Evaluation of the stability and intratumoral delivery of foreign transgenes encoded by an oncolytic Foamy Virus vector

Abstract

Foamy Viruses are cell cycle-dependent retroviruses capable of persisting unintegrated in quiescent cells until cell division occurs. This unique ability allows them to target slowly dividing human tumor cells which remains an unmet need in oncolytic virotherapy. We have previously reported the generation of oncolytic Foamy Virus (oFV) vector system and demonstrated its superiority over oncolytic Murine Leukemia Virus vectors in infecting slowly dividing cancer cells. In the present study we evaluated (i) the ability of oFV to carry foreign transgenes and (ii) the genetic stability of these vectors upon serial passage. The thymidine kinase (TK) and inducible caspase 9 (iCasp9) cDNAs could be detected in the oFV backbone for up to 3 in vitro passages. In vivo, GFP-, TK- and iCasp9- carrying oFV vectors propagated efficiently in subcutaneous xenograft glioblastoma tumors and drove transgene expression for up to 66 days. However, in vivo oFV vector spread eventually resulted in complete loss of the iCasp9 cDNA, minor loss of the TK cDNA and negligible loss of the GFP. Our results suggest that oFV is a promising gene delivery platform and that transgenes smaller than 1 kb might be most suitable for oFV arming.

Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection

“…These vectors can successfully infect multiple human cancer cells with slow kinetics, which resulted in growth arrest and prolonged survival in animal models [ 243 , 244 ]. In 2022, Budzik generated foamy viral oncolytic vectors carrying thymidine kinase and inducible caspase 9 [ 245 ]. These vectors are able to stably carry and express transgenes upon serial passage, suggesting foamy viruses as a promising oncolytic virus for OVT [ 245 ].…”

“…In 2022, Budzik generated foamy viral oncolytic vectors carrying thymidine kinase and inducible caspase 9 [ 245 ]. These vectors are able to stably carry and express transgenes upon serial passage, suggesting foamy viruses as a promising oncolytic virus for OVT [ 245 ]. Nonetheless, a better understanding of the strategies developed by retroviruses to ensure efficient integration and replication will be of great interest in order to engineer and optimize future OVT applications.…”

Oncolytic virotherapy using neural stem cells as a novel treatment option for glioblastoma multiforme

“…A strategy to use producer cells as a buffer between a therapeutic virus as well as the patient's immune system was developed as a result of this finding. 29 Multiple laboratories' studies showed that various stem cell lineages could act as vehicles for the undetected in vivo distribution of an F I G U R E 1 An illustration of the overview of oncolytic virotherapy for the treatment of glioblastoma multiforme. Therapeutic characteristics of oncolytic virotherapy and methods for its enhancement.…”

“…The early in vivo studies with OVs showed that anticancer effect may not be brought on by the virus itself, but rather by the infected virus‐producing cells. A strategy to use producer cells as a buffer between a therapeutic virus as well as the patient's immune system was developed as a result of this finding 29 . Multiple laboratories' studies showed that various stem cell lineages could act as vehicles for the undetected in vivo distribution of an oncolytic adenovirus to treat glioblastoma 27 .…”

Comparison of a Genotype 1 and a Genotype 2 Macaque Foamy Virus env Gene Indicates Distinct Infectivity and Cell-Cell Fusion but Similar Tropism and Restriction of Cell Entry by Interferon-Induced Transmembrane Proteins

“…Recently, zoonotic infections with gorilla SFV were found to be associated with hematological abnormalities and altered biochemical markers [ 9 ]. In addition, foamy viruses represent potential vector platforms for gene therapy [ 14 , 15 , 16 , 17 ] or oncolytic therapy [ 18 , 19 ], which warrants study of their cell entry mechanisms.…”