Next-Generation Precision Oncolytic HSV: Dual-Targeted Viral Therapy for Enhanced Safety and Potency

This invention is a recombinant oncolytic Herpes Simplex Virus (oHSV) engineered with dual-targeting mechanisms to selectively infect and destroy cancer cells while sparing healthy tissue. Its most significant advantage is the combination of tumor-specific surface receptor targeting with microRNA-regulated replication, ensuring high therapeutic efficacy without the neurotoxicity typically associated with viral therapies.

Description

The technology utilizes a modified HSV-1 vector that has been "retargeted" by incorporating non-HSV ligands into its surface glycoproteins (such as gD or gC). These ligands allow the virus to specifically bind to molecules highly expressed on cancer cells, such as EGFR or EGFRvIII, while bypassing the receptors used to infect normal cells. This structural modification ensures the virus primarily enters malignant cells. To provide an additional layer of safety, the vector's replication is controlled by tumor-specific microRNA (miRNA) profiles. Multiple copies of miRNA target sequences (e.g., miR-124) are inserted into essential viral genes, such as ICP4. Because these specific miRNAs are highly expressed in healthy brain tissue but absent in tumors, the virus is effectively "silenced" and cannot replicate in normal cells, yet it remains fully active and lethal within the cancerous environment

Applications

- Malignant Glioma Treatment: Primary application for treating Glioblastoma multiforme (GBM) and other aggressive brain tumors.
- Personalized Cancer Therapy: Utilization of patient-specific tumor antigen levels and miRNA profiles to optimize individual treatments.
- Broad Oncology Market: Potential application in various solid tumors that express specific markers like EGFR, CD133, or CEA.
- Viral Vector Platform: Licensing the dual-targeting architecture for use with other therapeutic payloads or transgene deliveries.
-Combination Therapies: Integration with existing standard-of-care treatments to enhance overall survival rates in fatal cancers.

Advantages

- Dual-Layered Safety: Combines entry retargeting with post-entry miRNA regulation to prevent off-target replication in healthy tissue.
- High Potency: Maintains robust lytic (cell-killing) capabilities in tumor cells without the attenuation-related loss of efficacy seen in earlier generations of oncolytic HSVs.
- Reduced Toxicity: Successfully demonstrated a lack of neurotoxicity in sensitive animal models, even at high doses.
- Customizable Platform: The vector can be tailored to different cancers by swapping the targeting ligands and miRNA response elements.
- Enhanced Spread: Can be engineered to express matrix metalloproteinases (like MMP9) to degrade tumor extracellular matrix, improving viral distribution throughout the tumor mass.

Invention Readiness

The technology has undergone extensive preclinical validation. Data generated from in vitro studies on patient-derived glioma cells and in vivo nude mouse brain models demonstrate that the vector effectively kills tumor cells while remaining non-toxic to healthy brain tissue. Specifically, animal models showed steady decline of viral content in healthy tissue over time with no lethal replication.

IP Status

https://patents.google.com/patent/US10201575B2/

Related Publication(s)

Goins, W. F., Huang, S., Hall, B., Marzulli, M., Cohen, J. B., & Glorioso, J. C. (2019). Engineering HSV-1 Vectors for Gene Therapy. In Methods in Molecular Biology (pp. 73–90). Springer New York. https://doi.org/10.1007/978-1-4939-9814-2_4

Glorioso, J. C., Cohen, J. B., Goins, W. F., Hall, B., Jackson, J. W., Kohanbash, G., Amankulor, N., Kaur, B., Caligiuri, M. A., Chiocca, E. A., Holland, E. C., & Quéva, C. (2021). Oncolytic HSV Vectors and Anti-Tumor Immunity. Current Issues in Molecular Biology, 381–468. https://doi.org/10.21775/cimb.041.381