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Publication Number
US-11684680-B2
Publication Date
2023-06-27
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 disclosure relates to a pharmaceutical composition for delivery of a gene in a subject using a synthetic circular DNA vector. The vector includes a promoter operably linked to the gene and is configured to lack an origin of replication, a drug resistance gene, and a site-specific recombination recognition site. The promoter is capable of inducing expression of the gene in the subject.
The synthetic circular DNA vector is described as persisting as episomes for long-term gene expression, including in quiescent cells, and includes circular episomal expression elements for episomal expression in subjects. The disclosure also includes synthetic circular or DD-containing DNA vectors and options for promoter control elements such as constitutive promoters, inducible promoters, native promoter options, polyadenylation, capping-related sequence elements, Kozak consensus sequence, and splicing/intron options.
The vectors are described as lacking bacterial plasmid DNA/signatures and as having reduced immunogenicity, including reduced or avoided CpG motifs or islands and bacterial-associated molecular patterns such as endotoxins (LPS) and other bacterial contaminants. The disclosure also provides pharmaceutical compositions comprising the synthetic circular DNA vector, optionally with a pharmaceutically acceptable carrier and delivery vehicles.
Claims Coverage
The provided material includes one independent claim. It defines a pharmaceutical composition for delivery of a gene in a subject using a synthetic circular DNA vector with promoter-driven expression and three excluded features: an origin of replication, a drug resistance gene, and a site-specific recombination recognition site.
Synthetic circular DNA vector lacking replication and recombination elements for promoter-driven expression
A pharmaceutical composition for delivery of a gene in a subject comprises a synthetic circular DNA vector comprising a promoter operably linked to the gene, the synthetic circular DNA vector lacking an origin of replication, a drug resistance gene, and a site-specific recombination recognition site, wherein the promoter is capable of inducing expression of the gene in the subject.
The claim coverage centers on a synthetic circular DNA vector formulated as a pharmaceutical composition for gene delivery, where promoter-driven expression is coupled with the absence of an origin of replication, a drug resistance gene, and a site-specific recombination recognition site.
Stated Advantages
Designed to be non-immunogenic, including via reduced immunogenicity, reduced or avoided CpG motifs or islands, and reduced cytokine response characteristics.
Elimination of bacterial signatures and reduced immunogenicity/contamination profiles, including reducing or avoiding bacterial-associated molecular patterns such as endotoxins (LPS) and other bacterial contaminants.
Enables long-term gene expression as episomes, including in quiescent cells.
Documented Applications
Pharmaceutical composition for delivery of a gene in a subject.
Episomal expression in subjects.
Treatment of Mendelian-heritable retinal dystrophies, including Leber's congenital amaurosis (LCA) and Stargardt disease, with ocular delivery contexts such as intravitreal/subretinal administration.
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