recombinant HSV-1 genome comprises an inactivating mutation in one or both copies of the ICP4 HSV-1 gene and an inactivating mutation in the ICP22 HSV-1 gene.
The document further describes placing the one or more transgene polynucleotides into defined HSV viral gene loci, including ICP4 loci and other named loci. It also describes optional transgene architectures and promoter configurations for expression, including modified mRNA or synthetic/modified ribonucleotides, miRNA binding sites, heterologous promoters, and polycistronic constructs with IRES and linker polypeptides.
Additional disclosed constructs include transgene polynucleotides encoding Col7 (COL7A1), LH3, and optionally KRT17 or chimeric Col7-LH3 constructs delivered using HSV-1 vectors that include replication-defective features. The document describes resulting expression and functional outcomes including increased anchoring fibril formation, epithelial basement membrane organization/adherence, and dermoepidermal junction integrity, with deposition of COL7 in cell/culture/mouse contexts.
Claims Coverage
The independent claims collectively cover delivering a human transgene to an eye using a replication-defective recombinant HSV-1, with transgene polynucleotides operably linked to a mammalian-cell promoter, administered topically or via injection to subjects with eye disorders associated with vision loss. The claims further require inactivating mutations in ICP4 and ICP22, and one claim also recites suitability for delivering the transgene to epidermis and/or dermis.
Replication-defective recombinant HSV-1 for eye transgene delivery
A pharmaceutical composition comprising a replication-defective herpes simplex virus type-1 (HSV-1) comprising a recombinant HSV-1 genome, wherein the recombinant HSV-1 genome comprises one or more polynucleotides comprising the human transgene.
Mammalian transcription promoter operable linkage
The one or more polynucleotides comprising the human transgene are operably linked to a promoter suitable for transcription in a mammalian cell.
Inactivating ICP4 and ICP22 HSV-1 genes
The recombinant HSV-1 genome comprises an inactivating mutation in one or both copies of the ICP4 HSV-1 gene and an inactivating mutation in the ICP22 HSV-1 gene.
Topical or via injection administration to the eye for vision-loss-associated disorder
The pharmaceutical composition is administered topically or via injection to the eye of a subject having a disorder or disease of the eye associated with vision loss, with a pharmaceutically acceptable carrier included in the composition.
HSV-1 suitable for delivering transgene to epidermis and/or dermis
The replication-defective HSV-1 is suitable for delivering the one or more polynucleotides comprising the human transgene to the epidermis and/or dermis of the subject.
The claims center on replication-defective recombinant HSV-1 for eye transgene delivery, with expression driven by a mammalian-cell promoter and safety addressed through inactivating mutations in ICP4 and ICP22, administered topically or by injection. One claim also includes suitability for delivery to epidermis and/or dermis.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Delivering a human transgene to an eye of a subject for an eye disorder or disease associated with vision loss.
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