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Publication Number
US-11602569-B2
Publication Date
2023-03-14
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 pharmaceutical compositions that comprise synthetic circular DNA vectors for treatment of ocular disorders. The vectors include a promoter operably linked to a gene encoding a therapeutic polypeptide effective for the ocular disorder, and the synthetic circular DNA vector lacks an origin of replication, a drug resistance gene, and a site-specific recombination recognition site. The compositions are formulated for ocular delivery and are directed to expression of the therapeutic polypeptide in ocular tissue in a subject.
The disclosure describes non-viral synthetic circular DNA vectors that optionally include terminal repeat elements and a DD element together with replication-avoiding vector characteristics. It further describes heterologous gene content and expression control elements including promoter/enhancer-related transcription initiation and termination features, RNA processing signals, and sequence elements including a Kozak consensus sequence. The vectors are associated with circular DNA structures lacking bacterial signatures and with long-term episomal expression and reduced immunogenicity.
The disclosed applications include ocular target contexts such as photoreceptor and retinal disease, including Mendelian-heritable retinal dystrophies, Leber’s congenital amaurosis, Stargardt disease, and ABCA4-associated disorder. The text also includes therapeutic replacement proteins, antigen-binding proteins/antibodies, epigenetic regulators, therapeutic nucleic acids such as siRNA, shRNA, miRNA, and CRISPRi, and trans-splicing molecules. The compositions are described as non-immunogenic or reduced immunogenicity pharmaceutical compositions for ocular delivery, including intravitreous, intraocular, subretinal, and related routes.
Claims Coverage
The claim coverage includes three inventive features. The independent claims center on ocular pharmaceutical compositions using synthetic circular DNA vectors lacking an origin of replication, a drug resistance gene, and a site-specific recombination recognition site, with promoter-linked therapeutic polypeptide expression in ocular tissue, and a narrower ABCA4-associated disorder claim tied to photoreceptor expression and subretinal delivery.
Synthetic circular DNA vector for ocular delivery without replication and accessory elements
A pharmaceutical composition for treatment of an ocular disorder comprising a synthetic circular DNA vector comprising a promoter operably linked to 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, and wherein the pharmaceutical composition is formulated for ocular delivery.
Promoter capable of inducing therapeutic polypeptide expression in ocular tissue
The pharmaceutical composition wherein the promoter is capable of inducing expression of the therapeutic polypeptide in ocular tissue in the subject.
Subretinal delivery for an ABCA4-associated disorder
A pharmaceutical composition for treatment of an ABCA4-associated disorder comprising a synthetic circular DNA vector comprising a promoter operably linked to an ABCA4 gene, wherein expression by the ABCA4 gene in a photoreceptor cell is effective for treatment of the ABCA4-associated disorder, wherein the synthetic circular DNA vector lacks an origin of replication, a drug resistance gene, and a site-specific recombination recognition site, and wherein the pharmaceutical composition is formulated for subretinal delivery.
The claims cover ocular pharmaceutical compositions using synthetic circular DNA vectors without replication and accessory elements, combined with promoter-linked therapeutic polypeptide expression in ocular tissue. A narrower claim addresses ABCA4-associated disorder treatment through photoreceptor expression and subretinal formulation.
Stated Advantages
Reduced immunogenicity compared with plasmids and AAV limits.
Long-term episomal expression.
Documented Applications
Treatment of an ocular disorder using a pharmaceutical composition containing a synthetic circular DNA vector formulated for ocular delivery and capable of inducing expression in ocular tissue.
Treatment of an ABCA4-associated disorder using a pharmaceutical composition containing a synthetic circular DNA vector with ABCA4 expression effective in photoreceptor cells, formulated for subretinal delivery.
Treatment of Mendelian-heritable retinal dystrophies, including Leber’s congenital amaurosis and Stargardt disease.
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