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Publication Number
US-12251395-B2
Publication Date
2025-03-18
Expiration Date
Abstract
RNAs, such as miRNA and siRNA, and their use in treating complement-mediated disorders, are described.
Core Innovation
The invention relates to RNA-based complement inhibition by inhibiting expression of C3 in a cell. The method comprises contacting the cell with an miRNA consisting of a nucleotide sequence that is at least 90% identical to any one of SEQ ID NOs: 76-77 or 79-85, or a portion thereof, or an siRNA comprising an antisense strand consisting of the same nucleotide sequence. The nucleotide sequence is specified as being 19-23 nucleotides in length.
The disclosed approach includes nucleic acid compositions for delivering the C3-inhibiting RNA, including nucleic acid-encoding compositions and compositions comprising expression vectors. The delivery scope further includes viral vectors, including adeno-associated viral (AAV) vectors, in particular AAV3B, and hepatocyte targeting.
The disclosure also extends to additional elements for complement inhibition, including optional co-delivery of a C3 inhibitor comprising aptamer, antibody, complement regulatory proteins, or mini factor H. Further stated targeting and sequence refinement include target sites within SEQ ID NO:75, modified siRNA/miRNA, conjugation strategies, nucleobase, sugar, and backbone modifications, phosphorothioate or methylphosphonate internucleotide linkages, and hepatocyte-targeting ligands such as GalNAc/ASGPR.
Claims Coverage
The independent claim coverage centers on inhibiting expression of C3 in a cell using miRNA or siRNA sequences defined by high sequence identity to specified SEQ ID NOs, with a 19-23 nucleotide length criterion and antisense-strand coverage for siRNA. Dependent refinements add nucleic acid-encoding compositions, expression vectors, AAV vectors, hepatocytes, and additional specified nucleic acid sequence options.
MiRNA or siRNA sequence-directed inhibition of C3 expression
Contacting the cell with an miRNA consisting of a nucleotide sequence at least 90% identical to any one of SEQ ID NOs: 76-77 or 79-85, or a portion thereof, wherein the nucleotide sequence is 19-23 nucleotides in length, or an siRNA comprising an antisense strand consisting of the nucleotide sequence.
Nucleic acid-encoding composition for RNA delivery
The contacting is carried out with a composition that includes nucleic acid encoding the miRNA or siRNA.
Expression vector delivery format
The composition includes an expression vector containing the nucleic acid.
AAV viral vector delivery format
The composition includes an adeno-associated viral (AAV) vector as the viral vector.
Hepatocyte targeting
The cell is a hepatocyte.
Specific nucleic acid sequence options
The nucleic acid comprises one of SEQ ID NOs: 86-87 or 89-115.
Across the claim set, the inventive coverage centers on inhibiting C3 expression in a cell using miRNA or siRNA sequences defined by at least 90% identity to specified SEQ ID NOs with a 19-23 nucleotide length constraint, delivered as nucleic acid-containing compositions, optionally via expression vectors and AAV vectors, including hepatocyte-targeted use. The claim set also includes additional specified nucleic acid sequence options.
Stated Advantages
Long-acting compstatin analogs via polymer-peptide conjugation using branched or star PEG architectures.
Linkage chemistries using carbamate or amide to avoid ester bonds and hydrolysis-prone linkages.
Compatibility with non-PEG polymers such as polyoxazoline.
Use of metal-free click chemistry with azide/alkyne partners using cyclooctyne-like reagents and triazole linkers.
Inhibits expression of C3 in a cell.
Documented Applications
Protection from complement-mediated damage, including RBC protection in PNH/aHUS, as described in the document’s therapeutic context.
Use in transplantation and ischemia/reperfusion (I/R) injury, described in connection with complement-mediated diseases and C3 inhibition.
Use in various chronic immune/inflammatory conditions described in the document’s broad therapeutic discussion.
Broad therapeutic uses for complement-mediated diseases, with emphasis on disorders linked to C3 inhibition as described in the document.
Polymer-peptide conjugates for long-acting compstatin analogs, including branched/star PEG and non-PEG polymer conjugation architectures.
Conjugation of compstatin analogs to polymers and clearance-reducing moieties using metal-free click chemistry with azide/alkyne partners and triazole linkers.
Functionalizing surfaces/devices for complement inhibition, including use in an extracorporeal circulatory support unit such as a hemodialyzer, associated with complement activation (e.g., C3).
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