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Publication Number
US-12227770-B2
Publication Date
2025-02-18
Expiration Date
Abstract
Provided is an alphavirus replicon particle (ARP), which comprises (i) alphavirus structural proteins comprising capsid and/or envelope, and (ii) an alphavirus replicon comprising a polynucleotide encoding alphavirus non-structural proteins nsp1, nsp2, nsp3 and nap4 and at least one gene of interest wherein at least one of capsid, and E3 and E2 in the envelope comprise one or more amino acid alteration but E1 in the envelope comprises no amino acid alteration.
Core Innovation
The invention relates to an alphavirus replicon particle (ARP) gene-delivery system for introducing a gene of interest into a cell in a subject in need thereof. The ARP includes alphavirus structural proteins comprising a capsid protein and E1 and E2 envelope proteins, together with an alphavirus replicon that comprises a polynucleotide encoding alphavirus nonstructural proteins nsp1, nsp2, nsp3 and nsp4 and at least one gene of interest.
The capsid protein contains a mutation in the Nuclear Localization Signal (NLS), specified as a substitution of lysine with asparagine at a position corresponding to position 64 of VEEV virus capsid protein. The claimed system builds on an ARP configured for administration to a subject for introduction of the gene of interest into cells.
The claims further restrict the envelope protein amino-acid alteration pattern so that E1 can have no amino-acid alteration. The approach also includes ARPs with CHIKV structural proteins together with replicon components that encode the nsp1–nsp4 set and the gene of interest, and chimeric ARPs can be produced using CHIKV structural proteins with VEEV-derived replicon components.
Claims Coverage
The partial content includes two independent claims (clm-00001 and clm-00007). Both independent claims share the same core architecture of the ARP: structural proteins plus a replicon encoding nsp1–nsp4 and a gene of interest, with a capsid NLS mutation as a lysine-to-asparagine substitution at the position corresponding to VEEV capsid position 64. The independent claims differ in the specified structural protein set, namely VEEV structural proteins versus CHIKV structural proteins.
Administering an ARP with capsid NLS lysine-to-asparagine substitution
Administering to the subject an alphavirus replicon particle (ARP) in which the capsid protein contains a mutation in the Nuclear Localization Signal (NLS), specified as the substitution of lysine with asparagine at the position corresponding to position 64 of VEEV virus capsid protein.
ARP with capsid plus E1 and E2 structural proteins and replicon encoding nsp1–nsp4 and a gene of interest
Administering an ARP comprising alphavirus structural proteins including a capsid protein and E1 and E2 envelope proteins, and an alphavirus replicon comprising a polynucleotide encoding alphavirus nonstructural proteins nsp1, nsp2, nsp3 and nsp4 and at least one gene of interest.
Chimeric structural proteins limited to VEEV structural proteins with the specified capsid NLS mutation
The ARP structural proteins comprise capsid protein, and E1 and E2 envelope proteins, wherein the ARP structural proteins are VEEV structural proteins.
CHIKV structural proteins in the ARP together with the same capsid NLS lysine-to-asparagine rule
The ARP structural proteins comprise CHIKV structural proteins including a capsid protein, and E1 and E2 envelope proteins, and the capsid protein contains the mutation in the Nuclear Localization Signal (NLS) specified as substitution of lysine with asparagine at the position corresponding to position 64 of VEEV virus capsid protein.
Across both independent claims, the ARP delivers a gene of interest using alphavirus structural proteins plus a replicon encoding nsp1–nsp4, with the key inventive limitation being a capsid NLS mutation: lysine-to-asparagine substitution at the position corresponding to VEEV capsid position 64. The independent claims further differ by requiring either VEEV structural proteins or CHIKV structural proteins as the structural-protein set used in the ARP.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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