Modified viral particles for gene therapy
Inventors
Assignees
Europaisches Laboratorium fuer Molekularbiologie EMBL • Borea Therapeutics Srl
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Publication Number
US-12551572-B2
Publication Date
2026-02-17
Expiration Date
Abstract
This invention relates to novel surface modified viral capsids and recombinant virions comprising the same. Furthermore, this invention concerns intermediates for the preparation of surface modified viral capsids. The surface modified viral capsids are designed to selectively and/or more efficiently deliver gene therapy. The surface modified viral capsids, when incorporated into a recombinant virion, can be used to treat an illness that is characterized by genetic abnormality.
Core Innovation
The disclosure relates to surface modified viral capsids comprising a ligand covalently conjugated to a viral capsid protein via a linker. The linker comprises a crosslinked moiety having a fused polycyclic moiety and one or more spacers, and is covalently attached to a primary amino group of the capsid protein primary sequence.
The crosslinked moiety is formed by selected reactions including strain-promoted alkyne-azide cycloaddition (SPAAC), strain-promoted alkyne-nitrone cycloaddition (SPANC), inverse electron demand Diels-Alder (IEEDD), Staudinger ligation, and [4+1] cycloaddition. The disclosure further describes functionalized viral capsids suitable for reaction with a functionalized ligand comprising a second member of a crosslinker reactive pair.
The disclosure also defines surface modified capsids by Formula I and Formula I-1, including ligand-to-capsid ratio concepts and integer parameters n, n′, and x, with embodiments in which either n or n′ is greater than 1. It further includes ligand attachment to primary amino groups, including N-terminal amino groups and residues such as lysine or arginine, and recombinant virions including rAAV.
Claims Coverage
The independent claims cover four main inventive features: covalent ligand conjugation to viral capsids through a linker with a fused polycyclic crosslinked moiety; Formula I-1 parameterized surface modified viral capsids; surface functionalized viral capsids for reaction with a functionalized ligand using selected bioorthogonal reactions; and a SPAAC-formed crosslinked moiety with ethylene glycol spacers. The claims also include recombinant virion embodiments, including rAAV.
Linker with fused polycyclic crosslinked moiety attached to a primary amino group
A surface modified viral capsid comprising a ligand covalently conjugated to a viral capsid protein via a linker, the linker comprising a crosslinked moiety having a fused polycyclic moiety and one or more spacers, wherein the linker is covalently attached to a primary amino group of the capsid protein primary sequence.
Formula I-1 parameterized surface modified viral capsid
A surface modified viral capsid according to Formula I-1, wherein a viral capsid is modified with a ligand L, n and n′ are independently an integer selected from 0 to 30, x is an integer from 1 to 500, and wherein either n or n′ is an integer greater than 1.
Surface functionalized capsid for reaction with a functionalized ligand using selected crosslinker reactions
A surface functionalized viral capsid comprising a first member of a crosslinker reactive pair and optionally one or more spacers, wherein the surface functionalized viral capsid is suitable for reaction with a functionalized ligand comprising a second member of the crosslinker reactive pair and optionally one or more spacers, wherein the members of the crosslinker reactive pair participate in a reaction selected from SPAAC, SPANC, IEEDD, Staudinger ligation, and [4+1] cycloaddition.
SPAAC-formed crosslinked moiety linker with ethylene glycol spacers attached to a primary amino group
A surface modified viral capsid comprising a ligand covalently conjugated to a viral capsid protein via a linker, the linker comprising a crosslinked moiety formed by a SPAAC reaction and one or more spacers comprising from 1 to 20 monomers of ethylene glycol, wherein the linker is covalently attached to a primary amino group of the capsid protein primary sequence.
Together, the independent claims define covalent ligand conjugation on viral capsids via linkers containing crosslinked moieties, constrain the crosslink-forming chemistry to selected bioorthogonal reactions, and specify Formula I-1 parameterization. A further claim narrows to a SPAAC-formed crosslinked moiety and ethylene glycol spacer segments while maintaining covalent attachment to a primary amino group.
Stated Advantages
Increased infectivity compared to an unmodified viral capsid having the same capsid protein sequence.
Reduced neutralizing-antibody recognition while maintaining neutralization under certain conditions.
Documented Applications
AAV gene delivery for treatment of genetic abnormalities.
Targeting of specific cell types using engineered AAV capsids, including DRG neurons and keratinocytes, associated with payload examples such as neurotrophins and other indicated ligands.
Delivery of gene editing cargos and other transgene payloads using engineered rAAV capsids, including Cas9 with gRNA/DNA and other gene editing components.
Immune-pertinent applications in the context of neutralizing-antibody recognition and immune cloaking using PEG/pHPMA associated with engineered capsids.
Recombinant virions comprising the specified surface-modified capsid, including rAAV.
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