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Publication Number
US-12180500-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present invention relates to viral vectors and methods of their production and use.
Core Innovation
The invention relates to an adeno-associated virus (AAV) capsid protein comprising a chimeric polypeptide. The chimeric polypeptide is a substitutional variant of a reference sequence comprising SEQ ID NO: 436 with at least 95% identity, and the VRVIII-CNS domain of SEQ ID NO: 436 is replaced with a donor sequence selected from any one of SEQ ID NOs: 547 or 549-553.
The disclosure describes chimeric AAV capsid proteins and related vector components, including vector genomes and regulatory components such as ITRs. It specifies acceptor and donor AAV sequence swapping and insertion into capsid variable regions to form chimeric capsids, and relates capsid function to capsid-tropism relevance via variable regions and the HI loop.
The document further addresses replication and safety by describing chimeric ITRs and non-AAV Rep/NS-1 equivalents for controlling replication, including references to Rep78/Rep68/Rep52/Rep40 and parvoviral Rep equivalents as well as JcDNV NS-1 binding and nicking. It also describes AAV particles that include the capsid protein together with a vector genome payload construct.
Claims Coverage
The document provides one independent claim that defines an AAV capsid protein chimeric polypeptide with a specified substitutional variant and a specific CNS-domain replacement, with dependent claims extending coverage to AAV particles and payload types. Overall, the inventive features focus on VRVIII-CNS domain replacement choices and the resulting capsid-containing AAV payload constructs.
Chimeric AAV capsid protein with SEQ ID NO: 436 substitutional variant
An adeno-associated virus (AAV) capsid protein comprising a chimeric polypeptide that is a substitutional variant of SEQ ID NO: 436, wherein the chimeric polypeptide has at least 95% identity with a reference sequence comprising SEQ ID NO: 436.
VRVIII-CNS domain replacement with selected donor sequence
The AAV capsid protein wherein the VRVIII-CNS domain of SEQ ID NO: 436 is replaced with a donor sequence selected from any one of SEQ ID NOs: 547 or 549-553.
AAV particle including the chimeric capsid and vector genome payload construct
An adeno-associated virus (AAV) particle containing the AAV capsid protein and a vector genome carrying a payload construct.
Payload construct encoding RNA-interference species
The AAV particle includes a payload construct with a polynucleotide sequence encoding siRNA, shRNA, miRNA, or a precursor of one of these.
Claim coverage centers on an AAV capsid protein defined by a substitutional chimeric polypeptide relative to SEQ ID NO: 436, specifically by replacing the VRVIII-CNS domain with a donor sequence selected from SEQ ID NOs: 547 or 549-553. Dependent claim scope extends this capsid concept to AAV particles with a vector genome payload construct and further narrows the payload to polynucleotides encoding siRNA, shRNA, miRNA, or precursors.
Stated Advantages
Increased bioavailability (AUC/Cmax).
Increased therapeutic window.
Altered volume of distribution (Vdist).
Production needs and cost and time limitations associated with viral vector production are addressed.
Documented Applications
CNS disorders.
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