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Publication Number
US-11766490-B2
Publication Date
2023-09-26
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 a synthetic circular DNA vector for treating cancer and other disorders by providing therapeutically effective episomal expression. The vectors are non-viral and are designed to persist episomally like AAV while being non-immunogenic and scalable.
The synthetic circular DNA vectors lack an origin of replication, a drug resistance gene, and bacterial DNA signatures, including CpG motifs and CpG islands, and may also lack RNAPII arrest sites. The vectors further include DNA vector control elements, such as promoter/enhancer elements, polyadenylation/polyA, Kozak consensus sequence, intron elements, and terminal repeat elements, and may optionally include a site-specific recombination site.
The document describes pharmaceutical compositions containing the synthetic circular DNA vectors and administration to induce episomal expression and treat disorders, including repeat dosing and systemic or local administration. It also describes production by rolling-circle amplification with Phi29 and/or cell-free methods, followed by restriction enzyme digestion and self-ligation to generate circular or linear concatameric constructs, including supercoiled or covalently closed circular DNA.
Claims Coverage
Two independent claim themes are represented in the provided content. The claim coverage centers on a cancer treatment method using a synthetic circular DNA vector that omits an origin of replication, a drug resistance gene, and a site-specific recombination recognition site, while encoding two or more therapeutic polypeptides with combined gene size greater than 10 Kb.
Synthetic circular DNA vector for cancer treatment lacking replication, drug resistance, and recombination sites
Administering to a subject a therapeutically effective amount of a synthetic circular DNA vector comprising two or more genes encoding two or more therapeutic polypeptides, wherein the synthetic circular DNA vector lacks an origin of replication, a drug resistance gene, and a site-specific recombination recognition site, thereby treating the cancer.
Multiple therapeutic genes or polypeptides with combined gene size greater than 10 Kb
The two or more genes are together greater than 10 Kb in size.
Episomal expression with non-immunogenic synthetic circular DNA vectors
Using a synthetic circular DNA vector for therapeutically effective episomal expression in treating disorders, where the vector lacks an origin of replication and drug-resistance genes and is described as non-immunogenic.
The claim coverage centers on cancer treatment with a synthetic circular DNA vector that lacks an origin of replication, a drug resistance gene, and a site-specific recombination recognition site, while carrying multiple therapeutic polypeptide-encoding genes whose combined size is greater than 10 Kb. The content also supports a broader claim theme directed to episomal expression using a non-immunogenic synthetic circular DNA vector.
Stated Advantages
Reduced immune response relative to a control vector containing an origin of replication, a drug resistance gene, and a site-specific recombination recognition site.
Does not cause an increase of cytokine levels compared to cytokine levels before administering.
Non-immunogenic episomal persistence like AAV.
Scalable vector design.
Vectors substantially devoid of viral particles or contaminants in the described pharmaceutical compositions.
Documented Applications
Treating cancer by administering a therapeutically effective amount of the synthetic circular DNA vector to a subject.
Treating disorders by inducing episomal expression via systemic or local administration.
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