Compositions and methods for delivery of AAV
Inventors
Sah, Dinah Wen-Yee • Patzke, Holger • Hou, Jinzhao • Nonnenmacher, Mathieu E. • Goulet, Martin • Carter, Todd
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12305189-B2
Publication Date
2025-05-20
Expiration Date
Abstract
The invention provides compositions and methods for the preparation, manufacture, formulation and therapeutic use of adeno-associated virus (AAV) particles for the prevention and/or treatment of diseases.
Core Innovation
The invention relates to an AAV delivery platform in which an AAV particle comprises an engineered AAV capsid and a viral genome. The platform is directed to decreasing expression of a gene of interest associated with a muscular dystrophy in a cell in a subject, and to improved biodistribution and efficient targeting of difficult tissues, including CNS structures across the blood-brain barrier and cardiomyocytes.
The viral genome architecture disclosed includes viral genome structures with inverted terminal repeats (ITRs), and embodiments including self-complementary AAV (scAAV) and single-stranded AAV (ssAAV). The payload includes nucleic acid sequences configured to inhibit or suppress gene expression and payloads configured to express proteins, including an RNAi payload comprising siRNA targeting an mRNA of the gene of interest.
The disclosure also provides a modulatory polynucleotide scaffold for RNAi in which variable 5′ flanking sequence lengths and similarity are selected to form a stem-loop structure with sense and antisense arms, complementarity thresholds defining pairing, and a loop motif whose length includes a UGUG motif. Optional spacer regions support the stem-loop architecture, and scaffold variants including seed/stem/loop mismatch and wobble variants are described as maintaining the modulatory polynucleotide scaffold concept.
Claims Coverage
The claim coverage centers on an AAV particle and RNAi delivery framework, with independent coverage directed to decreasing expression of a gene of interest associated with muscular dystrophy in a cell in a subject. Across the dependent claims, the coverage refines the engineered AAV capsid nucleic-acid sequence, the transduced cell types, and the administration routes.
AAV particle with engineered capsid and siRNA RNAi payload for muscular dystrophy gene expression decrease
Administering to the subject an effective amount of an AAV particle comprising an engineered AAV capsid and a viral genome encoding an RNAi payload comprising an siRNA, wherein the engineered AAV capsid comprises the amino acid sequence of SEQ ID NO: 1 and the siRNA targets an mRNA of the gene of interest associated with a muscular dystrophy.
Engineered capsid encoded by nucleic acid sequence SEQ ID NO: 1809
Using an engineered AAV capsid encoded by a nucleic acid sequence of SEQ ID NO: 1809.
Targeted transduction of muscle, heart, or brain cells
Transducing muscle cells, heart cells, or brain cells with the AAV particle.
Muscle-cell transduction
Transducing a muscle cell with the AAV particle.
Skeletal muscle cell or cardiomyocyte target selection
Transducing a muscle cell that is a skeletal muscle cell or a cardiomyocyte.
Intramuscular or intravenous delivery to the subject
Administering the AAV particle to the subject via intramuscular delivery or intravenous delivery.
The inventive scope centers on an AAV particle that uses an engineered capsid, including SEQ ID NO: 1 and an additional capsid encoding sequence SEQ ID NO: 1809 in refinements, to deliver a viral genome encoding an RNAi payload of siRNA targeting the mRNA of a muscular dystrophy-associated gene, with dependent claims narrowing transduced cell types and delivery routes.
Stated Advantages
Improved biodistribution.
Efficient targeting of difficult tissues, including CNS across the blood-brain barrier and cardiomyocytes.
Documented Applications
Treating muscular dystrophy by decreasing expression of a gene of interest associated with a muscular dystrophy in a cell in a subject.
CNS targeting across the blood-brain barrier using AAV delivery.
Cardiomyocyte targeting using AAV delivery.
Neurological and cardiovascular disease and heart failure treatment contexts are described.
Delivery/administration for CNS targeting is described via engineered AAV particles, including intrathecal and intraparenchymal administration contexts.
Interested in licensing this patent?