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US 12,203,092 B2Granted
Self-inactivating rabies virus vector encoding a nucleoprotein and degron
AssigneeMironid Limited
InventorsMarco Tripodi, Ernesto Ciabatti
Life of this patent
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Abstract
The invention relates to vectors based on a virus from the order Mononegavirales, and in particular a rabies virus. More specifically, it relates to a rabies virus vector which, having transfected a target cell, is switchable between replication-competent and replication-incompetent forms. Amongst other applications, the invention avoids the cytotoxicity associated with current vectors based on rabies virus.
Claims29
A rabies virus vector genome comprising a gene encoding a replication modulator protein,
- wherein the replication modulator protein comprises a viral protein moiety which is required for replication of the viral genome, and a regulator moiety,
- wherein the viral protein moiety is a rabies virus N (nucleoprotein) protein, wherein the regulator moiety comprises a protease cleavage site and a degron, wherein the degron is a PEST sequence, and wherein the protease cleavage site is located between the viral protein moiety and the degron,
- wherein the replication modulator protein is capable of adopting a targeted configuration displaying the degron, and an untargeted configuration which does not display the degron, and
- wherein the replication modulator protein is an inhibitory modulator switchable to the untargeted configuration on contact with a cognate activating agent, wherein the cognate activating agent is a protease, and wherein said vector is transcriptionally silent in the absence of the protease and transcriptionally active in the presence of the protease.
1 more element
A rabies virus vector genome comprising a gene encoding a replication modulator protein,
- wherein the replication modulator protein comprises a viral protein moiety which is required for replication of the viral genome, and a regulator moiety,
- wherein the viral protein moiety is a rabies virus N (nucleoprotein) protein,
- wherein the replication modulator protein encoded by the vector genome is an inhibitable modulator protein which is switchable to a targeted configuration displaying a degron on contact with a cognate inhibitory agent,
- wherein the replication modulator protein is capable of adopting a targeted configuration displaying the degron, and an untargeted configuration which does not display the degron,
- wherein
- the cognate inhibitory agent is a ligand for the regulator moiety, wherein the regulator moiety and cognate inhibitory agent are components of an inducible degron system, wherein:
- (i) the regulator moiety comprises a modified haloalkane dehydrogenase and the cognate inhibitory agent is a ligand thereof
- (ii) the regulator moiety comprises a LID-FKBP sequence and the cognate inhibitory agent is a ligand therefor;
- or
- (iii) the regulator moiety comprises an auxin-inducible degron sequence and the cognate inhibitory agent is a ligand therefor;
- wherein said vector is transcriptionally active in the absence of the cognate inhibitory agent and transcriptionally silent in the presence of the cognate inhibitory agent.
8 more elements
Dependencies are inferred from the claim text.