Modified HSV gH Retargeting for Safe High-Yield Propagation
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Solution Overview
Problem
Existing oncolytic herpes simplex viruses (o-HSVs) used for tumor treatment face limitations in high-yield production and specific tropism for tumor cells, and current methods do not provide safe propagation and production strategies in non-diseased cells.
Innovation Solution
A recombinant HSV with a modified gH protein, fused with a GCN4 yeast transcription factor peptide, allows retargeting to safe cells for propagation and production, maintaining infectivity and enabling high-yield production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wild-type HSV is used for tumor treatment, then high infectivity and cell destruction capability are achieved, but safety concerns arise due to high virulence
Solution Approach 1:
The virus system is segmented into two functional components: a replication-competent attenuated HSV backbone that provides safety, and a separately introduced retargeting glycoprotein (gD or gC) that provides tumor-specific infectivity. This segmentation allows independent optimization of safety and efficacy properties.
Solution Approach 2:
The patent creates a composite viral system by combining the attenuated HSV genome with heterologous glycoprotein sequences (such as gD fused to tumor-specific ligands like IL13α or gC fused to EPO). This composite structure integrates the safety features of attenuated viruses with the targeted infectivity of tumor-specific receptors.
2Object-affected harmful factors
If oncolytic HSV with gene deletions (e.g., γ134.5, UL39) is used, then safety is improved through attenuation, but productivity decreases due to failure to produce high yield of progeny viruses
Solution Approach 1:
The patent dynamically adjusts viral replication capacity by using conditionally attenuated viruses that can replicate efficiently in tumor cells (providing high progeny yield) while maintaining safety through controlled attenuation in normal cells. The replication dynamics are optimized through selective gene deletions that affect tumor and normal cells differently.
3Adaptability or versatility
If retargeting of HSV to tumor-specific receptors is achieved through gD modification, then specific tropism for tumor cells is improved, but the ability to bind to natural receptors is preserved causing diminished therapeutic effect
Solution Approach 1:
The patent extracts the natural receptor-binding function from the gD glycoprotein and replaces it with tumor-specific ligands. By taking out the non-specific binding capability and substituting it with targeted ligands (such as IL13α for IL13Rα2 or EPO for EPO receptor), the virus achieves selective tumor tropism while eliminating off-target binding to natural receptors.
4Adaptability or versatility
If gC is modified with inserted ligands (EPO or IL13) for retargeting, then attachment to specific cells is achieved, but infectious entry does not occur
Solution Approach 1:
The patent uses gC as an intermediary attachment protein that binds to tumor-specific receptors (EPO receptor or IL13Rα2), while the actual membrane fusion and infectious entry are mediated by the native HSV fusion machinery (gB, gH, gL). This intermediary approach separates the attachment function (performed by modified gC) from the entry function (performed by native fusion proteins), resolving the contradiction between specific attachment and infectious entry.
Data Source
AI summary
The present invention is directed to a recombinant herpesvirus which comprises the GCN4 yeast transcription factor or a part thereof fused to or inserted into glycoprotein H and is capable of binding to a target molecule present on a cell for propagation and production of the herpesvirus. The herpesvirus may comprise additional modification in glycoprotein D and/or glycoprotein B for retargeting the herpesvirus to a diseased cell. The present invention is further directed to a nucleic acid and a vector coding for the gH, a polypeptide comprising the gH, and a cell comprising the herpesvirus, nucleic acid, vector or polypeptide. Moreover, the present invention is directed to a cell having accessible on the surface a target molecule for the GCN4 yeast transcription factor or part thereof and to a method for producing the herpesvirus in said cell.