Introduction of Sindbis Virus as Oncolytic Virus
Introduction to Sindbis Virus
Sindbis virus (SINV), a member of the Togaviridae family, is a widely distributed alphavirus that can cause many diseases, such as sindbis fever in humans. Its genome encodes the core proteins that are responsible for viral replication and reproduction, including four non-structural proteins, the capsid protein, and two envelope proteins. In the past few years, a wide variety of SINV infection cases have been reported in different countries, including China, South Africa, as well as Australia. SINV has mainly transmitted via mosquito bite and the birds are the common host for SINV. Several of the symptoms for SINV infection, including headache, fever, rash, as well as urticaria, have been confirmed in most cases. Meanwhile, pilot studies have demonstrated that SINV can trigger a series of inflammatory responses and persistent joint and muscle pain.
Fig.1 Sindbis Virus 3D Model.
The Sindbis Virus as Oncolytic Virus in Disease Treatment
SINV is a single-stranded RNA virus with a length of about 11.7kb long. Humans infected with SINV can show no or mild symptoms, such as fever, rash, and arthritis. A new finding has revealed that SINV infection can cause persistent chronic diseases in recovering patients. Furthermore, previous studies have shown that SINV vectors target cancer cells by laminin receptor (LAMR). SINV-based vector has been considered as an attractive tool for transducing tumor cells in cancer therapy. Moreover, recent reports have indicated that several oncolytic SINV vectors targeting cancer cells have been generated for selective targeting and replication in various kinds of tumor-base animal models. For instance, the replication-defective (RD) oncolytic SINV vector can achieve transient transgene expression by replacing the structural gene sequences with specific target gene sequences. The data have suggested that this vector is capable of eliciting immune responses and has therapeutic efficacy in animal tumor models.
Fig.2 Sindbis viral vector transduces cancer cells through tumor vascular leakiness. (Tseng, 2010)
Nowadays, many actions have been taken to constantly improve the expression level of oncolytic SINV receptors and the specificity of oncolytic SINV vectors in a range of tumor cell lines. Besides, a group of clinical trials has been conducted on both healthy adult individuals and patients with various kinds of cancers, such as cervical and ovarian cancer, to assess the safety and efficacy in the clinic. In phase I, several healthy adult volunteers have been observed to identify the risk of oncolytic SINV vectors for human usage. In phase II, a double-blind and randomized single-dose study will be designed to evaluate the efficacy of oncolytic SINV-based drugs in both healthy individuals and patients with cancers. In phase III, the dose levels of drugs will be further determined on different stages of the tumor.
Reference
- Tseng, J. C.; et al. Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in the tumor. J Virol. 2010, 17(4): 244-55.