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Publication Number
US-11324839-B2
Publication Date
2022-05-10
Expiration Date
Abstract
Provided herein are isolated DNA vectors comprising a heterologous gene, wherein the DNA vector is devoid of bacterial plasmid DNA and/or bacterial signatures, which can abrogate persistence in vivo. The invention also features pharmaceutical compositions (non-immunogenic pharmaceutical compositions) including the DNA vectors of the invention, which can be used for induction of long-term, episomal expression of a heterologous gene in a subject. The invention involves methods of treating a subject by administering the DNA vectors of the invention, including methods of treating disorders associated with a defect in a target gene.
Core Innovation
The invention relates to treating or preventing an ocular disorder by administering to an eye of a subject in need thereof a therapeutically effective amount of a synthetic circular DNA vector. The synthetic circular DNA vector comprises a gene encoding a therapeutic polypeptide and is designed for episomal expression and episomal persistence in the target tissue. The vector lacks an origin of replication, a drug resistance gene, and a site-specific recombination recognition site.
The vector is further described as non-viral and devoid of bacterial plasmid DNA and bacterial signatures, including CpG motifs, LPS, and dsRNA, with promoter sequences that can substantially lack CpG islands. It includes control elements for transcription and expression of the therapeutic polypeptide, including promoters, polyadenylation signals, optional introns, Kozak consensus, 5′ regulatory elements, RNA processing and stability features, and secretion-enhancing sequence concepts.
The synthetic circular DNA vector can include AAV-like terminal repeat sequences such as double-D (DD) elements, including AAV inverted terminal repeat (ITR)-like terminal repeat sequences. Production and purification concepts are also described for circular DNA and DD-element DNA vectors, including Phi29 polymerase-mediated rolling-circle amplification and synthesis and purification approaches for circular DNA, followed by formulation concepts for unit dose and DNA topology, including monomeric and supercoiled fractions.
The described scope includes therapeutic replacement proteins and antigen-binding proteins encoded by the synthetic circular DNA vector. The application scope encompasses ocular disorders broadly, with particular mention of retinal dystrophy and named diseases, including Leber's congenital amaurosis (LCA), Stargardt disease, pseudoxanthoma elasticum, rod cone dystrophy, exudative vitreoretinopathy, Joubert syndrome, congenital stationary night blindness, age-related macular degeneration (AMD), retinitis pigmentosa, stickler syndrome, microcephaly and choriorretinopathy, Usher syndrome, and Wagner syndrome.
Claims Coverage
The consolidated claim coverage is directed to ocular therapy using a synthetic circular DNA vector encoding a therapeutic polypeptide and lacking an origin of replication, a drug resistance gene, and a site-specific recombination recognition site. The claim coverage further includes expression-control and composition refinements, ocular disorder scope, administration routes, dosing, and immune-response reduction, reflecting four core inventive features plus dependent claim attributes.
Synthetic circular DNA vector lacking replication, selection, and recombination sites
A synthetic circular DNA vector comprising a gene encoding a therapeutic polypeptide, wherein the synthetic circular DNA vector lacks an origin of replication, a drug resistance gene, and a site-specific recombination recognition site.
Administration of a therapeutically effective amount to the eye to treat or prevent an ocular disorder
A method of treating or preventing an ocular disorder comprising administering to an eye of a subject in need thereof a therapeutically effective amount of the synthetic circular DNA vector thereby treating or preventing the ocular disorder.
Expression-control and composition attributes for the synthetic circular DNA vector
Promoters and optionally inducible or native promoters, polyadenylation signals, optional introns, Kozak consensus, 5′ regulatory elements, RNA processing and stability features, secretion-enhancing sequence concepts, and a promoter sequence substantially lacking CpG islands.
Ocular delivery and scope refinements
Ocular disorder scope including retinal dystrophy and named diseases, administration intravitreally, intraocularly, intraorbitally, subretinally, or by eye drop, a pharmaceutical composition containing a unit dose of 10 μg to 10 mg, and reduced immune response versus a control vector.
Overall claim coverage centers on ocular treatment by administering a synthetic circular DNA vector for a therapeutic polypeptide while lacking an origin of replication, a drug resistance gene, and a site-specific recombination recognition site. Additional refinements specify expression-control and composition attributes, ocular delivery routes, unit dose, ocular disorder scope, and reduced immune response.
Stated Advantages
Treating or preventing the ocular disorder.
Reduced immune response versus a control vector.
Documented Applications
Treating or preventing ocular disorders, including retinal dystrophy, using administration to an eye of a subject in need thereof.
Treating or preventing ocular disorders, including retinal dystrophies selected from Leber's congenital amaurosis (LCA), Stargardt disease, pseudoxanthoma elasticum, rod cone dystrophy, exudative vitreoretinopathy, Joubert syndrome, congenital stationary night blindness including type 1C (CSNB-1C), age-related macular degeneration, retinitis pigmentosa, stickler syndrome, microcephaly and choriorretinopathy, congenital stationary night blindness 2 (CSNB 2), Usher syndrome, and Wagner syndrome.
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