Nestin promoter-driven Infected Cell Protein 34.5 (Nestin-ICP34.5)

Infected cell protein 34.5 (ICP34.5) is a critical neurovirulence factor of Herpes Simplex Virus 1 (HSV-1) that functions by antagonizing the host cell's innate antiviral response. It acts by recruiting protein phosphatase 1 (PP1) to dephosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2α), thereby preventing the global shutoff of protein synthesis typically induced by double-stranded RNA-activated protein kinase (PKR) [He et al., 1997, PubMed: 9233331]. In the context of oncolytic virotherapy for brain tumors, the ICP34.5 gene is placed under the control of the Nestin promoter to ensure that viral replication and the subsequent lysis of cells occur selectively within Nestin-expressing glioma cells [Kambara et al., 2005, PubMed: 15958514]. Nestin is an intermediate filament protein that is highly expressed in neural stem cells and glioblastoma but is largely absent in mature neurons, providing a mechanism for tumor-specific viral propagation [Dahlstrand et al., 1992, PubMed: 1506334]. This engineered construct, exemplified by the therapeutic candidate rQNestin34.5 (also known as CAN-3110), allows the virus to overcome translational arrest in tumor cells while remaining attenuated in healthy brain tissue [Chiocca et al., 2020, PubMed: 32015515]. The primary therapeutic goal is to induce direct oncolysis and stimulate a systemic anti-tumor immune response through the release of tumor-associated antigens.

Other names

rQNestin34.5CAN-3110gamma-1 34.5RL1Nestin-driven ICP34.5

Selective oncolytic viral replication and cell lysis mediated by tumor-specific expression of the viral neurovirulence factor ICP34.5 under the control of the Nestin promoter.