Treatment of diseases by liver expression of an enzyme which has a deoxyribonuclease (DNase) activity
Inventors
Genkin, Dmitry Dmitrievich • Tets, Georgy Viktorovich • Tets, Viktor Veniaminovich
Assignees
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Publication Number
US-11905522-B2
Publication Date
2024-02-20
Expiration Date
Abstract
The invention relates to the liver-specific delivery and/or expression of an enzyme which has a deoxyribonuclease (DNase) activity for enhanced clearance of cell free DNA (cfDNA) accumulated in hepatic porto-sinusoidal circulation and the use of such liver-specific delivery and/or expression for treatment of various diseases and conditions, including cancer and neurodegeneration.
Core Innovation
The invention relates to inhibiting growth of a primary tumor in a subject having a cancer accompanied by accumulation of cell free DNA (cfDNA) in the hepatic porto-sinusoidal circulation. The approach uses administration of a recombinant adeno-associated virus (rAAV) expression vector that provides deoxyribonuclease (DNase) activity in the liver, with a promoter operably linked to a nucleotide sequence encoding an enzyme with DNase activity and the promoter being a liver-specific promoter.
The document further describes DNase activity in hepatic compartments associated with hepatic porto-sinusoidal circulation, including periendothelial space and space of Disse. rAAV expression vectors are described with liver-specific promoters and secretion-oriented design to enable DNase to be present in sinusoidal spaces, and the disclosed nucleic acid comprises SEQ ID NO: 30 or SEQ ID NO: 31.
The disclosed DNase includes DNase I and hyperactive actin-resistant or actin-binding-site mutant forms. The document states that cfDNA accumulated in the hepatic porto-sinusoidal circulation forms a reservoir and that transgenic hepatic DNase expression achieves near-complete cfDNA clearance, with downstream therapeutic benefits including inhibition of tumor growth in the cancer context described.
Claims Coverage
The provided claim set includes two independent claims, both directed to inhibiting growth of a primary tumor in a subject with cancer accompanied by accumulation of cfDNA in hepatic porto-sinusoidal circulation. The inventive features focus on liver-directed expression of a DNase-activity enzyme using SEQ ID NO: 30 or SEQ ID NO: 31, with tumor growth inhibition as the stated result.
Liver-specific rAAV delivery of DNase for hepatic cfDNA-mediated tumor growth inhibition
Administering a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) expression vector comprising a capsid protein and a nucleic acid comprising a promoter operably linked to a nucleotide sequence encoding an enzyme which has deoxyribonuclease (DNase) activity, wherein the promoter is a liver-specific promoter, and wherein the nucleic acid comprises the sequence of SEQ ID NO: 30 or SEQ ID NO: 31, resulting in inhibiting growth of the primary tumor in the subject.
Liver-targeting expression vector for DNase activity to inhibit tumor growth
Administering an expression vector comprising a nucleic acid comprising a promoter operably linked to a sequence encoding an enzyme with DNase activity, wherein the promoter is a liver specific promoter and/or wherein the vector comprises one or more molecules capable of targeting the nucleic acid to liver cells, wherein the nucleic acid comprises SEQ ID NO: 30 or SEQ ID NO: 31, resulting in inhibiting growth of the primary tumor in the subject.
Across the independent claims, the core claim coverage centers on administering vectors that drive liver-directed DNase activity using nucleic acid sequences SEQ ID NO: 30 or SEQ ID NO: 31, with tumor growth inhibition as the stated result; one independent claim further specifies an rAAV vector with a capsid protein and a liver-specific promoter.
Stated Advantages
Inhibiting growth of a primary tumor in a subject having cancer accompanied by accumulation of cfDNA in the hepatic porto-sinusoidal circulation.
Near-complete cfDNA clearance in the hepatic reservoir when using transgenic hepatic DNase expression, contrasted with inefficiency of systemic DNase protein in clearing cfDNA.
Documented Applications
Cancer treatment in subjects with a primary tumor, where cancer is accompanied by accumulation of cfDNA in the hepatic porto-sinusoidal circulation, to inhibit primary tumor growth.
Portal-draining cancers and liver metastatic disease contexts where cfDNA is elevated, aligned with the stated tumor-growth inhibition outcome.
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